Author: "Christopher J Groves" - Searchworks@Jio Institute Digital Library Search Results

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1. Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study.

Author: Valborg Gudmundsdottir, Helle Krogh Pedersen, Karla Viviani Allebrandt, Caroline Brorsson, Nienke van Leeuwen, Karina Banasik, Anubha Mahajan, Christopher J Groves, Martijn van de Bunt, Adem Y Dawed, Andreas Fritsche, Harald Staiger, Annemarie M C Simonis-Bik, Joris Deelen, Mark H H Kramer, Axel Dietrich, Thomas Hübschle, Gonneke Willemsen, Hans-Ulrich Häring, Eco J C de Geus, Dorret I Boomsma, Elisabeth M W Eekhoff, Jorge Ferrer, Mark I McCarthy, Ewan R Pearson, Ramneek Gupta, Søren Brunak, and Leen M 't Hart
Subjects: Medicine, Science
Abstract: Glucagon-like peptide 1 (GLP-1) stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS) of GLP-1 stimulated insulin secretion in non-diabetic individuals from the Netherlands Twin register (n = 126). This GWAS was enhanced using a tissue-specific protein-protein interaction network approach. We identified a beta-cell protein-protein interaction module that was significantly enriched for low gene scores based on the GWAS P-values and found support at the network level in an independent cohort from Tübingen, Germany (n = 100). Additionally, a polygenic risk score based on SNPs prioritized from the network was associated (P < 0.05) with glucose-stimulated insulin secretion phenotypes in up to 5,318 individuals in MAGIC cohorts. The network contains both known and novel genes in the context of insulin secretion and is enriched for members of the focal adhesion, extracellular-matrix receptor interaction, actin cytoskeleton regulation, Rap1 and PI3K-Akt signaling pathways. Adipose tissue is, like the beta-cell, one of the target tissues of GLP-1 and we thus hypothesized that similar networks might be functional in both tissues. In order to verify peripheral effects of GLP-1 stimulation, we compared the transcriptome profiling of ob/ob mice treated with liraglutide, a clinically used GLP-1 receptor agonist, versus baseline controls. Some of the upstream regulators of differentially expressed genes in the white adipose tissue of ob/ob mice were also detected in the human beta-cell network of genes associated with GLP-1 stimulated insulin secretion. The findings provide biological insight into the mechanisms through which the effects of GLP-1 may be modulated and highlight a potential role of the beta-cell expressed genes RYR2, GDI2, KIAA0232, COL4A1 and COL4A2 in GLP-1 stimulated insulin secretion.
Published: 2018
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2. Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation.

Author: Momoko Horikoshi, Reedik Mӓgi, Martijn van de Bunt, Ida Surakka, Antti-Pekka Sarin, Anubha Mahajan, Letizia Marullo, Gudmar Thorleifsson, Sara Hӓgg, Jouke-Jan Hottenga, Claes Ladenvall, Janina S Ried, Thomas W Winkler, Sara M Willems, Natalia Pervjakova, Tõnu Esko, Marian Beekman, Christopher P Nelson, Christina Willenborg, Steven Wiltshire, Teresa Ferreira, Juan Fernandez, Kyle J Gaulton, Valgerdur Steinthorsdottir, Anders Hamsten, Patrik K E Magnusson, Gonneke Willemsen, Yuri Milaneschi, Neil R Robertson, Christopher J Groves, Amanda J Bennett, Terho Lehtimӓki, Jorma S Viikari, Johan Rung, Valeriya Lyssenko, Markus Perola, Iris M Heid, Christian Herder, Harald Grallert, Martina Müller-Nurasyid, Michael Roden, Elina Hypponen, Aaron Isaacs, Elisabeth M van Leeuwen, Lennart C Karssen, Evelin Mihailov, Jeanine J Houwing-Duistermaat, Anton J M de Craen, Joris Deelen, Aki S Havulinna, Matthew Blades, Christian Hengstenberg, Jeanette Erdmann, Heribert Schunkert, Jaakko Kaprio, Martin D Tobin, Nilesh J Samani, Lars Lind, Veikko Salomaa, Cecilia M Lindgren, P Eline Slagboom, Andres Metspalu, Cornelia M van Duijn, Johan G Eriksson, Annette Peters, Christian Gieger, Antti Jula, Leif Groop, Olli T Raitakari, Chris Power, Brenda W J H Penninx, Eco de Geus, Johannes H Smit, Dorret I Boomsma, Nancy L Pedersen, Erik Ingelsson, Unnur Thorsteinsdottir, Kari Stefansson, Samuli Ripatti, Inga Prokopenko, Mark I McCarthy, Andrew P Morris, and ENGAGE Consortium
Subjects: Genetics, QH426-470
Abstract: Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.
Published: 2015
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3. Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus.

Author: Anubha Mahajan, Xueling Sim, Hui Jin Ng, Alisa Manning, Manuel A Rivas, Heather M Highland, Adam E Locke, Niels Grarup, Hae Kyung Im, Pablo Cingolani, Jason Flannick, Pierre Fontanillas, Christian Fuchsberger, Kyle J Gaulton, Tanya M Teslovich, N William Rayner, Neil R Robertson, Nicola L Beer, Jana K Rundle, Jette Bork-Jensen, Claes Ladenvall, Christine Blancher, David Buck, Gemma Buck, Noël P Burtt, Stacey Gabriel, Anette P Gjesing, Christopher J Groves, Mette Hollensted, Jeroen R Huyghe, Anne U Jackson, Goo Jun, Johanne Marie Justesen, Massimo Mangino, Jacquelyn Murphy, Matt Neville, Robert Onofrio, Kerrin S Small, Heather M Stringham, Ann-Christine Syvänen, Joseph Trakalo, Goncalo Abecasis, Graeme I Bell, John Blangero, Nancy J Cox, Ravindranath Duggirala, Craig L Hanis, Mark Seielstad, James G Wilson, Cramer Christensen, Ivan Brandslund, Rainer Rauramaa, Gabriela L Surdulescu, Alex S F Doney, Lars Lannfelt, Allan Linneberg, Bo Isomaa, Tiinamaija Tuomi, Marit E Jørgensen, Torben Jørgensen, Johanna Kuusisto, Matti Uusitupa, Veikko Salomaa, Timothy D Spector, Andrew D Morris, Colin N A Palmer, Francis S Collins, Karen L Mohlke, Richard N Bergman, Erik Ingelsson, Lars Lind, Jaakko Tuomilehto, Torben Hansen, Richard M Watanabe, Inga Prokopenko, Josee Dupuis, Fredrik Karpe, Leif Groop, Markku Laakso, Oluf Pedersen, Jose C Florez, Andrew P Morris, David Altshuler, James B Meigs, Michael Boehnke, Mark I McCarthy, Cecilia M Lindgren, Anna L Gloyn, and T2D-GENES consortium and GoT2D consortium
Subjects: Genetics, QH426-470
Abstract: Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P
Published: 2015
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4. Evaluation of common type 2 diabetes risk variants in a South Asian population of Sri Lankan descent.

Author: Neelam Hassanali, N Maneka G De Silva, Neil Robertson, N William Rayner, Amy Barrett, Amanda J Bennett, Christopher J Groves, David R Matthews, Prasad Katulanda, Timothy M Frayling, and Mark I McCarthy
Subjects: Medicine, Science
Abstract: Most studies seeking common variant associations with type 2 diabetes (T2D) have focused on individuals of European ancestry. These discoveries need to be evaluated in other major ancestral groups, to understand ethnic differences in predisposition, and establish whether these contribute to variation in T2D prevalence and presentation. This study aims to establish whether common variants conferring T2D-risk in Europeans contribute to T2D-susceptibility in the South Asian population of Sri Lanka.Lead single nucleotide polymorphism (SNPs) at 37 T2D-risk loci attaining genome-wide significance in Europeans were genotyped in 878 T2D cases and 1523 normoglycaemic controls from Sri Lanka. Association testing was performed by logistic regression adjusting for age and sex and by the Cochran-Mantel-Haenszel test after stratifying according to self-identified ethnolinguistic subgroup. A weighted genetic risk score was generated to examine the combined effect of these SNPs on T2D-risk in the Sri Lankan population.Of the 36 SNPs passing quality control, sixteen showed nominal (p
Published: 2014
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5. BMI-associated alleles do not constitute risk alleles for polycystic ovary syndrome independently of BMI: a case-control study.

Author: Yvonne V Louwers, Nigel W Rayner, Blanca M Herrera, Lisette Stolk, Christopher J Groves, Thomas M Barber, Andre G Uitterlinden, Stephen Franks, Joop S E Laven, and Mark I McCarthy
Subjects: Medicine, Science
Abstract: Polycystic Ovary Syndrome (PCOS) has a strong genetic background and the majority of patients with PCOS have elevated BMI levels. The aim of this study was to determine to which extent BMI-increasing alleles contribute to risk of PCOS when contemporaneous BMI is taken into consideration.Patients with PCOS and controls were recruited from the United Kingdom (563 cases and 791 controls) and The Netherlands (510 cases and 2720 controls). Cases and controls were of similar BMI. SNPs mapping to 12 BMI-associated loci which have been extensively replicated across different ethnicities, i.e., BDNF, FAIM2, ETV5, FTO, GNPDA2, KCTD15, MC4R, MTCH2, NEGR1, SEC16B, SH2B1, and TMEM18, were studied in association with PCOS within each cohort using the additive genetic model followed by a combined analysis. A genetic allelic count risk score model was used to determine the risk of PCOS for individuals carrying increasing numbers of BMI-increasing alleles.None of the genetic variants, including FTO and MC4R, was associated with PCOS independently of BMI in the meta-analysis. Moreover, no differences were observed between cases and controls in the number of BMI-risk alleles present and no overall trend across the risk score groups was observed.In this combined analysis of over 4,000 BMI-matched individuals from the United Kingdom and the Netherlands, we observed no association of BMI risk alleles with PCOS independent of BMI.
Published: 2014
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6. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Author: Zari Dastani, Marie-France Hivert, Nicholas Timpson, John R B Perry, Xin Yuan, Robert A Scott, Peter Henneman, Iris M Heid, Jorge R Kizer, Leo-Pekka Lyytikäinen, Christian Fuchsberger, Toshiko Tanaka, Andrew P Morris, Kerrin Small, Aaron Isaacs, Marian Beekman, Stefan Coassin, Kurt Lohman, Lu Qi, Stavroula Kanoni, James S Pankow, Hae-Won Uh, Ying Wu, Aurelian Bidulescu, Laura J Rasmussen-Torvik, Celia M T Greenwood, Martin Ladouceur, Jonna Grimsby, Alisa K Manning, Ching-Ti Liu, Jaspal Kooner, Vincent E Mooser, Peter Vollenweider, Karen A Kapur, John Chambers, Nicholas J Wareham, Claudia Langenberg, Rune Frants, Ko Willems-Vandijk, Ben A Oostra, Sara M Willems, Claudia Lamina, Thomas W Winkler, Bruce M Psaty, Russell P Tracy, Jennifer Brody, Ida Chen, Jorma Viikari, Mika Kähönen, Peter P Pramstaller, David M Evans, Beate St Pourcain, Naveed Sattar, Andrew R Wood, Stefania Bandinelli, Olga D Carlson, Josephine M Egan, Stefan Böhringer, Diana van Heemst, Lyudmyla Kedenko, Kati Kristiansson, Marja-Liisa Nuotio, Britt-Marie Loo, Tamara Harris, Melissa Garcia, Alka Kanaya, Margot Haun, Norman Klopp, H-Erich Wichmann, Panos Deloukas, Efi Katsareli, David J Couper, Bruce B Duncan, Margreet Kloppenburg, Linda S Adair, Judith B Borja, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, James G Wilson, Solomon Musani, Xiuqing Guo, Toby Johnson, Robert Semple, Tanya M Teslovich, Matthew A Allison, Susan Redline, Sarah G Buxbaum, Karen L Mohlke, Ingrid Meulenbelt, Christie M Ballantyne, George V Dedoussis, Frank B Hu, Yongmei Liu, Bernhard Paulweber, Timothy D Spector, P Eline Slagboom, Luigi Ferrucci, Antti Jula, Markus Perola, Olli Raitakari, Jose C Florez, Veikko Salomaa, Johan G Eriksson, Timothy M Frayling, Andrew A Hicks, Terho Lehtimäki, George Davey Smith, David S Siscovick, Florian Kronenberg, Cornelia van Duijn, Ruth J F Loos, Dawn M Waterworth, James B Meigs, Josee Dupuis, J Brent Richards, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Oliver M Hofmann, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noël P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stephane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Andrew D Morris, Colin N A Palmer, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Richard M Watanabe, Goncalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Oluf Pedersen, Inês Barroso, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, Nicole Soranzo, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Paul Elliott, Denis Rybin, Abbas Dehghan, Jouke Jan Hottenga, Kijoung Song, Anuj Goel, Taina Lajunen, Alex Doney, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jerome Delplanque, Annette C Fedson, Antje Fischer-Rosinsky, Nita G Forouhi, Maria Grazia Franzosi, Pilar Galan, Mark O Goodarzi, Jürgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Caroline Hayward, Simon C Heath, Serge Hercberg, David R Hillman, Aroon D Hingorani, Jennie Hui, Joe Hung, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesaniemi, Mika Kivimaki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, María Teresa Martínez-Larrad, Jarred B McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J Neville, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Andreas F H Pfeiffer, Irene Pichler, Ozren Polasek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J Sharp, Beverley Shields, Gunnar Sigurðsson, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Anke Tönjes, André G Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, Kim L Ward, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Ingrid B Borecki, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Kaisa Silander, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, Manuel Serrano-Ríos, Lars Lind, Lyle J Palmer, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, Peter Paul Pramstaller, Alan F Wright, Michael Stumvoll, Anders Hamsten, Procardis Consortium, Thomas A Buchanan, Timo T Valle, Jerome I Rotter, Brenda W J H Penninx, Dorret I Boomsma, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Jarvelin, Leena Peltonen, Vincent Mooser, Robert Sladek, MAGIC investigators, GLGC Consortium, Kiran Musunuru, Albert V Smith, Andrew C Edmondson, Ioannis M Stylianou, Masahiro Koseki, James P Pirruccello, Daniel I Chasman, Christopher T Johansen, Sigrid W Fouchier, Gina M Peloso, Maja Barbalic, Sally L Ricketts, Joshua C Bis, Mary F Feitosa, Marju Orho-Melander, Olle Melander, Xiaohui Li, Mingyao Li, Yoon Shin Cho, Min Jin Go, Young Jin Kim, Jong-Young Lee, Taesung Park, Kyunga Kim, Xueling Sim, Rick Twee-Hee Ong, Damien C Croteau-Chonka, Leslie A Lange, Joshua D Smith, Andreas Ziegler, Weihua Zhang, Robert Y L Zee, John B Whitfield, John R Thompson, Ida Surakka, Tim D Spector, Johannes H Smit, Juha Sinisalo, James Scott, Juha Saharinen, Chiara Sabatti, Lynda M Rose, Robert Roberts, Mark Rieder, Alex N Parker, Guillaume Pare, Christopher J O'Donnell, Markku S Nieminen, Deborah A Nickerson, Grant W Montgomery, Wendy McArdle, David Masson, Nicholas G Martin, Fabio Marroni, Gavin Lucas, Robert Luben, Marja-Liisa Lokki, Guillaume Lettre, Lenore J Launer, Edward G Lakatta, Reijo Laaksonen, Kirsten O Kyvik, Inke R König, Kay-Tee Khaw, Lee M Kaplan, Åsa Johansson, A Cecile J W Janssens, Wilmar Igl, G Kees Hovingh, Christian Hengstenberg, Aki S Havulinna, Nicholas D Hastie, Tamara B Harris, Talin Haritunians, Alistair S Hall, Leif C Groop, Elena Gonzalez, Nelson B Freimer, Jeanette Erdmann, Kenechi G Ejebe, Angela Döring, Anna F Dominiczak, Serkalem Demissie, Panagiotis Deloukas, Ulf de Faire, Gabriel Crawford, Yii-der I Chen, Mark J Caulfield, S Matthijs Boekholdt, Themistocles L Assimes, Thomas Quertermous, Mark Seielstad, Tien Y Wong, E-Shyong Tai, Alan B Feranil, Christopher W Kuzawa, Herman A Taylor, Stacey B Gabriel, Hilma Holm, Vilmundur Gudnason, Ronald M Krauss, Jose M Ordovas, Patricia B Munroe, Jaspal S Kooner, Alan R Tall, Robert A Hegele, John J P Kastelein, Eric E Schadt, David P Strachan, Muredach P Reilly, Nilesh J Samani, Heribert Schunkert, L Adrienne Cupples, Manjinder S Sandhu, Paul M Ridker, Daniel J Rader, and Sekar Kathiresan
Subjects: Genetics, QH426-470
Abstract: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p
Published: 2012
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7. A genome-wide association search for type 2 diabetes genes in African Americans.

Author: Nicholette D Palmer, Caitrin W McDonough, Pamela J Hicks, Bong H Roh, Maria R Wing, S Sandy An, Jessica M Hester, Jessica N Cooke, Meredith A Bostrom, Megan E Rudock, Matthew E Talbert, Joshua P Lewis, DIAGRAM Consortium, MAGIC Investigators, Assiamira Ferrara, Lingyi Lu, Julie T Ziegler, Michele M Sale, Jasmin Divers, Daniel Shriner, Adebowale Adeyemo, Charles N Rotimi, Maggie C Y Ng, Carl D Langefeld, Barry I Freedman, Donald W Bowden, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Andrew P Morris, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Claudia Langenberg, Oliver M Hofmann, Josée Dupuis, Lu Qi, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noël P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, David J Couper, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Norman Klopp, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, John R B Perry, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stephane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Karen L Mohlke, Andrew D Morris, Colin N A Palmer, Peter P Pramstaller, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Nicholas J Wareham, Richard M Watanabe, Goncalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Frank B Hu, James B Meigs, James S Pankow, Oluf Pedersen, H-Erich Wichmann, Inês Barroso, Jose C Florez, Timothy M Frayling, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, Nicole Soranzo, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Toby Johnson, Paul Elliott, Denis Rybin, Peter Henneman, Abbas Dehghan, Jouke Jan Hottenga, Kijoung Song, Anuj Goel, Josephine M Egan, Taina Lajunen, Alex Doney, Stavroula Kanoni, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jerome Delplanque, Annette C Fedson, Antje Fischer-Rosinsky, Nita G Forouhi, Rune Frants, Maria Grazia Franzosi, Pilar Galan, Mark O Goodarzi, Jürgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Caroline Hayward, Simon C Heath, Serge Hercberg, Andrew A Hicks, David R Hillman, Aroon D Hingorani, Jennie Hui, Joe Hung, Antti Jula, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesaniemi, Mika Kivimaki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, Alisa K Manning, María Teresa Martínez-Larrad, Jarred B McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J Neville, Ben A Oostra, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Markus Perola, Andreas F H Pfeiffer, Irene Pichler, Ozren Polasek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Bruce M Psaty, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J Sharp, Beverley Shields, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Toshiko Tanaka, Anke Tönjes, André G Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, Kim L Ward, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, Ingrid B Borecki, Ruth J F Loos, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Kaisa Silander, Veikko Salomaa, George Davey Smith, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, George V Dedoussis, Manuel Serrano-Ríos, Lars Lind, Lyle J Palmer, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, Peter Paul Pramstaller, Alan F Wright, Michael Stumvoll, Anders Hamsten, Thomas A Buchanan, Timo T Valle, Jerome I Rotter, David S Siscovick, Brenda W J H Penninx, Dorret I Boomsma, Panos Deloukas, Timothy D Spector, Luigi Ferrucci, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Jarvelin, Dawn M Waterworth, Peter Vollenweider, Leena Peltonen, Vincent Mooser, and Robert Sladek
Subjects: Medicine, Science
Abstract: African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P
Published: 2012
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8. Low frequency variants in the exons only encoding isoform A of HNF1A do not contribute to susceptibility to type 2 diabetes.

Author: Bahram Jafar-Mohammadi, Christopher J Groves, Katharine R Owen, Timothy M Frayling, Andrew T Hattersley, Mark I McCarthy, and Anna L Gloyn
Subjects: Medicine, Science
Abstract: There is considerable interest in the hypothesis that low frequency, intermediate penetrance variants contribute to the proportion of Type 2 Diabetes (T2D) susceptibility not attributable to the common variants uncovered through genome-wide association approaches. Genes previously implicated in monogenic and multifactorial forms of diabetes are obvious candidates in this respect. In this study, we focussed on exons 8-10 of the HNF1A gene since rare, penetrant mutations in these exons (which are only transcribed in selected HNF1A isoforms) are associated with a later age of diagnosis of Maturity onset diabetes of the young (MODY) than mutations in exons 1-7. The age of diagnosis in the subgroup of HNF1A-MODY individuals with exon 8-10 mutations overlaps with that of early multifactorial T2D, and we set out to test the hypothesis that these exons might also harbour low-frequency coding variants of intermediate penetrance that contribute to risk of multifactorial T2D.We performed targeted capillary resequencing of HNF1A exons 8-10 in 591 European T2D subjects enriched for genetic aetiology on the basis of an early age of diagnosis (< or =45 years) and/or family history of T2D (> or =1 affected sibling). PCR products were sequenced and compared to the published HNF1A sequence. We identified several variants (rs735396 [IVS9-24T>C], rs1169304 [IVS8+29T>C], c.1768+44C>T [IVS9+44C>T] and rs61953349 [c.1545G>A, p.T515T] but no novel non-synonymous coding variants were detected.We conclude that low frequency, nonsynonymous coding variants in the terminal exons of HNF1A are unlikely to contribute to T2D-susceptibility in European samples. Nevertheless, the rationale for seeking low-frequency causal variants in genes known to contain rare, penetrant mutations remains strong and should motivate efforts to screen other genes in a similar fashion.
Published: 2009
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9. Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.

Author: Cecilia M Lindgren, Iris M Heid, Joshua C Randall, Claudia Lamina, Valgerdur Steinthorsdottir, Lu Qi, Elizabeth K Speliotes, Gudmar Thorleifsson, Cristen J Willer, Blanca M Herrera, Anne U Jackson, Noha Lim, Paul Scheet, Nicole Soranzo, Najaf Amin, Yurii S Aulchenko, John C Chambers, Alexander Drong, Jian'an Luan, Helen N Lyon, Fernando Rivadeneira, Serena Sanna, Nicholas J Timpson, M Carola Zillikens, Jing Hua Zhao, Peter Almgren, Stefania Bandinelli, Amanda J Bennett, Richard N Bergman, Lori L Bonnycastle, Suzannah J Bumpstead, Stephen J Chanock, Lynn Cherkas, Peter Chines, Lachlan Coin, Cyrus Cooper, Gabriel Crawford, Angela Doering, Anna Dominiczak, Alex S F Doney, Shah Ebrahim, Paul Elliott, Michael R Erdos, Karol Estrada, Luigi Ferrucci, Guido Fischer, Nita G Forouhi, Christian Gieger, Harald Grallert, Christopher J Groves, Scott Grundy, Candace Guiducci, David Hadley, Anders Hamsten, Aki S Havulinna, Albert Hofman, Rolf Holle, John W Holloway, Thomas Illig, Bo Isomaa, Leonie C Jacobs, Karen Jameson, Pekka Jousilahti, Fredrik Karpe, Johanna Kuusisto, Jaana Laitinen, G Mark Lathrop, Debbie A Lawlor, Massimo Mangino, Wendy L McArdle, Thomas Meitinger, Mario A Morken, Andrew P Morris, Patricia Munroe, Narisu Narisu, Anna Nordström, Peter Nordström, Ben A Oostra, Colin N A Palmer, Felicity Payne, John F Peden, Inga Prokopenko, Frida Renström, Aimo Ruokonen, Veikko Salomaa, Manjinder S Sandhu, Laura J Scott, Angelo Scuteri, Kaisa Silander, Kijoung Song, Xin Yuan, Heather M Stringham, Amy J Swift, Tiinamaija Tuomi, Manuela Uda, Peter Vollenweider, Gerard Waeber, Chris Wallace, G Bragi Walters, Michael N Weedon, Wellcome Trust Case Control Consortium, Jacqueline C M Witteman, Cuilin Zhang, Weihua Zhang, Mark J Caulfield, Francis S Collins, George Davey Smith, Ian N M Day, Paul W Franks, Andrew T Hattersley, Frank B Hu, Marjo-Riitta Jarvelin, Augustine Kong, Jaspal S Kooner, Markku Laakso, Edward Lakatta, Vincent Mooser, Andrew D Morris, Leena Peltonen, Nilesh J Samani, Timothy D Spector, David P Strachan, Toshiko Tanaka, Jaakko Tuomilehto, André G Uitterlinden, Cornelia M van Duijn, Nicholas J Wareham, Hugh Watkins, Procardis Consortia, Dawn M Waterworth, Michael Boehnke, Panos Deloukas, Leif Groop, David J Hunter, Unnur Thorsteinsdottir, David Schlessinger, H-Erich Wichmann, Timothy M Frayling, Gonçalo R Abecasis, Joel N Hirschhorn, Ruth J F Loos, Kari Stefansson, Karen L Mohlke, Inês Barroso, Mark I McCarthy, and Giant Consortium
Subjects: Genetics, QH426-470
Abstract: To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
Published: 2009
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10. Combining information from common type 2 diabetes risk polymorphisms improves disease prediction.

Author: Michael N Weedon, Mark I McCarthy, Graham Hitman, Mark Walker, Christopher J Groves, Eleftheria Zeggini, N William Rayner, Beverley Shields, Katharine R Owen, Andrew T Hattersley, and Timothy M Frayling
Subjects: Medicine
Abstract: BackgroundA limited number of studies have assessed the risk of common diseases when combining information from several predisposing polymorphisms. In most cases, individual polymorphisms only moderately increase risk (approximately 20%), and they are thought to be unhelpful in assessing individuals' risk clinically. The value of analyzing multiple alleles simultaneously is not well studied. This is often because, for any given disease, very few common risk alleles have been confirmed.Methods and findingsThree common variants (Lys23 of KCNJ11, Pro12 of PPARG, and the T allele at rs7903146 of TCF7L2) have been shown to predispose to type 2 diabetes mellitus across many large studies. Risk allele frequencies ranged from 0.30 to 0.88 in controls. To assess the combined effect of multiple susceptibility alleles, we genotyped these variants in a large case-control study (3,668 controls versus 2,409 cases). Individual allele odds ratios (ORs) ranged from 1.14 (95% confidence interval [CI], 1.05 to 1.23) to 1.48 (95% CI, 1.36 to 1.60). We found no evidence of gene-gene interaction, and the risks of multiple alleles were consistent with a multiplicative model. Each additional risk allele increased the odds of type 2 diabetes by 1.28 (95% CI, 1.21 to 1.35) times. Participants with all six risk alleles had an OR of 5.71 (95% CI, 1.15 to 28.3) compared to those with no risk alleles. The 8.1% of participants that were double-homozygous for the risk alleles at TCF7L2 and Pro12Ala had an OR of 3.16 (95% CI, 2.22 to 4.50), compared to 4.3% with no TCF7L2 risk alleles and either no or one Glu23Lys or Pro12Ala risk alleles.ConclusionsCombining information from several known common risk polymorphisms allows the identification of population subgroups with markedly differing risks of developing type 2 diabetes compared to those obtained using single polymorphisms. This approach may have a role in future preventative measures for common, polygenic diseases.
Published: 2006
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11. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author: Tove Fall, Anubha Mahajan, Dmitry Shungin, B. Balkau, Gerjan Navis, A. Metspalu, Anneli Pouta, Andrew A. Hicks, Ilja M. Nolte, Ian Ford, Aroon D. Hingorani, Stefan R Bornstein, Anuj Goel, Rona J. Strawbridge, Niek Verweij, Sarah H. Wild, Patricia B. Munroe, T.B. Harris, Jaana Lindström, Johnson Pcd., Nita G. Forouhi, Pierre Meneton, Patricia A. Peyser, Sarin A-P., Andrea Ganna, Timothy M. Frayling, Patrik K. E. Magnusson, Joanne M. Meyer, Yongmei Liu, Jeanette M. Stafford, Christian Herder, L Zudina, Maria G. Stathopoulou, May E. Montasser, Nicholas D. Hastie, Inês Barroso, Schwarz Peh., James B. Meigs, Perttu Salo, George Davey Smith, Gonneke Willemsen, Christopher J. Groves, Erik P A Van Iperen, M. A. Province, Veikko Salomaa, Naveed Sattar, Serena Sanna, Maria Dimitriou, Joop Jukema, Ulrika Krus, Albert V. Smith, Markku Laakso, James F. Wilson, George Nicholson, Loic Yengo, Tatijana Zemunik, Per Eriksson, Harold Snieder, Peter P. Pramstaller, Claudia Langenberg, R. Rauramaa, Alan R. Shuldiner, Pau Navarro, Veronique Vitart, Ross M. Fraser, Aaron Isaacs, C. Lecoeur, Jesper R. Gådin, Jackie F. Price, Letizia Marullo, L.F. Bielak, Sirkka Keinänen-Kiukaanniemi, Amélie Bonnefond, Michael Stumvoll, Alessia Faggian, Anke Tönjes, Tomohiro Tanaka, Wieland Kiess, Harry Campbell, Josée Dupuis, David Altshuler, João Fadista, Winfried März, G K Hovingh, Thomas Illig, Toby Johnson, H Grallert, Kari Stefansson, Reedik Mägi, Palmer Cna., de Geus Ejcn., Martina Müller-Nurasyid, Karen Kapur, Philippe Froguel, Dorret I. Boomsma, Anders Franco-Cereceda, Marcus E. Kleber, Boehnke M, Olga D. Carlson, Ozren Polasek, Andrew P. Morris, Alex S. F. Doney, Najaf Amin, Sara M. Willems, Vilmundur Gudnason, Jose C. Florez, Jeffery R. O'Connell, Nancy L. Pedersen, T. Saaristo, Wolffenbuttel Bhr., M. I. J. Uusitupa, Longda Jiang, Iva Miljkovic, James S. Pankow, Caroline Hayward, Hugh Watkins, Vasiliki Lagou, Johanna Kuusisto, Jaakko Tuomilehto, Alan F. Wright, Josephine M. Egan, Perry Jrb., C M van Duijn, Valeriya Lyssenko, Leif Groop, Stefania Bandinelli, Nigel W. Rayner, Tõnu Esko, Stela McLachlan, Momoko Horikoshi, Eric Boerwinkle, Rick Jansen, Richard N. Bergman, Gudmar Thorleifsson, Lyle J. Palmer, Vilmantas Giedraitis, Peter Kovacs, Nicholas J. Wareham, Luigi Ferrucci, N J Timpson, D Rybin, Anne U. Jackson, Tiinamaija Tuomi, Gonçalo R. Abecasis, Harst Pvd., Meena Kumari, Albert Hofman, Chiara Scapoli, Evelin Mihailov, Josine L. Min, Anders Hamsten, Hottenga J-J., Loos Rjf., Lars Lind, Ulf de Faire, Jaakko Kaprio, Guo Li, Beate St Pourcain, C Gieger, Amanda J. Bennett, Anna Ulrich, Nabila Bouatia-Naji, Satu Männistö, Antigone S. Dimas, Jarvelin M-R., Günther Silbernagel, F Karpe, A. Körner, David S. Siscovick, M Blüher, Rebecca J. Webster, Erik Ingelsson, Susan Campbell, Mika Kivimäki, Laura J. Rasmussen-Torvik, Heikki A. Koistinen, Sophie Visvikis-Siest, Bernhard O. Boehm, Inga Prokopenko, Ping An, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Kardia Slr., Richa Saxena, Igor Rudan, Richard M. Watanabe, Jian'an Luan, Marika Kaakinen, Shin S-Y., George Dedoussis, Panagiotis Deloukas, Mark I. McCarthy, Barbara Thorand, B.W.J.H. Penninx, Peter Vollenweider, Paul W. Franks, Leena Kinnunen, Markus Perola, Yvonne Boettcher, Timo A. Lakka, Nicole Soranzo, Stavroula Kanoni, Bakker Sjl., Winkelmann Br, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institute of Genomics [Tartu, Estonia], University of Tartu, Vrije Universiteit Amsterdam [Amsterdam] (VU), Vrije Universiteit Medical Centre (VUMC), Helmholtz-Zentrum München (HZM), University of Cambridge [UK] (CAM), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Università degli Studi di Ferrara (UniFE), Boston University [Boston] (BU), VU University Medical Center [Amsterdam], University of Bristol [Bristol], Biomedical Sciences Research Centre Alexander Fleming [Vari, Greece] (BSRC), Imperial College London, Karolinska Institutet [Stockholm], Institute for Molecular Bioscience, University of Queensland [Brisbane], Statens Serum Institut [Copenhagen], Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Cardiovascular Research Institute Maastricht (CARIM), Maastricht University [Maastricht], MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, National Institute on Aging [Baltimore, MD, USA] (NIH), University of Michigan [Ann Arbor], University of Michigan System, University of Maryland School of Medicine, University of Maryland System, The University of Western Australia (UWA), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Wake Forest University, National Institute for Health and Welfare [Helsinki], The Wellcome Trust Sanger Institute [Cambridge], University of Iceland [Reykjavik], University of Washington [Seattle], University of Groningen [Groningen], University of Glasgow, William Harvey Research Institute, Barts and the London Medical School, Université de Lausanne (UNIL), deCODE genetics [Reykjavik], Northwestern University Feinberg School of Medicine, Uppsala Universitet [Uppsala], University of Edinburgh, Medical Faculty [Mannheim], University of Graz, Ludwig-Maximilians-Universität München (LMU), Johannes Gutenberg - Universität Mainz (JGU), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Umeå University, Skane University Hospital [Malmo], Lund University [Lund], RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche [Roma] (CNR), University Medical Center Groningen [Groningen] (UMCG), Universität Leipzig [Leipzig], Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Split, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), University of Eastern Finland, Harokopio University of Athens, European Academy Bozen/Bolzano (EURAC), University of Kuopio, German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Ninewells Hospital and Medical School [Dundee], University College of London [London] (UCL), University of Essex, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], University of Helsinki, Leiden University Medical Center (LUMC), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Oulu, The University of Texas Health Science Center at Houston (UTHealth), University of Minnesota Medical School, University of Minnesota System, Keck School of Medicine [Los Angeles], University of Southern California (USC), Amsterdam UMC, University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Lee Kong Chian School of Medicine, Nanyang Technological University (NTU), Universität Heidelberg [Heidelberg], King Abdulaziz University, Pirkanmaa Hospital District, Tampere University Hospital, Cedars-Sinai Medical Center, Danube University Krems, Harvard School of Public Health, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Hannover Medical School [Hannover] (MHH), Universität zu Lübeck [Lübeck], University of Exeter, Regeneron Pharmaceuticals [Tarrytown], University of Adelaide, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Harvard T.H. Chan School of Public Health, John Radcliffe Hospital [Oxford University Hospital], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Université de Genève (UNIGE), Big Data Institute, University of Surrey (UNIS), University of Bergen (UiB), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford Cardiovascular Institute, University of Liverpool, University of Manchester [Manchester], Institute of Biochemistry and Genetics of Ufa Scientific Centre, Russian Academy of Sciences [Moscow] (RAS), Experimental Vascular Medicine, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, SIEST, Sofia, PreciDIAB Institute, the holistic approach of personal diabets care - - PreciDIAB2018 - ANR-18-IBHU-0001 - IBHU - VALID, Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging - DYNAHEALTH - - H20202015-04-01 - 2019-03-31 - 633595 - VALID, Beyond the Genetics of Addiction - ADDICTION - - EC:FP7:ERC2011-12-01 - 2017-05-31 - 284167 - VALID, Rise of scientific excellence and collaboration for implementing personalised medicine in Estonia - ePerMed - - H20202016-01-01 - 2018-12-31 - 692145 - VALID, University of Oxford, Helmholtz Zentrum München = German Research Center for Environmental Health, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Ferrara = University of Ferrara (UniFE), Université de Lausanne = University of Lausanne (UNIL), Karl-Franzens-Universität Graz, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Amsterdam UMC - Amsterdam University Medical Center, Nanyang Technological University [Singapour], Universität zu Lübeck = University of Lübeck [Lübeck], Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Université de Genève = University of Geneva (UNIGE), ANR-18-IBHU-0001,PreciDIAB,PreciDIAB Institute, the holistic approach of personal diabets care(2018), European Project: 633595,H2020,H2020-PHC-2014-two-stage,DYNAHEALTH(2015), European Project: 284167,EC:FP7:ERC,ERC-2011-StG_20101124,ADDICTION(2011), European Project: 692145,H2020,H2020-TWINN-2015,ePerMed(2016), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Functional Genomics, APH - Mental Health, Sociology and Social Gerontology, APH - Methodology, Hottenga, Jouke- Jan [0000-0002-5668-2368], Bouatia-Naji, Nabila [0000-0001-5424-2134], Jansen, Rick [0000-0002-3333-6737], Min, Josine L. [0000-0003-4456-9824], Faggian, Alessia [0000-0002-3799-9722], Bonnefond, Amélie [0000-0001-9976-3005], Isaacs, Aaron [0000-0001-5037-4834], Willems, Sara M. [0000-0002-6803-3007], Navarro, Pau [0000-0001-5576-8584], Jackson, Anne U. [0000-0002-9672-2547], Bielak, Lawrence F. [0000-0002-3443-8030], Saxena, Richa [0000-0003-2233-1065], Smith, Albert V. [0000-0003-1942-5845], Verweij, Niek [0000-0002-4303-7685], Goel, Anuj [0000-0003-2307-4021], Johnson, Paul C. D. [0000-0001-6663-7520], Strawbridge, Rona J. [0000-0001-8506-3585], Fall, Tove [0000-0003-2071-5866], Fraser, Ross M. [0000-0003-0488-2592], Kanoni, Stavroula [0000-0002-1691-9615], Giedraitis, Vilmantas [0000-0003-3423-2021], Kleber, Marcus E. [0000-0003-0663-7275], Müller-Nurasyid, Martina [0000-0003-3793-5910], Luan, Jian’an [0000-0003-3137-6337], Sanna, Serena [0000-0002-3768-1749], Nolte, Ilja M. [0000-0001-5047-4077], Zemunik, Tatijana [0000-0001-8120-2891], Kovacs, Peter [0000-0002-0290-5423], Wild, Sarah H. [0000-0001-7824-2569], McLachlan, Stela [0000-0003-0480-6143], Egan, Josephine [0000-0002-8945-0053], Hicks, Andrew A. [0000-0001-6320-0411], Thorand, Barbara [0000-0002-8416-6440], Hingorani, Aroon [0000-0001-8365-0081], Kivimaki, Mika [0000-0002-4699-5627], Koistinen, Heikki A. [0000-0001-7870-070X], Bakker, Stephan J. L. [0000-0003-3356-6791], Palmer, Colin N. A. [0000-0002-6415-6560], Jukema, J. Wouter [0000-0002-3246-8359], Sattar, Naveed [0000-0002-1604-2593], Snieder, Harold [0000-0003-1949-2298], Magnusson, Patrik K. [0000-0002-7315-7899], Blüher, Matthias [0000-0003-0208-2065], Wolffenbuttel, Bruce H. R. [0000-0001-9262-6921], Abecasis, Goncalo R. [0000-0003-1509-1825], Meigs, James B. [0000-0002-2439-2657], Wilson, James F. [0000-0001-5751-9178], Schwarz, Peter E. H. [0000-0001-6317-7880], Boehm, Bernhard O. [0000-0002-2706-7710], Metspalu, Andres [0000-0002-3718-796X], Deloukas, Panos [0000-0001-9251-070X], Körner, Antje [0000-0001-6001-0356], Wareham, Nicholas J. [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Männistö, Satu [0000-0002-8668-3046], Franks, Paul W. [0000-0002-0520-7604], Hayward, Caroline [0000-0002-9405-9550], Vitart, Veronique [0000-0002-4991-3797], Kaprio, Jaakko [0000-0002-3716-2455], Visvikis-Siest, Sophie [0000-0001-8104-8425], Altshuler, David [0000-0002-7250-4107], Rudan, Igor [0000-0001-6993-6884], van Duijn, Cornelia M. [0000-0002-2374-9204], Pramstaller, Peter P. [0000-0002-9831-8302], Boehnke, Michael [0000-0002-6442-7754], Frayling, Timothy M. [0000-0001-8362-2603], Peyser, Patricia A. [0000-0002-9717-8459], Harst, Pim van der [0000-0002-2713-686X], Smith, George Davey [0000-0002-1407-8314], Forouhi, Nita G. [0000-0002-5041-248X], Loos, Ruth J. F. [0000-0002-8532-5087], Salomaa, Veikko [0000-0001-7563-5324], Soranzo, Nicole [0000-0003-1095-3852], Boomsma, Dorret I. [0000-0002-7099-7972], Groop, Leif [0000-0002-0187-3263], Tuomi, Tiinamaija [0000-0002-8306-6202], Munroe, Patricia B. [0000-0002-4176-2947], Gudnason, Vilmundur [0000-0001-5696-0084], Lecoeur, Cecile [0000-0003-0075-6417], Jarvelin, Marjo-Riitta [0000-0002-2149-0630], Stefansson, Kari [0000-0003-1676-864X], Dermitzakis, Emmanouil T. [0000-0002-9302-6490], Lindgren, Cecilia M. [0000-0002-4903-9374], Froguel, Philippe [0000-0003-2972-0784], Kaakinen, Marika A. [0000-0002-9228-0462], Watanabe, Richard M. [0000-0003-1015-0531], Ingelsson, Erik [0000-0003-2256-6972], Dupuis, Josée [0000-0003-2871-3603], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Epidemiology, University Hospital Mannheim | Universitätsmedizin Mannheim, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Universität Leipzig, Universiteit Leiden, Universität Heidelberg [Heidelberg] = Heidelberg University, Karl-Franzens-Universität [Graz, Autriche], Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, General practice, APH - Digital Health, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Value, Affordability and Sustainability (VALUE), Cardiovascular Centre (CVC), Hottenga, Jouke-Jan [0000-0002-5668-2368], Min, Josine L [0000-0003-4456-9824], Willems, Sara M [0000-0002-6803-3007], Jackson, Anne U [0000-0002-9672-2547], Bielak, Lawrence F [0000-0002-3443-8030], Smith, Albert V [0000-0003-1942-5845], Johnson, Paul CD [0000-0001-6663-7520], Strawbridge, Rona J [0000-0001-8506-3585], Fraser, Ross M [0000-0003-0488-2592], Kleber, Marcus E [0000-0003-0663-7275], Luan, Jian'an [0000-0003-3137-6337], Nolte, Ilja M [0000-0001-5047-4077], Wild, Sarah H [0000-0001-7824-2569], Hicks, Andrew A [0000-0001-6320-0411], Koistinen, Heikki A [0000-0001-7870-070X], Bakker, Stephan JL [0000-0003-3356-6791], Palmer, Colin NA [0000-0002-6415-6560], Jukema, J Wouter [0000-0002-3246-8359], Magnusson, Patrik K [0000-0002-7315-7899], Wolffenbuttel, Bruce HR [0000-0001-9262-6921], Abecasis, Goncalo R [0000-0003-1509-1825], Meigs, James B [0000-0002-2439-2657], Wilson, James F [0000-0001-5751-9178], Schwarz, Peter EH [0000-0001-6317-7880], Boehm, Bernhard O [0000-0002-2706-7710], Wareham, Nicholas J [0000-0003-1422-2993], Franks, Paul W [0000-0002-0520-7604], van Duijn, Cornelia M [0000-0002-2374-9204], Pramstaller, Peter P [0000-0002-9831-8302], Frayling, Timothy M [0000-0001-8362-2603], Peyser, Patricia A [0000-0002-9717-8459], Forouhi, Nita G [0000-0002-5041-248X], Loos, Ruth JF [0000-0002-8532-5087], Boomsma, Dorret I [0000-0002-7099-7972], Munroe, Patricia B [0000-0002-4176-2947], Dermitzakis, Emmanouil T [0000-0002-9302-6490], Lindgren, Cecilia M [0000-0002-4903-9374], Kaakinen, Marika A [0000-0002-9228-0462], Watanabe, Richard M [0000-0003-1015-0531], Tampere University, Tays Research Services, Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), Fysiologie, RS: FHML MaCSBio, and RS: Carim - B01 Blood proteins & engineering
Subjects: Male, Anorexia Nervosa, medicine.medical_treatment, 45/43, Insulin Resistance/genetics, SUSCEPTIBILITY, Quantitative trait, Impaired glucose tolerance, 0302 clinical medicine, Architecture, LS2_1, IMPUTATION, Insulin, ComputingMilieux_MISCELLANEOUS, Fasting, Publisher Correction, 3. Good health, [SDV] Life Sciences [q-bio], Kruppel-Like Transcription Factors/blood, Endokrinologi och diabetes, Science & Technology - Other Topics, Adult, Blood Glucose, European Continental Ancestry Group, Female, Gene Expression, Genetic Loci, Genome-Wide Association Study, Glucose Intolerance, Humans, Insulin Receptor Substrate Proteins, Insulin Resistance, Kruppel-Like Transcription Factors, Middle Aged, Phenotype, Sex Characteristics, Sex Factors, Waist-Hip Ratio, Sex characteristics, medicine.medical_specialty, Science, 631/208/205/2138, Endocrinology and Diabetes, General Biochemistry, Genetics and Molecular Biology, White People, Gender-differences, 03 medical and health sciences, SDG 3 - Good Health and Well-being, 692/53/2421, GLYCEMIC TRAITS, GENOME-WIDE ASSOCIATION, Glycemic, GENDER-DIFFERENCES, Science & Technology, IDENTIFICATION, 692/699/2743/2815, Blood Glucose/metabolism, Diagnostic markers, medicine.disease, Anorexia Nervosa/blood, 030104 developmental biology, Endocrinology, Glucose, Insulin/blood, Anorexia Nervosa/ethnology, Anorexia Nervosa/genetics, Anorexia Nervosa/physiopathology, Fasting/blood, Glucose Intolerance/blood, Glucose Intolerance/ethnology, Glucose Intolerance/genetics, Glucose Intolerance/physiopathology, Insulin Receptor Substrate Proteins/blood, Insulin Receptor Substrate Proteins/genetics, Kruppel-Like Transcription Factors/genetics, 0301 basic medicine, Identification, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Genome-wide association studies, Waist–hip ratio, LS4_5, RISK, ARCHITECTURE, Multidisciplinary, article, Type 2 diabetes, Multidisciplinary Sciences, MENDELIAN RANDOMIZATION, Pre-diabetes, Medical Genetics, Risk, PATHOPHYSIOLOGY, 030209 endocrinology & metabolism, 3121 Internal medicine, 692/163/2743/137/773, NO, Insulin resistance, Internal medicine, Diabetes mellitus, medicine, Mendelian randomization, 631/208/480, Medicinsk genetik, business.industry, General Chemistry, Impaired fasting glucose, business
Abstract: Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes., Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.
Published: 2021

12. Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author: Stavroula Kanoni, Bakker Sjl., Winkelmann Br, Wieland Kiess, Josée Dupuis, Palmer Cna., James F. Wilson, Schwarz Peh., Maria Dimitriou, Joop Jukema, Sara M. Willems, J L Min, R. Rauramaa, Perry Jrb., Momoko Horikoshi, Timo A. Lakka, Nicole Soranzo, J Kaprio, Niek Verweij, Martina Müller-Nurasyid, Jaana Lindström, Toby Johnson, Olga D. Carlson, Nita G. Forouhi, George Dedoussis, Johnson Pcd., Patrick K.E. Magnusson, Gonçalo R. Abecasis, Ozren Polasek, Wolffenbuttel Bhr., M. I. J. Uusitupa, Longda Jiang, Nancy L. Pedersen, Beate St Pourcain, Erik P A Van Iperen, Iva Miljkovic, Stefania Bandinelli, M. A. Province, Veikko Salomaa, Andrew A. Hicks, Evelin Mihailov, Rick Jansen, James B. Meigs, D Rybin, Peter Kovacs, George Davey Smith, Rona J. Strawbridge, Gudmar Thorleifsson, Meena Kumari, Chiara Scapoli, Christopher J. Groves, Barbara Thorand, T.B. Harris, Ulf de Faire, Inga Prokopenko, Stela McLachlan, Ping An, Anubha Mahajan, L.F. Bielak, Rebecca J. Webster, David Altshuler, Susan Campbell, Bernhard O. Boehm, A. Metspalu, Perttu Salo, D.I. Boomsma, Ilja M. Nolte, Andrea Ganna, Timothy M. Frayling, Pau Navarro, N J Timpson, Kardia Slr., Jeanette M. Stafford, Tõnu Esko, Ulrika Krus, Richa Saxena, Per Eriksson, Peter P. Pramstaller, Anne U. Jackson, V Lagou, Anders Franco-Cereceda, David S. Siscovick, Josephine M. Egan, Loos Rjf., C Gieger, Amanda J. Bennett, Anna Ulrich, Satu Männistö, Mika Kivimäki, Loic Yengo, Caroline Hayward, George Nicholson, C M van Duijn, Anke Tönjes, Nigel W. Rayner, Jose C. Florez, Leif Groop, Valeri Lyssenko, Lyle J. Palmer, Vilmantas Giedraitis, Maria G. Stathopoulou, B. Balkau, Anneli Pouta, Anuj Goel, Pierre Meneton, Serena Sanna, Jesper R. Gådin, Claudia Langenberg, Alessia Faggian, H Grallert, Karen Kapur, Marcus E. Kleber, Philippe Froguel, Boehnke M, Harry Campbell, Anders Hamsten, T. Saaristo, Antigone S. Dimas, Jarvelin M-R., F Karpe, A. Körner, Leena Kinnunen, Markus Perola, Joanne M. Meyer, May E. Montasser, Erik Ingelsson, Naveed Sattar, Yvonne Boettcher, Sirkka Keinänen-Kiukaanniemi, Aaron Isaacs, Gerjan Navis, Ian Ford, Amélie Bonnefond, Reedik Mägi, Tove Fall, Dmitry Shungin, Jenna Price, Igor Rudan, Richard M. Watanabe, Luigi Ferrucci, Jian'an Luan, Harst Pvd., Marika Kaakinen, Tatijana Zemunik, Christian Herder, Shin S-Y., Veronique Vitart, Ross M. Fraser, Alan R. Shuldiner, Panagiotis Deloukas, C. Lecoeur, Letizia Marullo, Kari Stefansson, Lars Lind, Winfried März, L Zudina, Aroon D. Hingorani, Gonneke Willemsen, de Geus Ejcn., Albert V. Smith, Jeffery R. O'Connell, Yongmei Liu, James S. Pankow, Sarah H. Wild, Patricia B. Munroe, Patricia A. Peyser, Nicholas J. Wareham, Tiinamaija Tuomi, Nicholas D. Hastie, Markku Laakso, Albert Hofman, J. Tuomilehto, Emmanouil T. Dermitzakis, Thomas Illig, Tomohiro Tanaka, Cecilia M. Lindgren, Sarin A-P., Alex S. F. Doney, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Andrew P. Morris, Richard N. Bergman, Mark I. McCarthy, Nabila Bouatia-Naji, Günther Silbernagel, João Fadista, Harold Snieder, Ins Barroso, Michael Stumvoll, B.W.J.H. Penninx, M Blüher, Stefan R Bornstein, Laura J. Rasmussen-Torvik, Alan F. Wright, Peter Vollenweider, G K Hovingh, Heikki A. Koistinen, Sophie Visvikis-Siest, Vilmundur Gudnason, Eric Boerwinkle, Hottenga J-J., Guo Li, Paul W. Franks, Université de Lille, Centre de recherche en épidémiologie et santé des populations (CESP), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay
Subjects: Genetics, Multidisciplinary, Science, Insulin, medicine.medical_treatment, General Physics and Astronomy, Diagnostic marker, Genome-wide association study, General Chemistry, Type 2 diabetes, Quantitative trait locus, Biology, medicine.disease, GeneralLiterature_MISCELLANEOUS, General Biochemistry, Genetics and Molecular Biology, Fasting glucose, Sexual dimorphism, Pre diabetes, [SDU]Sciences of the Universe [physics], ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, medicine
Abstract: The original version of this Article contained an error in Fig. 2, in which panels a and b were inadvertently swapped. This has now been corrected in the PDF and HTML versions of the Article.
Published: 2021

13. Performance characteristics of five immunoassays for SARS-CoV-2: a head-to-head benchmark comparison

Author: Andrew J Kwok, Eleanor Barnes, R Levin, Derrick W. Crook, D Crawford-Jones, Y Peng, E Perez, Marta Oliveira, Peto Tea., Nicole Stoesser, S Camara, K K Chau, Monique Andersson, Sally Beer, Matthew Catton, Y Warren, M Borak, L Blackwell, Tim James, Anita Justice, Abbie Bown, A Espinosa, Ashley Otter, Alex J. Richardson, M Emmenegger, Katie Jeffery, W Dejnirattsai, M Fernandez Mendoza, Julian C. Knight, A Linder, L Koukouflis, T Lockett, Rutger J. Ploeg, Tao Dong, Alison Howarth, J K Baillie, H P Tsang, Daniel Ebner, Gillian Rodger, L Silva-Reyes, Sarah Hoosdally, Timothy M Walker, Richard Vipond, S Fassih, Silvia D'Arcangelo, Alex Sienkiewicz, C Wilson, Aimee R. Taylor, Nicola A. Burgess-Brown, Sarah Oakley, Bassam Hallis, Alexander J. Mentzer, Tim Brooks, Cathy Rowe, L Martins Ferreira, Conor Feehily, Thomas G Ritter, S Marinou, N Gent, George Doherty, S Dimitriadis, Juthathip Mongkolsapaya, D Fox McKee, Christopher J. Groves, F Karpe, Kate E. Dingle, Prem Perumal, U Leuschner, Teresa L Street, P M Hammond, Carrow I. Wells, David W Eyre, James Kavanagh, Brian D. Marsden, Richard J. Cornall, Donal T. Skelly, J Pascoe, A Sobrino Diaz, Elizabeth A. Clutterbuck, V Gallardo Sanchez, Justine K. Rudkin, L Mason, R K Young, Susanna Dunachie, T Fordwoh, D S Kim, Dequaire Jmm., Mukhopadhyay Smm., B Horsington, Devender Roberts, E Y Jones, Kathryn Auckland, K Withycombe, Jennifer Hill, H Pickford, Christina Dold, Sheila F Lumley, Angela Sweed, Heli Harvala, A Beveridge, Rory Fairhead, K Paddon, Sadia Bibi, John Frater, Lisa Stockdale, J Morrow, David I. Stuart, Matt J. Neville, M K Verheul, T H Foord, Stuart Cox, Alejandra Fernández-Cid, Christine S. Rollier, L Stafford, Andrew J. Pollard, Susan Wareing, R Kirton, Jesse Coker, Malcolm G Semple, Paul Klenerman, A Mobbs, Thomas Christott, H Thraves, D Georgiou, Gavin R. Screaton, S Felle, José William Martínez, Philippa C Matthews, Stephanie B Hatch, and Mark A. Ainsworth
Subjects: 0301 basic medicine, medicine.medical_specialty, medicine.diagnostic_test, Receiver operating characteristic, Head to head, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Assay sensitivity, Articles, Serology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Infectious Diseases, Immunoassay, Internal medicine, medicine, 030212 general & internal medicine, Symptom onset, business
Abstract: Summary Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic in 2020. Testing is crucial for mitigating public health and economic effects. Serology is considered key to population-level surveillance and potentially individual-level risk assessment. However, immunoassay performance has not been compared on large, identical sample sets. We aimed to investigate the performance of four high-throughput commercial SARS-CoV-2 antibody immunoassays and a novel 384-well ELISA. Methods We did a head-to-head assessment of SARS-CoV-2 IgG assay (Abbott, Chicago, IL, USA), LIAISON SARS-CoV-2 S1/S2 IgG assay (DiaSorin, Saluggia, Italy), Elecsys Anti-SARS-CoV-2 assay (Roche, Basel, Switzerland), SARS-CoV-2 Total assay (Siemens, Munich, Germany), and a novel 384-well ELISA (the Oxford immunoassay). We derived sensitivity and specificity from 976 pre-pandemic blood samples (collected between Sept 4, 2014, and Oct 4, 2016) and 536 blood samples from patients with laboratory-confirmed SARS-CoV-2 infection, collected at least 20 days post symptom onset (collected between Feb 1, 2020, and May 31, 2020). Receiver operating characteristic (ROC) curves were used to assess assay thresholds. Findings At the manufacturers' thresholds, for the Abbott assay sensitivity was 92·7% (95% CI 90·2–94·8) and specificity was 99·9% (99·4–100%); for the DiaSorin assay sensitivity was 96·2% (94·2–97·7) and specificity was 98·9% (98·0–99·4); for the Oxford immunoassay sensitivity was 99·1% (97·8–99·7) and specificity was 99·0% (98·1–99·5); for the Roche assay sensitivity was 97·2% (95·4–98·4) and specificity was 99·8% (99·3–100); and for the Siemens assay sensitivity was 98·1% (96·6–99·1) and specificity was 99·9% (99·4–100%). All assays achieved a sensitivity of at least 98% with thresholds optimised to achieve a specificity of at least 98% on samples taken 30 days or more post symptom onset. Interpretation Four commercial, widely available assays and a scalable 384-well ELISA can be used for SARS-CoV-2 serological testing to achieve sensitivity and specificity of at least 98%. The Siemens assay and Oxford immunoassay achieved these metrics without further optimisation. This benchmark study in immunoassay assessment should enable refinements of testing strategies and the best use of serological testing resource to benefit individuals and population health. Funding Public Health England and UK National Institute for Health Research.
Published: 2020
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14. Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium

Author: Azra Kurbasic, Femke Rutters, Markku Laakso, Joline W.J. Beulens, Caroline Brorsson, Mark Walker, Tarja Kokkola, Emmanouil T. Dermitzakis, Gary Frost, Andrew T. Hattersley, Hartmut Ruetten, Søren Brunak, Simone P. Rauh, Federico De Masi, Ramneek Gupta, Imre Pavo, Christopher J. Groves, Jerzy Adamski, Andrea Tura, Bernd Jablonka, Alison Heggie, Tue H. Hansen, Ana Viñuela, Martin Ridderstråle, Andrea Mari, Jane Kaye, Henrik Vestergaard, Robert W. Koivula, Kristine H. Allin, Harriet Teare, Michelle Hudson, Thomas E. White, Jochen M. Schwenk, Mark I. McCarthy, Maritta Siloaho, Mandy H Perry, Ewan R. Pearson, Oluf Pedersen, Ian M Forgie, Timothy J. McDonald, Soren Brage, Anubha Mahajan, E. Louise Thomas, Paul W. Franks, Anitra D.M. Koopman, Philippe Froguel, Torben Hansen, Jimmy D. Bell, Giuseppe N. Giordano, Adem Y. Dawed, Koivula, Robert W. [0000-0002-1646-4163], Pearson, Ewan [0000-0001-9237-8585], Franks, Paul W. [0000-0002-0520-7604], Apollo - University of Cambridge Repository, Vinuela Rodriguez, Ana, Dermitzakis, Emmanouil, Epidemiology and Data Science, APH - Health Behaviors & Chronic Diseases, APH - Methodology, ACS - Diabetes & metabolism, APH - Aging & Later Life, ACS - Heart failure & arrhythmias, Koivula, Robert W [0000-0002-1646-4163], and Franks, Paul W [0000-0002-0520-7604]
Subjects: 0301 basic medicine, Blood Glucose, Male, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, Cohort Studies, 0302 clinical medicine, DESIGN, ddc:590, Glycaemic control, Glucose/metabolism, ddc:576.5, Prediabetes, Prospective Studies, Prospective cohort study, RISK, education.field_of_study, Glucose tolerance test, Blood Glucose/drug effects/metabolism, Genome, medicine.diagnostic_test, Insulin secretion, Middle Aged, Insulin sensitivity, Metformin, 3. Good health, TESTS, Cohort, Endokrinologi och diabetes, Female, Life Sciences & Biomedicine, Cohort study, medicine.medical_specialty, Population, 030209 endocrinology & metabolism, Endocrinology and Diabetes, Article, Ectopic fat, 1117 Public Health and Health Services, Diet, Ectopic Fat, Glycaemic Control, Insulin Secretion, Insulin Sensitivity, Personalised Medicine, Physical Activity, Type 2 Diabetes, Prediabetic State, Endocrinology & Metabolism, 03 medical and health sciences, SDG 3 - Good Health and Well-being, BETA-CELL FUNCTION, Internal medicine, Diabetes mellitus, Diabetes Mellitus, Internal Medicine, medicine, Humans, Metformin/therapeutic use, IMI DIRECT Consortium, education, Prediabetic State/blood/epidemiology, Aged, RELEASE, Science & Technology, business.industry, Physical activity, 1103 Clinical Sciences, Glucose Tolerance Test, FAT-CONTENT, medicine.disease, 030104 developmental biology, Glucose, Diabetes Mellitus, Type 2, COHORT PROFILE, 1114 Paediatrics and Reproductive Medicine, Personalised medicine, GLUCOSE-TOLERANCE, Type 2/blood/drug therapy/epidemiology, business, RESISTANCE, Biomarkers/blood, Biomarkers
Abstract: Aims/hypothesis Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up). Methods From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6–24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at ~18 months (both cohorts) and at ~48 months (cohort 1) or ~36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe. Results Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean ± SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m2; fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants’ clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m2; fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants’ clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l. Conclusions/interpretation The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes. Electronic supplementary material The online version of this article (10.1007/s00125-019-4906-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Published: 2019

15. The genetic architecture of type 2 diabetes

Author: Clement Ma, Liisa Hakaste, Claes Ladenvall, Massimo Mangino, Lars Lind, Aaron G. Day-Williams, Ryan Poplin, Thomas Schwarzmayr, Annette Peters, Thomas Meitinger, Satish Kumar, Kyong Soo Park, Ching-Yu Cheng, Farook Thameem, Kyle J. Gaulton, Olov Rolandsson, Yossi Farjoun, Neil Robertson, Mauricio O. Carneiro, Mark A. DePristo, Pierre Fontanillas, Ruth J. F. Loos, Heather M. Highland, Vilmantas Giedraitis, Gemma Buck, Fredrik Karpe, Mohammad Kamran Ikram, Alex S. F. Doney, Hae Kyung Im, Eric S. Lander, Johanna Kuusisto, Dorothée Thuillier, Denis Rybin, Jacquelyn Murphy, Benjamin M. Neale, Martina Müller-Nurasyid, Eric R. Gamazon, Johanne Marie Justesen, Tin Aung, Vincent K. L. Lam, John Danesh, Donna M. Lehman, Goo Jun, Marit E. Jørgensen, Christian Herder, Edmund Chan, Pamela J. Hicks, Todd Green, Claudia Langenberg, Yoon Shin Cho, James G. Wilson, Daniel E. Hale, Rector Arya, Giriraj R. Chandak, Juan Fernandez Tajes, Jaakko Tuomilehto, Christopher P. Jenkinson, Anders Rosengren, Torsten Lauritzen, Michael Griswold, Karen L. Mohlke, Amy J. Swift, Alena Stančáková, Christian Fuchsberger, Iksoo Huh, Nikhil Tandon, João Fadista, Christa Meisinger, Gonçalo R. Abecasis, Pål R. Njølstad, Dwaipayan Bharadwaj, Richard M. Watanabe, Shaun Purcell, Veikko Salomaa, Tim D. Spector, Paul W. Franks, Adam E. Locke, Sharon P. Fowler, Panos Deloukas, Reedik Mägi, Solomon K. Musani, Kee Seng Chia, Barbara Thorand, Soo Heon Kwak, Annemari Käräjämäki, Evelin Mihailov, John Blangero, Thomas Wieland, Christian Gieger, E. Shyong Tai, Jianjun Liu, James B. Meigs, Teemu Kuulasmaa, Martin Hrabé de Angelis, Francis S. Collins, Tim M. Strom, Tibor V. Varga, Juyoung Lee, Mark I. McCarthy, Domenico Palli, Jong-Young Lee, Benjamin Glaser, Tasha E. Fingerlin, Stephen O'Rahilly, Andrew T. Hattersley, Gil Atzmon, Manuel A. Rivas, Noël P. Burtt, Ivan Brandslund, Young-Jin Kim, Dorairaj Prabhakaran, Xu Wang, Taylor J. Maxwell, Valeriya Lyssenko, Frank B. Hu, Adolfo Correa, Khalid Shakir, Kathleen A. Jablonski, Yingchang Lu, Wei-Yen Lim, Min Jin Go, William R. Scott, Hanna E. Abboud, Leena Kinnunen, Inês Barroso, Gabriela L. Surdulescu, Peng Chen, Robert Sladek, Marju Orho-Melander, Xueling Sim, Robert A. Scott, Joanna M. M. Howson, Markku Laakso, David Altshuler, Vidya S. Farook, Harald Grallert, Janina S. Ried, Vineeta Agarwala, Philippe Froguel, Nicholas J. Wareham, Tiinamaija Tuomi, Joon Yoon, Heikki A. Koistinen, Toni I. Pollin, Heiner Boeing, Marie Loh, Nicola L. Beer, Joanne E. Curran, Lars Lannfelt, Dorota Pasko, Taesung Park, David Buck, Nir Barzilai, Stephen C. J. Parker, Michael Roden, Bok-Ghee Han, David Aguilar, Timothy Fennell, Sian-Tsung Tan, Gregory P. Wilson, Momoko Horikoshi, Cramer Christensen, Craig L. Hanis, Gilean McVean, Benjamin F. Voight, Wolfgang Rathmann, Jared Maguire, Ashok Kumar, Donald W. Bowden, Michael L. Stitzel, Yongkang Kim, Christine Blancher, Jason Carey, Min-Seok Kwon, Nicholette D. Palmer, Oluf Pedersen, Niels Grarup, Peter S. Chines, Cornelia Huth, James Scott, Torben Hansen, Konstantin Strauch, Erwin P. Bottinger, Andrew D. Morris, Anette P. Gjesing, Erik Ingelsson, Colin N. A. Palmer, Claudia H. T. Tam, Stacey Gabriel, Pablo Cingolani, Beverley Balkau, Michael Boehnke, Peter M. Nilsson, Wing-Yee So, Andrew R. Wood, Lili Milani, Ravindranath Duggirala, Qibin Qi, Mark Walker, Weiping Jia, Mark Seielstad, Narisu Narisu, Tien Yin Wong, Martijn van de Bunt, Anubha Mahajan, Davis J. McCarthy, Ann-Christine Syvänen, Jennifer Kriebel, N. William Rayner, Han Chen, Jinyan Huang, Chiea Chuen Khor, Richard N. Bergman, Shah Ebrahim, Dylan Hodgkiss, Weihua Zhang, Manjinder S. Sandhu, Richard D. Pearson, Juliana C.N. Chan, Rainer Rauramaa, Ralph A. DeFronzo, Andrew Farmer, Yoshihiko Nagai, Allan Linneberg, Herman A. Taylor, Jose C. Florez, Jaspal S. Kooner, Lori L. Bonnycastle, Jeroen R. Huyghe, Leif Groop, Joseph Trakalo, Sobha Puppala, Bong-Jo Kim, Kathleen Stirrups, Kerrin S. Small, Cecilia M. Lindgren, Jennifer E. Below, Heung Man Lee, Inga Prokopenko, Liming Liang, Timothy M. Frayling, Uzma Afzal, Mark J. Daly, Yik Ying Teo, Andrew P. Morris, Phoenix Kwan, Yvonne T. van der Schouw, Cheng Hu, Katharine R. Owen, Alisa K. Manning, Christopher J. Groves, Josée Dupuis, Ryan P. Welch, Loukas Moutsianas, Joshua D. Smith, Tanya M. Teslovich, Robert C. Onofrio, Maggie C.Y. Ng, Peter Donnelly, Tõnu Esko, Matt Neville, Bo Isomaa, Anne U. Jackson, Jette Bork-Jensen, Barry I. Freedman, Yi Chen, Danish Saleheen, Lu Qi, Laura J. Scott, Jasmina Kravic, Paul Elliott, Mette Hollensted, Carmen Navarro, Selyeong Lee, Benjamin Lehne, Thomas Illig, Nancy J. Cox, Jonathan C. Levy, George B. Grant, John C. Chambers, Adam S. Butterworth, Ronald C.W. Ma, Teresa Ferreira, John R. B. Perry, Eleftheria Zeggini, Hyun Min Kang, Loic Yengo, Eric Banks, Jae-Hoon Lee, Anna L. Gloyn, Christopher Hartl, Wei Zhao, Andres Metspalu, Keng-Han Lin, Graeme I. Bell, Jason Flannick, Torben Jørgensen, Thomas W. Blackwell, Heather M. Stringham, Olle Melander, Omri Gottesman, Other departments, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), Massachusetts Institute of Technology. Department of Biology, Altshuler, David M, Internal Medicine, Perry, John [0000-0001-6483-3771], Butterworth, Adam [0000-0002-6915-9015], Howson, Joanna [0000-0001-7618-0050], Danesh, John [0000-0003-1158-6791], Johnson, Kathleen [0000-0002-6823-3252], O'Rahilly, Stephen [0000-0003-2199-4449], Langenberg, Claudia [0000-0002-5017-7344], Sandhu, Manjinder [0000-0002-2725-142X], Barroso, Ines [0000-0001-5800-4520], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, PROTEIN INTERACTION NETWORKS, SUSCEPTIBILITY LOCI, Genotyping Techniques, General Science & Technology, DNA Mutational Analysis, SEQUENCING ASSOCIATION, 030209 endocrinology & metabolism, Genome-wide association study, Biology, Research Support, N.I.H, 03 medical and health sciences, 0302 clinical medicine, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, MD Multidisciplinary, Genetic predisposition, Journal Article, Humans, Exome, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Non-U.S. Gov't, Exome sequencing, Alleles, Genetic association, Genetics, RISK, Multidisciplinary, HERITABILITY, Research Support, Non-U.S. Gov't, COMPLEX TRAITS, Extramural, Genetic Variation, Genetic architecture, HUMAN-DISEASE, Europe, 030104 developmental biology, Diabetes Mellitus, Type 2, RARE VARIANTS, Sample Size, LOW-FREQUENCY, Imputation (genetics), Common disease-common variant, Genome-Wide Association Study
Abstract: The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
Published: 2016

16. Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: an overview of the data from the epidemiological studies within the IMI DIRECT Consortium

Author: Philippe Froguel, Anubha Mahajan, Simone P. Rauh, Maritta Siloaho, Henrik Vestergaard, Mandy H Perry, Adem Y. Dawed, Jochen M. Schwenk, Imre Pavo, Torben Hansen, Mark Walker, Ian M Forgie, Timothy J. McDonald, Jimmy D. Bell, Anitra D.M. Koopman, E. Louise Thomas, Azra Kurbasic, Kristine H. Allin, Christopher J. Groves, Giuseppe N. Giordano, Bernd Jablonka, Ramneek Gupta, Tarja Kokkola, Andrew T. Hattersley, Femke Rutters, Caroline Brorsson, Paul W. Franks, Emmanouil T. Dermitzakis, Jerzy Adamski, Robert W. Koivula, Mark I. McCarthy, Hartmut Ruetten, Tue H. Hansen, Thomas E. White, Harriet Teare, Ana Viñuela, Michelle Hudson, Jacqueline M. Dekker, Andrea Tura, Ewan R. Pearson, Oluf Pedersen, Andrea Mari, Gary Frost, Federico De Masi, Alison Heggie, Markku Laakso, Soren Brage, Søren Brunak, and Martin Ridderstråle
Subjects: 0303 health sciences, medicine.medical_specialty, business.industry, 030209 endocrinology & metabolism, Type 2 diabetes, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Cohort, medicine, media_common.cataloged_instance, Blood sugar regulation, Prediabetes, European union, business, Prospective cohort study, 030304 developmental biology, media_common, Cohort study
Abstract: /SummaryBackground and aims:Understanding the aetiology, clinical presentation and prognosis of type 2 diabetes (T2D) and optimizing its treatment might be facilitated by biomarkers that help predict a person’s susceptibility to the risk factors that cause diabetes or its complications, or response to treatment. The IMI DIRECT (Diabetes Research on Patient Stratification) Study is a European Union (EU) Innovative Medicines Initiative (IMI) project that seeks to test these hypotheses in two recently established epidemiological cohorts. Here, we describe the characteristics of these cohorts at baseline and at the first main follow-up examination (18-months).Materials and methods:From a sampling-frame of 24,682 European-ancestry adults in whom detailed health information was available, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm and enrolled into a prospective cohort study (n=2127) undertaken at four study centres across Europe (Cohort 1: prediabetes). We also recruited people from clinical registries with recently diagnosed T2D (n=789) into a second cohort study (Cohort 2: diabetes). The two cohorts were studied in parallel with matched protocols. Endogenous insulin secretion and insulin sensitivity were modelled from frequently sampled 75g oral glucose tolerance (OGTT) in Cohort 1 and with mixed-meal tolerance tests (MMTT) in Cohort 2. Additional metabolic biochemistry was determined using blood samples taken when fasted and during the tolerance tests. Body composition was assessed using MRI and lifestyle measures through self-report and objective methods.Results:Using ADA-2011 glycaemic categories, 33% (n=693) of Cohort 1 (prediabetes) had normal glucose regulation (NGR), and 67% (n=1419) had impaired glucose regulation (IGR). 76% of the cohort was male, age=62(6.2) years; BMI=27.9(4.0) kg/m2; fasting glucose=5.7(0.6) mmol/l; 2-hr glucose=5.9(1.6) mmol/l [mean(SD)]. At follow-up, 18.6(1.4) months after baseline, fasting glucose=5.8(0.6) mmol/l; 2-hr OGTT glucose=6.1(1.7) mmol/l [mean(SD)]. In Cohort 2 (diabetes): 65% (n=508) were lifestyle treated (LS) and 35% (n=271) were lifestyle + metformin treated (LS+MET). 58% of the cohort was male, age=62(8.1) years; BMI=30.5(5.0) kg/m2; fasting glucose=7.2(1.4)mmol/l; 2-hr glucose=8.6(2.8) mmol/l [mean(SD)]. At follow-up, 18.2(0.6) months after baseline, fasting glucose=7.8(1.8) mmol/l; 2-hr MMTT glucose=9.5(3.3) mmol/l [mean(SD)].Conclusion:The epidemiological IMI DIRECT cohorts are the most intensely characterised prospective studies of glycaemic deterioration to date. Data from these cohorts help illustrate the heterogeneous characteristics of people at risk of or with T2D, highlighting the rationale for biomarker stratification of the disease - the primary objective of the IMI DIRECT consortium.Abbreviations:ASATAbdominal subcutaneous adipose tissueDIRECTDiabetes Research on Patient StratificationEUEuropean UnionMMTTMixed-meal tolerance testMRIMagnetic resonance imaginghpfVMHigh-pass filtered vector magnitudeIAATIntra-abdominal adipose tissueIGRImpaired glucose regulationIMIInnovative Medicines InitiativeMEmultiechoNGRNormal glucose regulationOGTTOral glucose tolerance testPAPhysical activityTAATTotal abdominal adipose tissueT2DType 2 Diabetes
Published: 2018
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17. Cancelled operations: a 7-day cohort study of planned adult inpatient surgery in 245 UK National Health Service hospitals

Author: Jennifer Morrish, Emily J Robson, Georgina Ashfield, Karuna Kotur, Jashmin Maria, Charlotte Downes, Shweta Patro, Mark Scrutton, George Gladstone, Andy Burton, Paula Mulligan, Wei Lin Allen, Michael McCusker, Dee Leonard, James Edwards, Sarah Dolling, Katherine Pass, Hywel Garrard, Francis Young, Paul Edgar, Elaine Matthews, Douglas Findlay, Helen Whittle, Aillison MacLean, Chris Levett, Claire-Marie Agius, Kim Porter, Nurse Charlotte White, Bridget Campbell, Gemma Scotland, Patrick Haywood, Liz Shenton, Tom Hatton, Laura McAffrey, Jane Hunt, Jaime Carungcong, Sara Owen, Fiona Christie, Lesley Milne, Liza Tharakan, Ruth Smith, Henry Nash, Timothy Gould, Jodie Fitzgerald, Wael Zghaibe, Mark Gaskell, Dushyanthi Jayasekera, Elana Owen, Kinga Dwornik, Amr Ali, Donna Cotterill, Martyn Cain, Peter Wicks, Daniel West, Catriona Walker, Rebecca Lee, Amanda Isaac, Naresh Rajasekar, Sally Collins, Laura Hammon, Tim Hendra, Yemi Adelaja, Mike Pollard, Ellen L. Brown, Matt Clayton, Rachel Bown, Sally Moore, Keyury Desai, Tony Kinsey, Charlotte Dunn, Li Lian Loh, Emelia Passaro, Timothy Faccini, Stephen Linter, Sumant Shanbhag, David Lee, David Restall, Angela Cook, Simon Ripoll, Rachael Bird, Vicky Murray, Alex Wollaston, Daniel Yarwood, Sonia Bhangu, Sahar Biuk, Jenny Ferry, Alexander Michael Stewart, Ceri Lynch, Lucy Sheppard, Denise Webster, Jamie Allen, Merle Cohen, James Hanison, Shilpa Rawat, Prabhakaran Premraj, Gamunu Ratnayake, Clare Bird, Lorna Filby, Clare Allcock, Babak Sedghi, Celly Weegenaar, Dawn Collier, Sreekanth Rayalu Uppugonduri, Amanda Whileman, Su Ying Ong, Jack Carmichael, Victoria O'Loughlin, Barbara Linklater-Jones, Maria Lackmann, Vitul Manhas, Albert Brennan, Alasdair Waite, Andrew Smallwood, Salvatore Bruni, Catriona Barr, Thomas Murphy, Gemma Hudson, Khalid Hasan, Alison J. Campbell, Radu Chiravasuta, Charlotte Maden, Roddy Chapman, Jon Clark, Nauman Iftikhar, Sarah Hagyard, Denis O'Leary, Steven Forde, Joanne Webb, Ryan W Haines, Andrea Galloway, Richard Siviter, Heidi Lightfoot, Hew D.T. Torrance, Christopher Smith, Hollie Robinson-Perrie, Josh Wall, Carina Cruz, Andrew Song, Stephen T. Webb, Nurse Sara-Beth Sutherland, Carol-Ann Woolley, Susan Martin, S.L.M. Walker, George Koshy, Renee Ford, Mona Mubarak, Robert Stuart, Keshava Reddy Burijinti Chenna, Rizana Ghafoor, Katie Hanlon, Fiona Faulds, Hiba Khaled, Richard Jones, Karin Duckett, Cathryn Matthews, Charles Chan, Sanjeewa Ranaweera, Nurse Rebecca Hinch, Richard Shawyer, Jo Cudlip, Marion Ashe, Steve Harris, Ravi K. Alagar, Jonathan Hetherington, Sara Churchill, Yolanda Baird, Maria Tritean, Gabriela Wong, Dermot Moloney, Lee Tbaily, Jonathan Finnity, Norbert Bokor, Peter Indoe, Lucy Stelfox, Simon Marcus, Bryony Burrill, Ellie Roderick, Carina Lilley, Alex Yusaf, Lucy Corbett, Esther Neilly, Christine Ryan, Amon Wijunamai, Katie Atterbury, Abigail Clarke, Josh Patch, Otto Mohr, Ronan Mukherjee, Asokan Krishnaier, Chen Yun-Han, Prasan Panagoda, Polly Rice, Katherine Jones, James Hudson, Sophie Uren, Peter Sutton, Evangelia Poimenidi, Tracy Marsden, Veronica Barnes, Alice Drysdale, Tara Lawrence, Lisa Sharpe, John G. Francis, N. M. Wharton, Claire Kurasz, Marina Iaverdino, Caradog Thomas, Emma Gold, Raj McNab, Tom E.F. Abbott, Claire Dowse, Jane Hamilton, Tony Sutherland, Robert P. Jones, Peter Alston, Daniel Haslam, Philippa Marshall, Bernadette Tilley, Cathleen Chabo, Adam Carpenter, Steve Cole, Nicholas Hooper, Kate Arrow, Alka Shah, Rosie Furness, Susie Chapman, Sachini Dhamaratne, Constandinos Papageorgiou, Michael Girgis, Sandra Pearson, Andrew W. Wood, Jaya Nariani, Sonia White, Christopher Godden, Mary Bellamy, Indra Chadbourn, Laura Parker, Peter Knowlden, Cat Griffiths, Jeanette Smith, David Brooks, Jonathan Smith-Williams, Elizabeth Barnes, Sunil Jamadarkhana, Andrew Feneley, Maria Croft, Tom Disney, Paramesh Kumara, Anna Warrington, Seetal Aggarwal, Zackriah Badsha, Suman Biswas, Suzanne Shuttleworth, Ben Jones, Jose Lourtie, Mark Stubbington, Asya Mussad, Patrick Johnson, Sister Amanda Cowton, James Spargo, Kelly Hard, Annette Fraine, William Weston, Farrukh Ameer, Andrew Prenter, Lisa Bacon, Sunil kumar Chaurasia, Claire Nicholas, Amy Kitching, Sneha Prasad, Catriona Ferguson, Martin P. Huntley, Claire Cameron, Hugh Cutler, Anne Harrison, Kunal Joshi, Anna Cormack, Rebecca Jones, Martin Paul, Jean Bage, Stephen Cole, Usman Razaque, Robert Lewis, David O'Callaghan, Samantha Strong, Victoria Frost, Peter Ip, Victoria Male, Mat Molyneux, Christopher Worth, Michael Brett, Megan Smith, Shayan Arshed, Timothy McMillan, Lorri James, Frances Lay, Jennifer Bennett-Britton, Patrick Colhoun, Alison Shaw, Michael Stewart, Maie Templeton, Karin Gupwell, Mujeeb Khan, Elena Stanton, Chandini Chuni, Janette Brown, Mariam Latif, Rebecca L. Wilson, Felix Fombon, Jo Novaga, Cindy Persad, Matthew Thomas, Maryna Garmash, Metod Oblak, Sarah Maher, Rahul Muddanyake, Morgan Foster, Kris Parker, Tim Sutton, Ndi Ekwere, Samuel Armanious, Mohammad Bhatti, Steve Phillips, Maria Rivero-Bosch, Nick Spittle, David Harding, Henry Hammerbeck, Rose Buckley, Jonathan Hatton, Ahmed Gilani, Ali Watts, Neeraj Bhardwaj, Lesley McShane, Simon Ridler, Martin Murphy, Vandana Goel, S Ramani Moonesinghe, Sophie Scutt, Sanniah Hussain, Hannah Donaldson, Tom Bennett, Helen Boys, David Steven Davies, Bev Hammond, Bryan Yates, Victoria Hawley, Chris Gibb, Ulrika Winstone, Keith Couper, Benedict Williams, Louise Duncan, Georgina Wilson, Anil Hormis, Emily Dana, Jens Full, Amina Chohan, Amanda Ebejer, Sian McKillop, Tomas Bakonyi, Georgina Bird, George Davies, Christina Penny, Helen Thornley, Karen Jewers, Kingsin Ang, Mishell Cunningham, Conny Blunt, Ronald Carrera, Kay Finney, Alvin Soosay, Nagaraj Rao, Jason Mann, Carol Edwards, Richard Lowe, Paul Stevens, Hilary Ashton, Rachel Codling, Rhys Davies, Muthuraj Kanakaraj, Zoe Apple, Kirsty Meats, Tammy Smith, Charmaine Beirnes, John Gardner, Peter Featherstone, Claire Williams, Rohit Mittal, Emma Shinn, Alex Moore, Michael Whitear, Hannah Rose, Paul Kelly, Megan Thomas, Matthew Gibbins, Jack Reid, Caroline Clarke, Victoria Irvine, Bhavesh Pratap, Ella Buchanan, Nurse Francesca Wright, Vatsharlan Santhirapala, Richard Gould, Dionne Dervin, Behzad Sohail, Lauren Duraman, Thecla Scully, Adnaan Qureshi, Muditha Peiris, Thomas Ratcliffe-Law, Samuel J. Clark, Ben Vowles, Sam Keable, Hoda Abou Ghoneim, Becky Morris, Aidan Hulbert, Rachael Craven, Ashish Kundu, Emma M. Casely, Maya Kommer, Tom Poulton, Greg Nussbaum, Ahmad Huda, Caroline Davis, Suzanne Gleeson, Paul Clements, Matt Willis, Isobel Amey, David J. Perry, Rachel Harford, Bianca Hulance, Kirsty Baron, Charlotte Grove, Sergio Dominguez, Susanna Richie-Mclean, John Stones, Ioana Simionescu, Khaled Razouk, Cristina Niciu, Ben Hyams, Mark Doran, Carolyn Colvin, Jonathan Rivers, Raluca Ene, Rebecca Jackson, Jonathan Edgar, Ben Robinson, Lisa Wilkinson-Guy, Aji Mathew, Christopher Patrick, Gauhar Sharih, Ismail Tariq, Andrea Kay, Joshua O'Donnell, Dafydd Watterson, Lail Zaheer, Fiona Reed, Tom Johnson, Christopher Oscier, Mirain Phillips, Edmund Gerrans, Joanna Hackney, Sally M. Dunlop, Elizabeth Willetts, Jiang Yuchen, Lizzie Ashton, Theresa Cooper, Paul W. Davies, Carly Brown, James Small, Julie Lowe, Amarjeet Patil, Filipe Helder, Joshua Cuddihy, Faisal Sheikh, Hayley Tarft, Enid Leung, Adrian Percuin, Paolo Mazzone, Rochelle Rhodes, Jane Pilsbury, Kerry Cullis, Peter Brook, Helen McNamara, Carin Swanevelder, Claire Frith, Adrian Clarke, Stuart Watson, Glenn Vetuz, Zoe Riddell, Drew Welch, Geoff Warnock, Lalani Induruwage, Paul Mallett, Elizabeth Cervi, Santinder Dalay, Supriya Antrolikar, Sinead O'Kane, Toby Hoskins, Stephen Duberley, Sophie Parcell, Jayne Sutherland, Lynn Fairless, Dave Parkinson, Matron Beryl Davis, Abigail Patrick, Jithu Jayan, Nicola Harvey, Catherine Pitman, Donata Banni, Samuel Passey, Omar Alex Pemberton, Becky Sands, Hon Sum Liu, Alexandra Mudd, Sheldon Zhang, Ange Lise John-Baptiste, Thomas Clayton, Charlotte Marriot, Tom Reevell, Nicola Mackenzie, Temitope Aiyedun, Andy Cruickshanks, Jacqueline Gunn, Alison Moss, Martyn Clark, Swetha Rambhatla, Claire Matata, Ben Cracknell, Pauline Mercer, Matthew Morgans, Catrin Williams, Shareef Madhi, Jane Montgomery, George Kohler, Yasir Hameed, Muneeba Ahmed, Glenn Saunders, Anand Kulkarni, Craig Pinner, Lauren Pearce, Vishnu Bhardwa, Judi Ramsey, Meghna Sharma, Rob Hull, Srinivasan Perumal, Julia Critchley, Stephen Hill, Bethany Fitzmaurice, Robert Crichton, Cormac O'Connor, M. Dickinson, Alison Pearce-Smith, Julie Toms, Kathleen Horan, Ammy Dodd, Rachel Crone, Graeme Finnie, Suman Shrestha, Saul Sundayi, Shamini Sivakumaran, Robert Collin, Janine Musselwhite, Yuvaraj Kummur, Mariana Bernardo, Amrinda Sayan, Gabrielle De Selincourt, Laura Bridge, Melissa Rosbergen, Philip Barclay, Garry Davenport, Daniel Murrell, Andrew Drummond, Eireann Allen, Emma Fadden, Subha Arunachalam, David Robinson, Stephanie Dukes, Catherine Jardine, Sunny Bhat, Hemantha Shiva, Amy Kerr, Henry Elms, Anam Asif, Sandra Evans, Girish Rangaswamy, Laura Thomson, Asad Javed, Jenny Shuttleworth Davies, Maren Kleine-Brueggeney, Sian Edwards, Jean-Paul Zahra, Jo simpson, Priya Verma, Bhamini Tharmalingam, Matthew Edmunds, Stephen Adshead, Hannah Luckhurst, Lara Allen, Colin Merrill, Fiona Lyle, Falguni Choksey, Mohyman El Habishi, Holly Notman, Lisa Murthen, Christiana Georgiou, Georgina Singleton, Tim Cook, Melba Knighton, Shirley Pyke, Amit Gadre, Maria Rehnstrom, Helen Hothersall, Anja Kuttler, Anita Boltres, Sarah Williams, Sarah Welch, Yamuna Madhu, Pramod Nalwaya, Alistair Coleman, Jeanie Worthington, Jasmine Samuel, Rajashekar Gowni, Karen Burt, Shamim Haque, Reynard Knoetze, Hakeem Yusuff, Tom Taylor, Val Parkinson, Sheik Pahary, Jonathan Fortune, Natalie Long, David Gilhooly, Karthick Duraisamy, Duncan Baines, Shondipon Laha, Marie Appleby, Jyothi Hosahalli, Christine Catley, Jasmine Jose, Damien Mantle, Dinkar Gowda, Permendra Singh, Ramesh Khoju, Carol Bradbury, Sarah Hazeldine, Karan Kanal, Sonal Lodhi, James Craig, Rachel Wong, Teresa Ferreira, Charis Banks, Ben Chandler, Asia Sarwar, Sivaprakash Vaitheeswaran, Sam Bews, Katie Hunter, Sohan Bisonoothan, Lauren Hunt, Melony Hayes, Nilesh Chauhan, Janet Pickett, Sharon Dealing, Jamie Plumb, Thomas Hollins, Claire Hill, Claire Hindmoor, Nicolas Hooker, Hannah Davis, Laura Mee, Elizabeth Thomas, James Self, Jenny May-Ling Cheung, Jane Varin, Manish Kakkar, Anuj Wali, Omar Siddique, Sophie Earl, Elizabeth Longdon, Alison Meadows, Shafi Ahmed, David MacPherson, Shaima Elnour, Suzi Hale, Ramez Ibrahim, Fei Long, Orlanda Allen, Alice Groves, Mohammed Wahid, Angela Stevens, Carl Ilyas, Richard Robley, Nichola Bleasby, Peter Havalda, Ursula McHugh, Judith Brade, Georgia Monantera, Stuart Younie, Brian Johnston, Jamie Brookes, Linda Park, Graeme Wilson, Mark Greasley, Lohita Nanda, Vineetha Jayakumar, Ian M. Lyons, Ayman Abdu, Paul Athanasopoulos, Justin Woods, Kariem El-Boghdadly, Diane Simpson, Georgina Williamson, Jonathan McCarter, Anil Golhar, Alicia Waite, Claire Halligan, Sarah Anne Leir, Joanne Turner, Matthew O'Meara, Claire Atkinson, Adam Yarnold, Mark Fernie, Rhiann Marie O'Shaughnessy, Jamie Elwood, Laura Harvey, Ali Atrah, Helen Terrett, Sam Scholes, Rebecca E. Saunders, Vin Vyapury, Amir Rafi, Peter Bradley, Srikant Ganesh, Zehrin Nassa, Ulf Buhmann, Laura Carrick, Natalie Rogers, Said Seifalan, Ian Ryder, Jennifer Partridge, Tim Lovell, Martin Priestley, Caroline Wrey Brown, Joanna Moore, Vidhya Nagaratnam, Saba Iqbal, Francesca Mazzola, Samantha Weller, Laura Gould, Helen Johnston, Jenny Spimpolo, Carmen Scott, Stephen J. Brett, Paul Cripps, Amit Kurani, Alexander Knight, Nirav Shah, Pushkar Patankar, Fraser Waterson, Sarah Martindale, Johannes Mellinghoff, Joanne Wootton, Sarah McCormick, Sameer Somanath, Bilal Yasin, Christopher Skeoch, Toby Jacobs, Katrina Eaton, Lynne Connell, Harry Soar, Yvonne Bramma, Tom Gately, Renjith Joseph, Anish Gupta, Lucie Hobson, Charindri Wariyapola, Maryam Zaky, Nimu Varsani, Gerhardus Van Rensberg, Jackie Evans, Rosahn Saleh, William Sutcliffe, Louise Potter, Harvey Dymond, Catherine (Katie) Patton, Andrew Selman, Stephen Traynor, Kate Tizzard, Rumyana Nyathi, Caroline Reavley, Saima Hashmi, Kerry Hughes, Isabelle Sykes, Kate Slade, Anne Troy, David Castillo, Jennifer Quinton, Anne Adams, Joanne Gresty, Stella Wright, Victoria Christenssen, Iain Mooney, Fiqry Fadhlillah, Seema Pai, Gabor Debreceni, Aleinmar Winthein, Denise Griffin, Hannah Beadle, Elisa Kam, Marie Williams, Helen Howes, Tariq Tabiner, Saxon Prentice, James Bedford, Emma Craig, Peter Standen, Stephen Petley, Janaki Pearson, Cheryl Marriott, Harry Barclay, Alexandra Matson, Michael P.W. Grocott, Alison Thorne, Joanne Humphreys, Vishal Patil, Nick Greenwood, Richard Wassall, S.K. Harris, Valpuri Luoma, Dancho Ignatov, Rebecca Fry, Anamika Sehgal, Antonio Paredes-Guerra, Manjula Yadagiri, Yuvraj Doriaswami, Benjamin O'Donovan, Adam Mounce, Stephanie Wright, Linda Webber, Tracy Hazelton, Ethan Bateson, Theresa Garrett, Chris Honstvet, John Scriven, Rahul Dimber, Phillip Lo, Jenny Stead, Catherine Plowright, Rachel Morris, Pallavbhai Desai, Nicola Johnson, Neil Muchatuta, Vijayakumar Gopal, Sherma Turner, Karina Fitzgibbon, John B. Davis, Sarah Patch, Erica Jolly, Rob Gregory, Christopher Lochrin, Geoffrey Ryder, Sam Michlig, Liana Zucco, Susan Nimmo, Jessica Whiston, Sarah Goellner, Rohan Babla, Deborah Skelton, Lucy Mcmanoman, Darcy Pearson, Diane Forrest, Sanjeev Garg, Joanne Bradley-Potts, Joel Perfitt, Danny J.N. Wong, Mike Weisz, Caroline Lowrie, Timothy Alce, Alice Michell, Charlotte Soulsby, Dominic Hayes, Arnab Mandal, Stephanie Ridgway, Angela Willberry, Alka Grover, Simran Minhas, Kerwei Tan, Sharon Jones, Sam Marcangelo, Ben Millette, Hilary Thatcher, Greg Foster, Krishna Balachandar, Megan McAtear, Richard Shellard, Chris Littler, Thunga Setty, Kavita Sasi-Kumar, Theodore Floyd, Duncan Adshead, Stephen Hickey, South Yorkshire Hospitals Audit, Amy Barker, Ewen Cameron, Dawn Trodd, Wendy Nichols, Beth Farr, Mike Salmon, Naomi Fleming, Umairali Ikram, Ben Straughan, Peter J O'Brien, Laura Purandare, Janine Thomas, Elizabeth Wood, Kate Bosworth, Stewart Mckie, Samantha Evans, Tamilselvan Rajamanickam, Srinivasan Dhileepan, Paul Hindmarch, Colin Bergin, Sange Mansoor, Lisa Armstrong, Nagendra Natarajan, Irmeet Banga, Fiona Osborne, Lynne Williams, Pieter Bothma, Jade Woolley, Joanne Finn, Bernd Oliver Rose, Shaman Jhanji, Bennur Katyayani, Gillian Robertson, Laura Bird, Pauline Fitzell, Sally Anne Smith, Serena Yen, Stuart Clelland, Thomas Urwin, Luff Delme, Rocio Ochoa Ferraro, Nurse Cheryl Padilla Harris, Asad Naqvi, Andy Cumpstey, Natalie C. Wood, Samar Al-Rawi, Pulak Padhi, Claire Botfield, Bhavesh Raithatha, Michael Briskoe, Jolyon Cohen, Ben Gibbison, John John, Stephen Washington, Jayne Foot, Karen Chadwick, Naomi Cochrane, Sophie Spencer, Alexandra Gatehouse, Susan Smolen, Aaron D'Sa, John Sturrock, Christopher P Bourdeaux, Kumud Bhandari, Neil Kellie, Elizabeth Denman, Samson Tou, Laura Kettley, Alex Eros, Stuart McLellan, Nicola Ball, Emily Kirk, Sue Smyth, Kim Gibson, Oliver Barker, Mohammad Masood, Dabeeruddeen Ahmed, Geoff Thorning, Jennifer Van Ross, Esme Elloway, Kat Rhead, Sei Nishimura, Maximiliane Kellner, Benjamin Jacobs, Sanjoy Shah, Matthew Stubbs, Faye Moore, Greg Cox, Nishita Patel, Ashok Nair, Elizabeth Hawes, A Espinosa, Kavita Wankhade, Vladimir Bashliyski, Carina Bautista, Susan Lyjko, Michelle Rowe, Nikita Whotton, Julie Temple, Inthu Kangesan, Gemma McIntosh, Samir Nazir, R. N. Kumar, Jen Warren, Alex Coombs, Marilyn Boampomaa, Kaya Jeyarajah, Heather Savill, Claudette Jones, Vinayak Vanjari, Caroline Tierney, Santhana Kannan, Jennifer Aston, Helen Melsom, Valantine Woodham, Nichola White, Niraj Barot, Paolo Perella, Mayumi Vianzon, Padmanabhan Vatsala, Claire Boynton, Alexandra Edwards, Elisa Masoni, Jayne Edwards, Julie Edwards, Thomas Garth, Amanda Skinner, Kate Blethyn, Jonathan Chambers, Katie Ramm, Rosada Jackson, Thomas Coleman, Tracey White, Emma McKenna, Kanchan Umbarje, Thomas Sheppard, Deepa Jumani, Emma Murphy, Peter Lawley, David Howe, Daisy Alston, Ania Dean, Prasun Mukerjee, Julian Hood, Mahmoud Alkholany, Sarah Goff, Gillian Rennie, Bridget Fuller, Ciara Walker, Jonathan Pipe, Alex Eeles, Wai Soon, Catherine McMillan, Martha Wrigley, Neil Brown, Peter Sandbach, Claire McCahill, Anna Wilson Charlotte Yates, Paul Sampson, Natasha Muzengi, Colum Slorach, Moyra Hynd, Arjun Ardeshna, Trish Boateng, James C. Geoghegan, Rhys Williams, Karoline Middleton, Brian Campbell, Srikanth Chukkambotla, Daniel Leslie, Sherrie Samuels, Michael Allan, Ruth Clarke, Christopher Nutt, Kirsten Reid, Hannah Smith, Surabhi Jain, Stephanie Reed, Hywel Evans, Irene Gardner, Ben Griffiths, Guy Shinner, Marek Frenkiel, Jacek Zeber, Gary Minto, Simon Parrington, Louise Harrison, Carlos Kidel, Hawa Desai, Lois Steuart, Claire Hirst, Johann Harten, Marc Slorach, Angela Christofides, Claire Macey, Helen Moore, Chantal Busby, Andrew Robertson, Leanne Milner, Catherine Chapman, Rebecca Reeves, Lawrence Wilson, Alice Aarvold, Lizzie Irvine, Narayanan Suresh, Kirsteen Brown, James Dalton, Sam Miller, Yasir Rashid, Andrew Swain, Liliana Czukowska, Natasha Permall, Carys Durie, Peter Carroll, Lauren Cooper, Prerna Mehrotra, Sarah Clayton, Martina McMonagle, Sarah Buckley, Enoch Onya, Elizabeth Perritt, Domonique Georgiou, Manjeet Save, Lauren Friedman, David W. Hewson, Katherine McAndrew, Simon Morton, James Morgan, Susan Underwood, Helen Bowyer, Avninder Chana, Lucy Sootheran, Kieron Rooney, Pooja Patel, Jessica Summers, Laura Farmer, Kiran Keshvara, Victoria Richardson, Hannah Crowther, Geejo Rappai, Adam E. Green, Sarah Willcock, Smitangshu Mukherjee, Samuel Tyrrell, Geraldine Landers, Claire McAteer, Jennifer Awolesi, Sarah Higgin, Orla O'Neill, Chrissie Chevis, Paul Winwright, Vikram Malhotra, Jonathan Ogor, Maria Muelmenstaedt, Richard Stead, Lindsay Roughley, Sara Balliston, Nevena Kalcheva, Marc Wittenberg, Adrian Taylor, Lydia Shatanda, Anjali Soodan, Angela Moon, Sarah Elgarf, Matthew Roche, Sanchita Bhatia, Clare Howcroft, Emma Butterfield, Emily Gannon, Matthew Needham, Jacqueline McCormick, Daniel Bendel, Victoria Martinson, David Hall, Richard A. Armstrong, Lara Herbert, Beverly Kilner, Kathy Dent, Victoria Thwaites, Issy Thomas, Maggie Peat, Lisa Macbeth, Alex James, Rachel Flight, Nick Black, Elizabeth Boyd, Catherine Gedling, Suzanne Body, Nadine Farrell, Samantha Clayton, Paula Hiltout, Richard Haddon, Bethany Philpott, Victoria A Burgess, John Jackson, Anita Patil, Chris Platt, Lindsey Iles, Chrissy Braybrook, Katherine Morris, Emma Karsten, Minna Meritahti, Anastasia Lynn-Smith, Dorothy Hutchinson, Rebecca Darbyshire, Joanne Riches, Astri Luoma, Andy Gibson, Dushanthi Thurairasa, Roisin Baker, Xantha Holmwood, Alda Remegoso, Trusha Mistry, Sarah Hennell, Suganthi Joachim, Stephen Harris, Sam Eggleston, Melanie Morrison, Boon Ang, Natalie Jackson, Nicola Jones, Zena Haslam, Beata Iwanicka, Laura Graham, King Dhar, Melanie Kent, Daniel Wirth, Umakanth Kempanna, Laura Troth, Robert Orme, D. Campbell, Raquel Duarte, Muzaffar Sheik, Robert Maher, Jon Bramall, Rebecca Coates, Tracey Cosier, Sarah Vest, Kajan Kamalanathan, Graeme Foggo, Amanda Mohabir, Ritoo Kapoor, Precious Basvi, Jamie McCanny, Christian Frey, Bruce Emerson, Anantharaman Venkataraman, Karen Burns, Gail Pottinger, Mohamed Elwkhiee, Farkhunda Waqas, Alison Loftus, Amanda Kirrage, Ilma Songaile, Craig Smith, Jo Mullender, Hannah McPhee, Miriam Namih, Linda Gregson, Rachel K. Walker, Iain K. Moppett, Christine Adamson, Katie Flower, Tina Stoycheva, Beena Parker, Caroline Thompson, Kootharajan Kamraj, Vignesh Ashok, Ranjit Gidda, Istvan Koczka, Sadie Perkin, Vandita Ralhan, Arun Sengottaiyans, Ruth Hodgson, Peter Valentine, David Nunn, John Hickman, Molly Waldron, Lauren Elliott, Irene Echaveznaguicni, Lisa Dunlop, Julian Sonksen, Robert Fallon, Huw Griffiths, Thoy Ruth, Olivia Clancy, Lucy Dudgeon, Alicia Rodgers, Pamela Oracki, Phoebe Syme, Maria Newton, Stuart P. D. Gill, Julie Foxton, Jane Perez, Liam Gleeson, Richard Green, Sally Beer, Rohit Juneja, Loretta Barnett, Alex Bonner, Eunice Emeakaroha, Andrew V. Bradley, Ravishankar Jakkala Saibaba, Dipali Verma, J. Joseph Kinsella, Swee Ang Tung, Anju Raina, Verity Calder, Andrea Ortu, Chris Walmsley, Suneal Sharma, Michelle Reichman, Tom Stocks, Annika Smith, Ross Cruikshank, Sharon Storton, Matyas Andorka, Abhishek Kakkar, Allison Daniels, Priya Datar, Nichola Wakeford, Sheila Black, Usman Choudhry, Stephen Hackett, Huw Wilkins, Kirtida Mukherjee, Tim Green, Rebecca Hill, Ishan Dharmarathna, Jennifer Crooks, Serah Mungai, Luisa Howlett, Niveen El-Wahab, Linda Prasad, Amy Sadler, David Sharpley, Daphne Varveris, Victoria Ashton, Rajeev Jeevananthan, Safia Begum, Helen Anderson, Katherine Nahajski, Vanessa Linnett, Laura Morland, Stephen Mowat, Nenette Abano, Kathryn James, Ian Butler, Madelaine Ocampo, D. Williams, Gabriella Frunza, Wendy Deamer, Dominic Espitalier-Noel, Sian Liddle, Jane McConniffe, Anthony E. Pickering, Lisha Aju, Catherine Morgan, Hao Ern Tan, Jemma Tate, Emma Dooks, Anna Moore, Alison Hardwick, Liam Scott, Zak Rob, Rajeev Jha, Sujesh Bansal, Lynda Connor, Seliat Sanusi, Sophie Mason, Nipun Agarwal, James Woodier, Julian Giles, Lauren Collis, Jill Brown, Natalie Constable, Nichola Cahill, Anne Cowley, Mai Wakatsuki, Kelly Mintrim, Glenn Arnold, Donna Doyle, Ryhs Millington, Richard Dobson, Monica Serrano, Saqib Naji, Walid Hammad, Jacob Osbourne-Wylde, David Rollins, Claudia Paoloni, Nathan Anderson, Rachel Ingham, Alison Whitcher, Vicky Hills, Nina Toms, Jon Witby, Amy Nash, Marcus Fletcher, Jane Gibson, Martin Warin, Katherine McDowall, William Malein, Madhurima Das, Wael Abdelrhamen, Tom Neal, Sister Jenny Ritzema, James Collins, Chandana Rao, Joyce Yeung, Nadeem Shakir, Andrea Weigert, Atideb Mitra, Hari Arunachalam, Amy Morgan, Richard J. Jackson, Julie Chadwick, Debbie Callaghan, Frank Swinton, Lorraine Lock, Rahul Wakhle, Krish Kapoor, Ryan Humphries, Sarah Beavis, John-Paul Cutts, Julie Wilson, Keith Kelly, James Gill, Angela Loughlin, Rhys Rhidian, Christopher McGovern, Tom Hickish, Rachel Campbell, James Pennington, James Tozer, Philip Coakley, Lynn Fenner, Sally Tomkins, Lester Ribeiro, Shabir Qadri, Hristina Petkova, Christina Timmons, Katy Smith, Jonathan Perry, Stephen Crotty, Tanmay Patil, Mayavan Abayalingam, Ahmed Foly, Anna Wahed, Lewys Winfield-Young, Naomi Goodwin, Mark Verlander, Clare Donovan, Milena Vannahme, David Helm, Murali Vallabhaneni, Clare Ingram, Neil Moreland, Lorraine Stephenson, Jenny Jackson, Lindsay McOwat, Sathya Visvendra, Rhiannon Jones, Sarah Bird, M. H. Nathanson, Beryl Jones, Claire Davies, Beena David, Ian Sheldrake, Jeremy Guilford, Sister Bryony Storey, Rajeev Mishra, Irina Halfacree, Kiran Rait, Sameer Ahmed, Victoria Poyntz, Pamela Birks, Tom Kennedy, Angiy Michael, Michael McEvoy, Ian Davies, James Chan, Sajjad Ahmed, Laura Sweeney, Anne Whaley, Andrew Moores, Stella Gillies, Gearoid Crosbie, Antoinette Wilson, Iain Walker, Fiona Brailsford, Virginia Solanki, Elizabeth Turnbull, Lyndon Harkett, Sarah Ramsay, Thomas Syratt, Pushpaj Gajendragadkar, Cathal Small, Joanna Poole, Annabelle Whapples, Raghavendran Krishnaiyan, Elizabeth Smee, Richard Pierson, Taslima Rabbi, Alexandra Murphy, Angela Rooney, Sarah Crawford, Peter Bamford, Stephen Worthy, Sarah Munsie, Lucy Venyo, Henry Wang, Aditya Kuravi, Dennis Barnes, Ruth Han, Benjamin Gupta, Nurse Lynn Wren, Robert Hartley, Emma Edmunds, Laura Blood, Valerie J. Page, Thomas Judd, Puvan Suppiah, Emma Jenkins, Kate Gallagher, Fionnuala Lenehen, Rashidat Adeniba, Julius Cranshaw, Julie Wollaston, Kathryn Allison, Richard Kirkdale, Samantha Griffith-Norris, Jenna Kelly, Snehasish Guha, Stefan Schraag, Joy Dearden, Elizabeth Bell, Stephen Smith, Sarah Longhurst, Elizabeth Wilby, Annaliza Sevillano, Raksha Mistry, Aalisha Mariam Karimi, Kaung Pyae, Sarang Puranik, Maggie Collingborn, Karen Cranmer, Chandrashekhar Vaidyanath, M. Chincholkar, Narendra Siddaiah, Gillian Bell, Edward Rintoul, Nicki Devooght-Johnson, Tom Lovejoy, Eleanor Roscoe, Zoe Neilson, Joanne Hill, Kamal Sharif, Sharon Meehan, Bassey Nkanang, Thomas Georgiou, Martin Goodman, Prashant Kakodkar, Rebecca Martin, Philip Roddam, Evanna McEvoy, Peter Tsim, Janakan Anandarajah, Shub Gupta, Oliver Pratt, Yang Ng, Francesca Th'ng, Linda Kent, Graham Soulsby, Danielle Kirk, Ramana Govindaraju, Rebecca McClean, Samantha Harkett, Obaid Tarin, Shalini Chinna, Susan Gallagher, Laura Gardiner, Marc Turnbull, James Briscoe, Anna McSkeane, Melanie Claridge, Gillian Fleming, Thomas Huttley, Elaine Spruce, Lianne Hufton, Susan Hendy, Adrian Barry, Jeremy Drake, Cody Allen, James Hillier, Manju Patel, C. Gray, Nasreen Iqbal, Karen Markwell, Linzi Heaton, Michelle Nicholas, Gary Lau, Laura Catchpole, Nurse Sonia Walia, Kerry Elliott, Jake Hartford-Beynon, Amee Samani, Kathryn King, José William Martínez, Skylar Paulich, Ifan Patchell, Killian McCourt, Rebekah Rodgers, Christine Wood, Richard Wan, Karan Verma, H. W. Cain, Eleonore Quinn, Lisa Richardson, Muhammad Usman Latif, Nicholas Hingley, Rajesh Gilla, Roopa McCrossan, Mayeth Recto, Russell Hedley, Lucy McClelland, Suzie Marriott, Deepak Seharawat, Gururaj Mudimadagu, Claire Jones, Michelle Yare, Sophia Henderson, Rupinder Kaur, Emily Spence, David Wright, Bhaskar Dutta, Tom Pettigrew, Vikki Atkinson, Lorna Sissons, Segun Oladele, Sue Thomas, Hani Ali, Rebecca Robson, David Buckley, Kevin Hamilton, Amanda Hall, Anaesthetic Audit, Anna Watkin, Donna Kelly, Graham White, Sarah Sanders, Henry Boyle, Joao Galente, Thomas Williams, Justin Ang, Sarah Horton, Abdelrahman Soliman, Vijay Jeganath, Kavita Upadhyaya, Plamen Stoyanov, Murray Geddes, Alan Pope, Khaled Ellisy, Thomas Walker, Emma Finlay, Penny Parsons, McDonald Mupudzi, Adam Duffen, James Goodwin, Rob Penson, Laura O'Sullivan, Vinesh Mistry, Ravindra Mallavalli, Krzysztos Guz, Deepti Bhuwanee, Eleanor Andrews, Justine Burns, Sarah Kirk, Faith Kibutu, Sam Stafford, Julia Blackburn, Joellene Mitchell, Robert Spencer, Helen Williams, Karen Riley, Gabbie Young, Tom Williams, James Wu, Emma Wheatley, Alistair Johnstone, Rachel Stoeter, Timothy Cominos, Guy Coady, Ruth Mawhinney, Sam Spinney, ruthy Arumugam, Myura Nagendram, Jason Lie, Sian Hughes, Linda Bairkdar, Peter Evans, Daniel Pygall, Graeme Brown, Susan Livingstone, Norbert Skarbit, Amit Pruthi, Zakaulla Belagodu, Ben Linton-Willoughby, Richard A Cowan, Helena Prady, Mike Raffles, Sonia Rasoli, Katherine Cullen, Jessica Lees, Peter Lax, Ashok Puttapa, Fran Millinchamp, Aneta Oborska, Benita Adams, Kathryn Newton, Mrutyunjaya Rao Rambhatla, Sunny Nayee, Madlena Ivanova Vrazhalska, Jonathan Clarke, Aariana Sohal, Siobhan King, James Bain, Jessica Wilson, Anthony Carver, Jack Davies, Lucy Connolly, Samuel Morrish, Robyn Lee, Lucia Stancombe, Satyanarayan Jakkampudi, Kath Rosedale, Philip Hopkins, Clovis Rau, Katherine Hunter, Amy Farrow, Kathleen Holding, Elizabeth Vassell, Oliver Boney, Julia Icke, Ewa Prusack, Osi Egole, Fiona Linton, Suresh Eapen, Wendy Goddard, Ayda Borjian Boroojeny, Simon J. Davies, Jackie Terry, Fiona Graham, Thomas Pratt, Hanzla Naeem, Viv Colclough, Yeng Yap, Tejuswi Patel, Susan Midgley, Mark MacGregor, Ben Marshall, Talitha Devries, Cheng Ong, Katie Molloy, Kat Walker, Katy Irwin, Abbas Majeed, Mark Pinkerton, Nicki Russell, Sibtain Anwar, Ian A Jenkins, Lucy Allen, Elaine Coulborn, Ganesh Nair, Stewart Brown, Melissa Addy, Matt Milner, Amr Hassan, Victoria Millar, Sarah Turner, Gary Baigel, Amanda Lyle, Simon Young, Kathy Malinovszky, Heather Short, Mary Newmarch, Colin McAdam, Andrew Robert Bailey, Kevin Draper, Michael Agyemang, Kieran Oglesby, Clare Mewies, Ruth Ugochukwu, Shibu Jacob, Susan O'Connell, Charlotte Topham, Xiao Zhao, Shay Willoughby, Ossian Aukland Child, Manish Torne, Ben Wetherell, Divya Veluvolu, Dominic Wu, Elizabeth Evans, Daniel Eden, Suzannah Peggler, Lucy Emmett, Romit Samanta, Ravi Parekh, Jane Hermanowski, Will Shankey-Smith, Sam Papadopoullos, Julie Camsooksai, Sara Mistry, James Wigley, Anna Todd, Bally Purewal, Natalie Baldry, Kate Wilkinson, Aalia Sange, Kirsty Baillie, Joanne Topliffe, Denise McSorland, Saheli Das, Nikki Staines, Catherine Harris, Anna-Marie Boniface, Gemma Milne, Tessa Rowlands, Leanne Quinn, Svetlana Kulikouskaya, Christopher Bull, Angus Sutherland, Mihir Desai, Hannah Goodhand, Meenal Rana, John Bugo, Maria Chazapis, Sarah Kent, Sarah Siew, Marcin Pachucki, Tim Forsyth-Jones, John McKenna, Sarah Driscoll, Laura Hunter, Penny Bedoes, Natasha Santana-Vaz, Sandra Latham, Robert Coe, Sharon Christie, Lawrence R Kidd, Katy Redington, Alastair Sawyer, Abdalla Ali, Rekha Jayapal, Manfred Staber, Emma Pearson, Stuart Reilley, Tom Bird, Kristofor Inkpin, Annette Haines, Manish Verma, Naomi Wee, Ozerah Choudhry, Daniel Tucker, Euan Campbell, Aaron Stokes, Ashley Allan, Emma Reeves, Helen Fenner, Melanie Cockroft, Tom Nicholls, Sinan Bahlool, Sharon Drake, Nalini Sethia, Lesley Jordan, Martin Northey, Paul Glyn Jones, Lara Jeanes, Emma Simpson, Julia Brown, Samantha Coetzee, James Nicholas, Adam Samways, Ritesh Ganesh, Martin Ward Platt, Mizan Khondoker, Helen Wibberley, Lauren Simmonds, Sunita Agarwal, Linda Titinchi, Fran O'Higgins, David Pritchard, Laura Beard, Yvonne Lester, Charlotte Hirst, Louise Wills, Kevin Windsor, Haren Jyothiraj, Carmela Martella, Stephanie Bell, Christopher Nwaefulu, Hemamangala Venkatesh, Camilla Stagg, Soumi Ghosh, Thomas Dawes, Jennifer Lockhart, Stavros Papadopoulos, Nanci Doyle, Gillian Whalley, Rachael Britton, James Goddin, Maggie Dawson, Carole Holder, Elaine Morsman, Rachel Lovatt, Venu Mehta, John J.B. Allen, Anna Perham, Stephanie Wallis, Dmitry Zabauski, Peter Hart, Tracy Sharp, Martin Pope, Jo Knight, Jane Wright, Nageena Hussain, Josie Snell, Thomas Knight, Philippa Hill, Nic Martins, Robin Williams, Beverley Stidolph, Beth Peers, Brian Lafferty, Alicja A'Court, Joanna Collins, Charlie Kennedy, Andy Bates, Graham Walkden, Mia Marsden, Lauren Shillito, Poonam Bopanna, Raheel Ahmed, Ada Ezihe-Ejiofor, Kate Driver, Mevan Gooneratne, Carolyn Smith, Caroline Abernethy, Kathy Shammas, Chanice Alcock, Yin Yong Choo, Mark Vertue, Ratna Makker, Victoria C. Smith, Sachin Mehta, Clare Denford, Wint Mon, Jose Miguel Sabugueiro, Liz Varghese, Mohamed Ahmed, Rebekah Chan, Alexandra Williams, Stephanie Pauling, Maria Faulkner, Ryan Wilkins, Sara Stevenson, Kathryn Simpson, Moiz Alibhai, Patricia Williams, Pascal Defeyter, Siva Sangaralingham, Lucy Evans, Shirley Cocks, Simon Dyer, William Rea, Caroline Renton, Karl Braid, Ranjit Bains, Holly Owen, Sue Brixey, Calum Taylor, Laura Coleman, Andrew Peeling, Daniel Solomon, Christopher Perman, Roisin McCallum, Helen Church, Martin Watson, Amy Bamford, Elizabeth Bradshaw, Elizabeth Turner, Owen Vale, Suneetha Ramani Moonesinghe, Preeti Mahidik, Lynsey Cubitt, Catherine Hunter, Eleanor Warwick, Sam McAleer, Suresh Singaravelu, James Hilton, Rebecca Aspinall, Icel Souleimanova, Muna Elsheikh Idris, Wei Teo, Sarah El-Sheika, Adrienne Stewart, Sadia Habib, Emily Wade, Liesl Despy, Sharmin Shohelly, Colin Williams, Louise Shaw, Shree Voralia, Dafydd Lloyd, Barbara A. Crooks, Laura D Howe, Una Gunter, Edward Hare, Louise Nimako, Ruth Young, Helen Doherty, Sock Huang Koh, Stephen Merron, Martina Coulding, Agilan Kaliappan, Clare Bolton-Hill, Jill Wain, Maria O'Callaghan, Catherine Cartmell, Nicola Pemberton, Hannah Bennett, Lynda Garcia, Riquella Abbott, Sally Jeffrey, Thomas McLoughlin, Andrew Gratrix, Christopher Harrison, Matt Mackenzie, Jayshree Gracey, Chris Moore, Benjamin Parsons, Nehal Patel, Stephanie Brooks, Catherine Riley, Jemma Gilmore, Ilya Kantsedikas, Simon Whiteley, Emily Pallister, Angie Organ, Yohinee Rajendran, Gopinath Selvraj, Priya Thorat, Ilona Schmidt, Pauline Austin, Nitin Madhukar Sadavarte, James Haddock, Alastair Duncan, Richard Bateman, Elaine Chinery, Martin Gray, Felicity Corcoran, Shanelle Tharuka Wijesuria, Bryany Bond, Charlene Otieno, Sion Lewis, Cieron Roe, Dan Freshwater-Turner, Annette Bolger, Sarah Steynberg, Louie Saclot, Charlotte Busby, Jack Roberts, Richard Dagnan, Jasna Comara, Krishnakar Melachuri, Sian Gibson, Joanne Taylor, Manju Agarwal, Mark Sheils, Matthew Bell, Rosemary Anna Lewis, Kiran Patel, Mansoor Siddiqui, Christopher J. Groves, Mini Thankachen, Sharon Turney, Viral Dalal, Pele Banugo, Andrew Baird, Euan Kerr, Simon Tomlins, Laura Osbourne, Nicola Pattison, Stuart Joy, Susan Merotra, Lorna Ryan, Lisa-Jayne Cottam, Chye Siaw, Keelan Jerram, Nurse Diane Scarletta, Carole Paley, Jennie Smith, Will Gatfield, Stephen Alderson, Claire Swarbrick, Amelia van Manen, Stephan Clements, Sophia Strong-Sheldrake, Jake Drinkwater, John McLenachan, Lucinda Williams, Dianne Heaton, Sandor Orosz, Chloe O'Hara, Nina Barratt, Justine Elliot, Michael Gardner, Nicola Crowther, Bharati Rajdev, Linda Hall, Youssef Girgis, Michael Kinsella, Alison Potter, Matthew Martin, Rosie Reece-Anthony, Richard Pugh, Tracey Taylor, Esme Marshall, Wendy Stoker, Helen Worrell, Kay Housley, Rebecca Leslie, Helen Jewitt, Sandeep Sharma, Maire Gallagher, Jon Fenn, Jade Harrison, Hannah Watson, Natalie Morris, Lewis Schofield, Nisha Pattni, Charlotte Thomas, Eleanor Walshe, Richard Snooks, Ruth Murphy, Emily Pickford, Gnanshree Krishnamurthy, Donna McIntosh, Rachel Dolan, Emma Stoddard, Kelly Goffin, Shady Elhallous, Adrian Butler, Ildiko Nemeth, Hannah Wilson, James Sylvester, Melanie Sahni, James Wardlow, Ann Lachana, Emma Barr, Kayleigh Gilbert, Yazzim Hammoud, Peter Csabi, Maqsood Bajwa, James D Turner, Alex Hunt, Samantha Moore, Stephanie Hii, Philip Atkinson, Michelle Walter, Elizabeth Bailey, Frances Tait, Annie Newby, Jane Martin, Greg Forshaw, Bert Quartermain, Sally Humphreys, Aoife Hegarty, Caroline Bennett, Satyajeet Ghatge, Charles Prior, Kribashnie Nundlall, Priaykam Chowdhury, Jill Fitchett, Daiva Bernotaitis, Sandeep Varma, Alex Dunn, Rebecca Dooley, Mahamed Mostafa, Shelly Wood, James Humphreys, Anna Celnik, John Bailes, Mark Snazelle, Christina McCarroll, Matthew Govier, Emert White, Matthew Taylor, Alastair Rose, Brigid Hairsine, Natalie Whybro, Allen George, Robin Wilson, Filipe Vieira, Leon Cohen, Jonathan Womack, Thomas Woodward, Nimali Lochanie, Ben Howes, Joshua Nelson, Preea Gill, Gayle Clifford, Lushani Suntharanathan, Duncan Wagstaff, Steve Pryn, Lalindra Bandara, Sneh Shah, Nowfal Rahman, Iolo Roberts, Mirriam Sangombe, Shaik Subhani, Hannah Phelan, William Udall, Katy Allan, Nicola Zondo, Tim J Peters, James Roe, Catherine Addleton, Angus McKnight, James McCaul, Flora Kormendy, Anil Rao, Luke Vamplew, Andrew Rees, Jeanette Gilbert, Mandy Austin, Thomas Hunt, Sian Birch, Catherine Lloyd, Stewart D'Sylva, Jill Smith, Wendy Lum Hee, Michael Munro, Jean Denton, Julia Hindle, Alice Brown, Ursula Kirwan, Dinithi Yogya, Maria Mclaughlin, Nurse Louise Moran, Larysa Duniec, Sophie Benoliel, Gail Evans, Linda Bailey, Colin Hall, Katie Rowland, Krupali Patel, Ashwini Keshkamat, Zorba Begum, Resti Varquez, Victoria Apps, Giles Bond-Smith, Shirin Dastur, Andy Chapman, Amy Smith, Sarada Gurung, Ruth Delascasas, Nicole Issit, Pauline Sibley, Jaina Parmar, George Madden, Eveliina Nurmi, Katja van de Snepscheut-Jones, Louise Peacock, Vanja Srbljak, Kellie Allen, Andy Chamberlain, Suhail Zaidi, Andrew Boyle, Daniel Stolady, Rita Saha, Mark Clayton, Mitul Patel, Emily King, Hannah Oliver, Ewa Werpachowska, Holly Coles, John Dereix, Agnieszka Kubisz-Pudelko, Clare Watkinson, David Rogerson, Laurence Inman, Jaspreet Rayet, Jenny Finch, Emma Stewart, K. E. Wilson, Emma Tyson, Asif Gani, Reni Jacob, Neil Smith, Johnny Holland, Max Richardson, Mark Chen, Richard George, Helen Laycock, Anoushka Winton, Emily Hignell, Li Fang, Emma Welfare, Rochelle Velho, Fayaz Baba, Finbar O'Sullivan, Lisa Zeidan, N. Beauchamp, Neil Rasburn, Guy Rousseau, Victoria Roberts, Hollie Bancroft, Holly Maguire, Mechele Couch-Upite, Rahul Kumar, Chandra Bhimarasetty, Matt Lovell, Sujata Anipindi, Charlotte Small, Matthew Faulds, Alex Mattin, Alice O'Donnell, James Jack, Richard Boulding, Tarek Mostafa, Rhian Bull, Corinne Pawley, Ruth Killen, Jessica Lowe, Frances Taylor, Ethel Black, Michael F. M. James, Jenny Child, Lisa Emery, Kim Hoyland, David Hay, Janet Cotta, Josephine Stewart, Sue Spearritt, Laura MacNally, Fatma Lahloub, Katie Welham, Sanjoy Bhattacharyya, Shanteela McCooty, Heena Bidd, Hugo Buckley, Ervin Shpuza, Zaid Ahmed, Emily Craven, Amanda Cook, Caroline Dixon, Tara Pauley, Tariq Azad, Helena Barcraft-Barnes, Sindy Lee, Kate Penhaligon, Bernice Dudkowsky, Karen Ellis, Laura Montague, Ching Pang, Elsie Bickmore, Veronica Marsh, Toby Winterbottom, Marta Campbell, Rhys Hughes, Issie Gardner, Elizabeth Steel, Ramai Santhirapala, Katie Sweet, Michelle Scott, John Ekpa, Bhavia Janardhana, Catriona Frankling, Julia Ottaway, Alexander Middleditch, Elna Cifre, Annabel Pearson, Amanda Cotterill, Sarah Raut, Hannah Blanshard, Sara Eddy, Garry Henry, Elizabeth Hood, Maria Loy, Matthew Campbell, Marc Gimenez, Jessica Thrush, Jeremy Henning, Vlad Kushakavsky, Nikolaos Makris, Deborah Fradkin, Karen Fan, Fiona Hammonds, Kathryn Jackson, John Hadfield, Pyda Venkatesh, David Read, Daniel Zeinali, Ryan Hynd, James Carvell, Richard McCormick, Emily Dodds, Sana Rizvi, Amelia Daniel, Dan Sellers, Thomas E. Miller, Daniel Haigh, Nicky Moss, Patrick Dill-Russell, Priya Shekar, Teresa Melody, Randeep Dhaliwal, Nigel Hollister, Andrew Burtenshaw, Adrian Wagstaff, Ben Scoones, Eduardo Osorio, Joanna Allison, Lucy Willsher, Carol McArthur, Stephan Dalchow, Elaine Winkley, Eleanor Reeves, Ben Eden Green, Andrea Ingham, Mohammad Auldin, Freda Amoakwa-Adu, Jonathan Adams, Fiona Oglesby, Charlotte Steeds, Nurse Sara Greig, Obla Suganthi, Puja Chhaniyara, Clare De'Ath, Chandrakant Gosavi, Bart Ordys, Adele Flowerdew, Doug Tunney, Rachel Alexander, Oliver Griffith, Thomas Saunders, Matthew Maton-Howarth, Gabi Metiu, Akmal Shakoor, Elizabeth Willard, Katherine Russell, Matthew Robinson, Emma O'Kane, Meera Raja, Phillippa Falkner, Kerry Colling, Natasha Joshi, Laura Pearse, Tim J. Smith, Anitha James, Mona Mohamed, Richard Kennedy, Samson Ma, Tasmeen Ghafoor, Matthew N. Davies, Henry Lewith, Samuel Mindel, Sarah-Jane Dunn, Hemangini Barot, Sadie Diamond-Fox, Jenny Macallan, Arun Menon, Helen Farrah, Emma Plunkett, Brendon Spooner, Sorana White, Katie Samuel, David Crabtree, Katherine Cheshire, Gareth Harrop, Dionne Wortley, Tim Warrener, Joanne Mullen, Peter Taysum, John Whitaker, Kathy Wilkinson, Jean Dent, Nicola Farmer, Thelma Darian, Guru Hosdurga, Phillipa Wakefield, Christopher W Horner, Julie Steen, Elena Teh, Helen Gerrish, Betty Travasso, Mhairi Jhugursing, Michelle Gardener, Alexandra Crook, Edward W. Miles, Patricia Doble, Ashok Raj, Hanna Wong, Kay Protheroe, Chiraag Talati, Banher Sandhu, Cara Marshall, Matt Holl, Julie Sheriff, Frances Forrest, Adam Mitchell, Hindusha Keerthikumar, Mohamad Mahmoud, Simon Ben-Nathan, Janice Hartley, Danielle Ormandy, Hayleigh Morris, Steven Tran, Imogen Hayes, Trudy Smith, Kirsty Duell, Jennifer Cunningham, Richard Appleton, Lucy Pippard, Debroah Beeby, Hayley Bridger, Manuel Pinto, Susan Beames, Huiqi Wang, Cain Hunter, Flora Darch, Debbie Weller, Jonathan Hulme, Jacqueline Howes, Michael Kriger, Badrinath Manikundalam, D.J.N. Wong, Tim Arnold, Belinda Wroath, Rachel McKendry, Harry Knight, Caroline Bushell, Victoria Siddons, Louise Humphries, Joanne Vere, Vinanti Cherian, Janine Birch, Kate Blyth, Tatyana Bolonenkova, Meredith Harris, Alice Sisson, Sarah Clark, Sandeep Saxena, Samira Green, Amit Ranjan, Gillian Bennett, Chris Smales, Laura Ferguson, Ash Bharti, Francisca Mautadin, Katherine Brown, Lydia Jones, Christopher Adeney, Nikkita Carden, Sanjay Behl, Sonia Sathe, Elizabeth Neale, Helen French, Charlotte Mundy, Anna Batchelor, David Morris, Nithin Roy, Evelyn Philip, P.A.-A. Marc Hastie, Andrea Cole, Edmund Quak, Claire Totten, Karen McIntosh, Fiona Davis, Søren Kudsk-Iversen, Vanessa Unsworth, Andrew McIndoe, Jeremy Bewley, Sarbpreet Sarao, Laura Wood, Elaine Walker, Egidio Da Silva, Danielle Gilmour, Richard Yardley, Zara Eagle, Vijay Ragothaman, Sean Rayappu, Moira Tait, Alex Hamilton, Chris Gillett, Adeel Majeed, John Elton, Arlo Whitehouse, Fiona Robertson, Tim Martindale, Kin So, Kathryn Dixon, Toby Shipway, Fiona Mcneela, Simon Cousins, Brian Conway, Merate Place, Phil Duggleby, Rhian Morgan, Racquel Carpio, Carina Casey, Edward Mew, Jo Han Gan, Caroline Clark, Natasha Sharma, Kay Anne Mak, Gahan Bose, Chris Ford, Ruoling Yan, Anand Sathiapillai, Panagiotis Sgardelis, Sue Redhead, Arjun Alva, Cathy Jones, Vincent Hamlyn, Gemma Squires, Karen Smallshaw, John Whitwell, Sarah Shaw, Paul Watson, Michelle Cheeseman, Kimberley Netherton, Juneenath Karattuparambil, Niyesa Ranasinghe, Jeet Patel, Rob Lyons, Gemma Bown, Helen Bromhead, Zhana Ignatova, Kudakwashe Nyangoni, Linden Baxter, Thomas Moody, Sachin Valap, Esme Sleap, Mario Fernandes, Kinga Bodo, Jane Silk, Charlie Pope, Donna Ferraioli, Chloe Billingham, Rachel Butterworth, Andrew Kelly, Lesley Hawkins, Issac Gill, Hannah Greenlee, Sue Kirby, Jessica Giles, Anna Pierson, Roxana Sandhar, Claire Smyth, Rhona Younger, Ciara Coary, Arif Qureshi, Tahir Abbas, Corinne Rimmer, James Evans, Ida Ponce, Fenner Christoper, Buzz Shephard, Sophie Tang, Lauren Milian, Joanne Hiden, Dhania Haron, Jamie Calderwood, David Freeman, Virginia McTaggart, Carla Lewis, Chai Obeysekera, Alan H. Cohen, Melvin Leong, Jenni Law, Noor Elahi, Kim Holland, Victor Maduekwe, James Garwood, Lizzie Dawson, Virginia Iqbal, Thomas J Craig, Daniel Shuttleworth, Anand Perumal, Mahmood Saad, Seema Charters, Bethany Tookey, P Gunning, Suresh Panchakshariah, I.J. Wrench, Mayur Murali, Susan McInerney, Paul Foley, Charlotte Perkins, Marie-Louise Svensson, Karen Birnie, Samantha Hagan, Emily Hetherington, Anna-Marie Love, Annette Woods, Karen Green, Steve Hillier, Hannah Conway, Rebecca Reilly, Laura Bubb, Amy Ashford, Andrew Savva, Melody MacGregor, Stephen Lord, Ahmed Hassanin, Ramdas Howard, Laura Ashton, Arihant Jain, Simon Williams, Michael Shaw, Jill Deane, Abbie Singleton, Catriona Routley, Christopher Hall, Robin Webber, Tressy Pitt-Kerby, Stuart M. White, Shannon Gawley, Nick Heseltine, Christina Lalani, Claudia Dulea, Arindam Biswas, Rebecca Harris, Aislinn Brown, Nicholas Francis, Ben Holst, Ryan Perry, Cathie Melvin, Mark Darbyshire, Stephen Mulvany, Amy Ashton, Petrus Fourie, Emma Temlett, Jason Cupitt, Vanisha Patel, Alice Trimble, Andrew Brammar, Sarah Grayland, Eleanor Pett, Tom Standley, Carly Webb, Manamohan Rangaiah, Laura Peltola, Leanne Darwin, Yvonne Grimes, Elizabeth Brodier, Scott Berwick, Adam Janeczko, Madeleine McKee, Katherine Davidson, Jan Woodward, Saurabh Mehotra, Tara Keogh, Kofi Mensah, Joyce Guy, James King, Matt Aldridge, Nicolas Price, Alaine Done, Teresa Jones, Julia Sampson, Smita Bapat, Lauren Perkins, Tamas Szelei, Ryan Kingan, Suleman Mulla, Celia Montgomery, Alex Belcher, Salma Kadiri, Bryan Singizi, Peter Chater-Lea, Jennifer Claire Taylor, Lauren Oswald, Stephanie L. Lee, Rhys Griffiths, Samuel Pestell, John Livesy, Sarah Ciechanowicz, Alexander Stephen Harrison, Richard Partridge, Alex Daniels, Beth Penhaligan, Lyndsay Bibb, Jonathan Little, Margaret Cullen, Anya Eijk, Charlotte Earnshaw, Elena Lynes, Nicholas Jenkins, Inthekab Mohammed Ali, Madhu Balasubramaniam, Vusumuzi Shabangu, Paul-Simon Whitney, Rebecca Denyer, Kathryn Potts, Andrew Ray, Jonny Guy, Mike (Stephen) Kinsella, Pearl Baker, Olga Fernandez, Julian Berry, Callum Forbes, Southcoast Peri-operative Audit, Rebecca Rice, Lisa Horner, Sally Pitts, Kirat Panesar, Joe Stevens, Timothy Molitor, Oon Chiu, Piers Murphy, Sudeshkumar Muniyappa, David George, Jonathan Veitch, Shifa Yaruk, Lynn O'Donohoe, Theresa Murray, Laura Tasker, Johanna Wales, Diane Mellers, Robert Sparrow, Olivia Ward, Emma Shacklock, Janet Middle, Sarah MacLennan, Martin Knight, Lindsay Dawson, Teodora Orasanu, Jo Fletcher, Sarah Martin, Pnt Laloë, Gregor Imrie, Harriet Pudge, Tamsin Gregory, Andrea Wood, Colin Christie, James Penketh, Mia Andrews, Nicky Ford, Ellie Fisher, Sophie Robin, Richard Stewart, Steve Williams, Harriet Gardiner, Alison Evans, Guanmei Luo, Urmila Ratnasabapathy, Ruth Joslyn, R. Sneyd, John Westwood, Naomi Cassells, Olivia Kay, Jordi Margalef, S Butler, Hari Nageswaran, Chloe Searles, Geoffrey Wright, Thomas Potter, Drew Norwood-Green, Jonathan Ramsden, Sarah Bean, Emma Sadler, Anaesthetic Trainees, Stephanie Lewis, Kevin E. Thorpe, Sarah MacLean, Paul Ogle, Mary O'Sullivan, Diane Whitehouse, Mandy Oakley, Rachel Coathup, Harisg Venkatesh, Lisa Burgess, Daniela Smith, Kimberley Plummer, Hilary Robb, Jeanette Grocott, Rebecca Mairs, Helen Gilfillan, Moira Morrison, Sharon Garner, and Tammy Towers
Subjects: Adult, medicine.medical_specialty, Adolescent, State Medicine, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, 030202 anesthesiology, Pregnancy, Risk Factors, Neoplasms, medicine, Humans, 030212 general & internal medicine, Prospective Studies, Young adult, Prospective cohort study, health care economics and organizations, Aged, Aged, 80 and over, Health Facility Size, Postoperative Care, Models, Statistical, business.industry, Incidence (epidemiology), Incidence, Health services research, Operating room management, Odds ratio, Middle Aged, Confidence interval, United Kingdom, Surgery, Obstetrics, Anesthesiology and Pain Medicine, Hospital Bed Capacity, General Surgery, Female, business, Emergency Service, Hospital, human activities, Cohort study
Abstract: Background: cancellation of planned surgery impacts substantially on patients and health systems. This study describes the incidence and reasons for cancellation of inpatient surgery in the UK NHS. Methods: we conducted a prospective observational cohort study over 7 consecutive days in March 2017 in 245 NHS hospitals. Occurrences and reasons for previous surgical cancellations were recorded. Using multilevel logistic regression, we identified patient- and hospital-level factors associated with cancellation due to inadequate bed capacity. Results: we analysed data from 14 936 patients undergoing planned surgery. A total of 1499 patients (10.0%) reported previous cancellation for the same procedure; contemporaneous hospital census data indicated that 13.9% patients attending inpatient operations were cancelled on the day of surgery. Non-clinical reasons, predominantly inadequate bed capacity, accounted for a large proportion of previous cancellations. Independent risk factors for cancellation due to inadequate bed capacity included requirement for postoperative critical care [odds ratio (OR)=2.92; 95% confidence interval (CI), 2.12–4.02; PConclusions: a significant proportion of patients presenting for surgery have experienced a previous cancellation for the same procedure. Cancer surgery is relatively protected, but bed capacity, including postoperative critical care requirements, are significant risk factors for previous cancellations.
Published: 2018

18. Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study

Author: Dorret I. Boomsma, Søren Brunak, Adem Y. Dawed, Gonneke Willemsen, Mark I. McCarthy, Martijn van de Bunt, Karina Banasik, Leen M 't Hart, Valborg Gudmundsdottir, Mark H. H. Kramer, Jorge Ferrer, Eco J. C. de Geus, Axel Dietrich, Caroline Brorsson, Ramneek Gupta, A.M.C. Simonis-Bik, Anubha Mahajan, Elisabeth M. W. Eekhoff, Hans-Ulrich Häring, Thomas Hübschle, Christopher J. Groves, Andreas Fritsche, Harald Staiger, Joris Deelen, Karla V. Allebrandt, Helle Krogh Pedersen, Nienke van Leeuwen, Ewan R. Pearson, Internal medicine, ACS - Diabetes & metabolism, AII - Inflammatory diseases, Division 6, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Movement Sciences - Rehabilitation & Development, Biological Psychology, APH - Mental Health, APH - Health Behaviors & Chronic Diseases, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, and APH - Personalized Medicine
Subjects: Netherlands Twin Register (NTR), 0301 basic medicine, Proteomics, Physiology, medicine.medical_treatment, Gene Identification and Analysis, lcsh:Medicine, Adipose tissue, Gene Expression, White adipose tissue, Genetic Networks, Biochemistry, Mice, Endocrinology, Glucagon-Like Peptide 1/metabolism, Glucagon-Like Peptide 1, Insulin Secretion, Medicine and Health Sciences, Insulin, lcsh:Science, Receptor, Regulation of gene expression, Multidisciplinary, Genomics, Adipose Tissue, Protein Interaction Networks, Anatomy, Network Analysis, medicine.drug, Research Article, medicine.medical_specialty, Computer and Information Sciences, General Science & Technology, Context (language use), Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Gene Types, Internal medicine, MD Multidisciplinary, Journal Article, medicine, Genetics, Genome-Wide Association Studies, Animals, Humans, Gene Regulation, Insulin/secretion, Endocrine Physiology, Liraglutide, lcsh:R, Biology and Life Sciences, Computational Biology, Human Genetics, Actin cytoskeleton, Genome Analysis, 030104 developmental biology, Biological Tissue, Regulator Genes, lcsh:Q
Abstract: Glucagon-like peptide 1 (GLP-1) stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS) of GLP-1 stimulated insulin secretion in non-diabetic individuals from the Netherlands Twin register (n = 126). This GWAS was enhanced using a tissue-specific protein-protein interaction network approach. We identified a beta-cell protein-protein interaction module that was significantly enriched for low gene scores based on the GWAS P-values and found support at the network level in an independent cohort from Tübingen, Germany (n = 100). Additionally, a polygenic risk score based on SNPs prioritized from the network was associated (P < 0.05) with glucose-stimulated insulin secretion phenotypes in up to 5,318 individuals in MAGIC cohorts. The network contains both known and novel genes in the context of insulin secretion and is enriched for members of the focal adhesion, extracellular-matrix receptor interaction, actin cytoskeleton regulation, Rap1 and PI3K-Akt signaling pathways. Adipose tissue is, like the beta-cell, one of the target tissues of GLP-1 and we thus hypothesized that similar networks might be functional in both tissues. In order to verify peripheral effects of GLP-1 stimulation, we compared the transcriptome profiling of ob/ob mice treated with liraglutide, a clinically used GLP-1 receptor agonist, versus baseline controls. Some of the upstream regulators of differentially expressed genes in the white adipose tissue of ob/ob mice were also detected in the human beta-cell network of genes associated with GLP-1 stimulated insulin secretion. The findings provide biological insight into the mechanisms through which the effects of GLP-1 may be modulated and highlight a potential role of the beta-cell expressed genes RYR2, GDI2, KIAA0232, COL4A1 and COL4A2 in GLP-1 stimulated insulin secretion.
Published: 2018

19. Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic β-cells

Author: Soren K. Thomsen, Nicola L. Beer, Mark I. McCarthy, Mahesh M. Umapathysivam, Jenny C Censin, Anna L. Gloyn, Christopher J. Groves, Xiao Qing Dai, Austin Bautista, Benoit Hastoy, Anthony Payne, Shahana Sengupta, Jocelyn E. Manning Fox, Patrick E. MacDonald, Anubha Mahajan, Anne Raimondo, P Rorsman, Anne Clark, Amy Barrett, and Aliya F. Spigelman
Subjects: 0301 basic medicine, medicine.medical_specialty, endocrine system diseases, medicine.medical_treatment, Genome-wide association study, Type 2 diabetes, Biology, Polymorphism, Single Nucleotide, Article, Cell Line, Mixed Function Oxygenases, Mice, 03 medical and health sciences, Insulin-Secreting Cells, Internal medicine, Diabetes mellitus, Insulin Secretion, parasitic diseases, Genetics, medicine, Animals, Humans, Insulin, Genetic Predisposition to Disease, Allele, Alleles, geography, geography.geographical_feature_category, HEK 293 cells, nutritional and metabolic diseases, medicine.disease, Islet, HEK293 Cells, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Cell culture, Amidine-Lyases
Abstract: The molecular mechanisms underpinning susceptibility loci for type 2 diabetes (T2D) remain poorly understood. Coding variants in peptidylglycine α-amidating monooxygenase (PAM) are associated with both T2D risk and insulinogenic index. Here, we demonstrate that the T2D risk alleles impact negatively on overall PAM activity via defects in expression and catalytic function. PAM deficiency results in reduced insulin content and altered dynamics of insulin secretion in a human β-cell model and primary islets from cadaveric donors. Thus, our results demonstrate a role for PAM in β-cell function, and establish molecular mechanisms for T2D risk alleles at this locus. Coding variants in peptidylglycine α-amidating monooxygenase (PAM) associated with type 2 diabetes risk negatively impact overall PAM activity via defects in expression and catalytic function, resulting in reduced insulin content and altered dynamics of insulin secretion.
Published: 2018
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20. OMIP-043: Identification of human antibody secreting cell subsets

Author: Jeffrey, Carrell and Christopher J, Groves
Subjects: Humans, Antibody-Producing Cells, Immunophenotyping
Published: 2017

21. Type 2 Diabetes Risk Alleles Reveal a Role for Peptidylglycine Alpha-amidating Monooxygenase in Beta Cell Function

Author: A Clark, Austin Bautista, Nicola L. Beer, Anne Raimondo, Amy Barrett, M Umapathysivam, J. E. Manning Fox, Anna L. Gloyn, P Rorsman, Christopher J. Groves, B Hastoy, Patrick E. MacDonald, Dai X-Q., and Soren K. Thomsen
Subjects: 0303 health sciences, medicine.medical_specialty, Insulin, medicine.medical_treatment, 030302 biochemistry & molecular biology, Chromogranin A, Monooxygenase, Biology, Exocytosis, Cell biology, 03 medical and health sciences, Endocrinology, Internal medicine, medicine, biology.protein, Gene silencing, Allele, Beta cell, Peptidylglycine alpha-amidating monooxygenase, 030304 developmental biology
Abstract: Molecular mechanisms underpinning the genetic risk for type 2 diabetes (T2D) remain poorly understood, hindering translation into new therapies. Recently, genome-wide studies identified two coding variants inPeptidylglycine Alpha-amidating Monooxygenase(PAM) associated with T2D risk and measures of beta cell dysfunction. Here, we demonstrate that both risk alleles impact negatively on overall PAM activity, but via distinct effects on expression and catalytic function. In a human beta cell model,PAMsilencing caused decreased insulin content and altered dynamics of granule exocytosis. Analysis of primary human beta cells from cadaveric donors confirmed an effect on exocytosis in carriers of the p.D563G T2D-risk allele. Finally, we show that the granular packaging protein Chromogranin A is a PAM substrate and a strong candidate for mediating downstream effects on insulin secretion. Taken together, our results establish a role for PAM in beta cell function, and uncover a novel mechanism for T2D-associatedPAMalleles.
Published: 2017
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22. A genome-wide association study of IVGTT-based measures of first-phase insulin secretion refines the underlying physiology of type 2 diabetes variants

Author: Jaakko Tuomilehto, Lorena Boquete-Vilarino, Andrea Natali, Robert L. Hanson, Anny H. Xiang, Markku Laakso, Nicholette D. Palmer, Donald W. Bowden, Ewan R. Pearson, Oluf Pedersen, Leen M 't Hart, Jussi Paananen, Francis S. Collins, Anne U. Jackson, Mark I. McCarthy, Dorret I. Boomsma, Richard M. Watanabe, Karina Banasik, Nienke van Leewen, Anette P. Gjesing, Christopher J. Groves, Andreas Fritsche, Timon W. van Haeften, Karen L. Mohlke, Michael Boehnke, Anubha Mahajan, Nan Wang, Lynne E. Wagenknecht, Mark H. H. Kramer, Jill M. Norris, Timothy M. Frayling, Andrew R. Wood, Alena Stančáková, Annemarie M. C. Simonis-Bik, Giel Nijpels, Eco J. C. de Geus, Leslie J. Baier, Andrea Mari, Kent D. Taylor, Torben Hansen, Niels Grarup, Thomas A. Buchanan, Anna Jonsson, Elisabeth M. W. Eekhoff, Hans Eiberg, Richard N. Bergman, Mark Walker, Sayuko Kobes, Joris Deelen, Yii-Derr Chen, Ulf Smith, Internal medicine, ACS - Diabetes & metabolism, AGEM - Endocrinology, metabolism and nutrition, AMS - Musculoskeletal Health, AMS - Physical Functioning in Major Disease, General practice, APH - Health Behaviors & Chronic Diseases, Biological Psychology, APH - Mental Health, APH - Methodology, and Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Blood Glucose, Genotyping Techniques, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Type 2 diabetes, chemistry.chemical_compound, Endocrinology, Insulin-Secreting Cells, Insulin Secretion, Insulin, Alleles, C-Peptide, Diabetes Mellitus, Type 2, Genetic Variation, Genome-Wide Association Study, Genotype, Glucose Tolerance Test, Humans, Linear Models, Liver, Transcription Factor 7-Like 2 Protein, Internal Medicine, Glucose tolerance test, medicine.diagnostic_test, C-peptide, Genetics/Genomes/Proteomics/Metabolomics, Diabetes and Metabolism, Type 2, Insulin processing, medicine.medical_specialty, Diabetes risk, Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Diabetes mellitus, Internal medicine, medicine, Journal Article, Diabetes Mellitus, medicine.disease, 030104 developmental biology, chemistry, TCF7L2
Abstract: Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose–raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGF2BP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1, and TMPRSS6 loci. The fasting glucose–raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide–based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits.
Published: 2017

23. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

Author: Tazeen H. Jafar, Lars Lind, Peter Almgren, Wendy Winckler, Eitaro Nakashima, Young Min Cho, Annette Peters, Rona J. Strawbridge, Ananda R. Wickremasinghe, Katharine R. Owen, Lee-Ming Chuang, Tien-Jyun Chang, Graeme I. Bell, James B. Meigs, Bill Musk, Timo A. Lakka, Elin Grundberg, Wei Lu, Sarah Edkins, George Dedoussis, Weiping Jia, Danish Saleheen, Suthesh Sivapalaratnam, Maria Samuel, Tien Yin Wong, Lu Qi, Pierre Fontanillas, Momoko Horikoshi, Jirong Long, Abdul Basit, Anubha Mahajan, Andrew T. Hattersley, Markus M. Nöthen, Denis Rybin, Inger Njølstad, S. Krithika, Miguel Cruz, Delilah Zabaneh, Leena Peltonen, Jasmina Kravic, Sangsoo Kim, David Couper, Lori L. Bonnycastle, Heather M. Stringham, Yi-Cheng Chang, Paul Elliott, Eric J.G. Sijbrands, Nita G. Forouhi, Alena Stančáková, Ghazala Mirza, Robert W. Lawrence, Ruth J. F. Loos, Norman Klopp, Shiro Maeda, Martina Müller-Nurasyid, Jer-Yuarn Wu, Jianjun Liu, Kee Seng Chia, Elodie Eury, Loukianos S. Rallidis, Timothy M. Frayling, Ken Yamamoto, David Altshuler, Gunnar Sigurosson, Harald Grallert, Jackie F. Price, Barbara Thorand, Jouko Saramies, Malene M. Kristensen, Sonali Pechlivanis, Inês Barroso, Jong-Young Lee, Melissa Parkin, Josée Dupuis, Stéphane Lobbens, Jesús Kumate, Elena Tremoli, Sudhir Kowlessur, Xueling Sim, Norihiro Kato, Philippe Froguel, Kathleen Stirrups, Eero Lindholm, Alex S. F. Doney, Andres Metspalu, Yu-Tang Gao, Roman Wennauer, Xiao-Ou Shu, Marilyn C. Cornelis, Veikko Salomaa, Nanette R. Lee, Johanna Kuusisto, Caroline S. Fox, Man Li, James Scott, Wing-Yee So, Andrew R. Wood, Inga Prokopenko, Oddgeir L. Holmen, Tin Aung, Ryoichi Takayanagi, Chen Suo, Hara Kazuo, Carl G. P. Platou, Ann M. Kelly, Teresa Ferreira, Karl-Heinz Jöckel, Wei-Yen Lim, James F. Wilson, Tom Forsén, Qi Sun, Valur Emilsson, Gonçalo R. Abecasis, Fan Zhang, Timo Saaristo, Harry Campbell, Ying Wu, Mark Seielstad, Wei Zheng, Han Chen, Stavroula Kanoni, Yuqian Bao, Jose C. Florez, Wan Ting Tay, Ronald C. WMa, Gerald Steinbach, Min Jin Go, Rong Zhang, Junbin Liang, Vasiliki Lagou, Leif Groop, Emil Rehnberg, Nabi Shah, Weihua Zhang, Yun Li, Bengt Sennblad, Olle Melander, Nancy L. Pedersen, Muhammed Islam, Jaakko Tuomilehto, Young Jin Kim, Richard N. Bergman, Juliana C.N. Chan, Eleftheria Zeggini, Andrew D. Johnson, Kees Hovingh, Joban Sehmi, Rainer Rauramaa, Satu Männistö, Reedik Mägi, Samuel Liju, Mingyu Yang, Ayellet V. Segrè, Noël P. Burtt, Mozhgan Dorkhan, Beverley Balkau, Neelam Hassanali, Hyun Min Kang, Fabrizio Veglia, Eeva Korpi-Hyövälti, Loic Yengo, Elizabeth J. Rossin, Angela Silveira, Maggie C.Y. Ng, Yuan-Tsong Chen, Anders Hamsten, David R. Matthews, Mark J. Caulfield, Emmi Tikkanen, Tanya M. Teslovich, John R. B. Perry, Karen L. Mohlke, Sarah E. Hunt, Soo Heon Kwak, Jorge Escobedo, Christopher J. Groves, Ulf de Faire, Jeremy B M Jowett, Gudmar Thorleifsson, Michael Roden, Evelin Mihailov, Viswanathan Mohan, Craig L. Hanis, Thomas WMühleisen, Congrong Wang, Sonia Shah, Kyle J. Gaulton, Jaspal S. Kooner, Jiro Nakamura, Mustafa Atalay, Linda S. Adair, S Wiltshire, Tõnu Esko, Anna Jonsson, Antigone S. Dimas, Karin Leander, Li Ching Chang, George B. Grant, Bo Isomaa, Anne U. Jackson, Claudia Langenberg, Kristian Hveem, Yoon Shin Cho, Astradur B. Hreidarsson, Xu Wang, Keizo Ohnaka, Alexandra C. Nica, Simon D. Rees, Pau Navarro, Sekar Kathiresan, Rob M. van Dam, Zafar I. Hydrie, Bok Ghee Han, Francis S. Collins, Fuu Jen Tsai, Unnur Thorsteinsdottir, Ross M. Fraser, Caroline Hayward, Cornelia M. van Duijn, Samuli Ripatti, Mieke D. Trip, Hyung Lae Kim, Rafn Benediktsson, Candace Guiducci, Bruna Gigante, Kyong Soo Park, Wen Hong L. Kao, Tom Wilsgaard, Leena Kinnunen, John Danesh, Alan James, Alan R. Shuldiner, Mitsuhiro Yokota, Jen Mai Lee, Kari Stefansson, Erik Ingelsson, Colin N. A. Palmer, David J. Hunter, Paul Zimmet, Manickam Chidambaram, Sirkka Keinänen-Kiukaanniemi, Laura J. Scott, Susanne Moebus, Benjamin F. Voight, Wolfgang Rathmann, Hassan Khan, Thomas Illig, Prasad Katulanda, Christian Gieger, Andrew D. Morris, Yik Ying Teo, Andrew P. Morris, Venkatesan Radha, N. William Rayner, Johan G. Eriksson, Christian Dina, Igor Rudan, Sailaja Vedantam, Cheng Hu, James S. Pankow, Ann-Christine Syvänen, Karl Gertow, Valeriya Lyssenko, Guillaume Charpentier, Albert Hofman, Chiea Chuen Khor, Joseph Trakalo, Peter Kraft, Takashi Kadowaki, Qiuyin Cai, John C. Chambers, André G. Uitterlinden, Simon C. Potter, Nicholas J. Wareham, Soumya Raychaudhuri, Jian'an Luan, Tiinamaija Tuomi, Anthony H. Barnett, Juha Saltevo, Robert A. Scott, Valgerdur Steinthorsdottir, Peng Keat Ng, Mark I. McCarthy, Åsa K. Hedman, Kerrin S. Small, Julia Meyer, Frank B. Hu, Cecilia M. Lindgren, Jennifer E. Below, Nancy J. Cox, Jennie Hui, Andrew Crenshaw, Latonya F. Been, Nam H. Cho, Janani Pinidiyapathirage, A. Samad Shera, Bernhard OBoehm, Jason Carey, Augustine Kong, Twee Hee Ong, Philippe M. Frossard, Donald W. Bowden, Toshimasa Yamauchi, Steve E. Humphries, Cordelia Langford, Xinzhong Li, Hiroshi Ikegami, Stéphane Cauchi, Ching-Ti Liu, Michael Boehnke, Peter M. Nilsson, Debashish Das, John Beilby, Robin Young, Christian Herder, Asif Rasheed, Neil Robertson, Raimund Erbel, Fumihiko Takeuchi, Markku Laakso, Esteban J. Parra, Panos Deloukas, Eric Boerwinkle, Adan Valladares-Salgado, Chien-Hsiun Chen, Kay-Tee Khaw, Damiano Baldassarre, Ashok Kumar, E. Shyong Tai, Peter S. Chines, Dharambir KSanghera, Peter Donnelly, [ 1 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 2 ] Natl Inst Hlth, Ctr Genome Sci, Gangoe Myeon, Yeonje Ri, South Korea [ 3 ] Univ London Imperial Coll Sci Technol & Med, London, England [ 4 ] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA [ 5 ] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX1 2JD, England [ 6 ] NHLBI, Framingham Heart Study, Framingham, MA USA [ 7 ] Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA [ 8 ] Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA [ 9 ] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London, England [ 10 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England [ 11 ] Ctr Noncommunicable Dis Pakistan, Karachi, Pakistan [ 12 ] Natl Univ Singapore, Dept Epidemiol & Publ Hlth, Singapore 117548, Singapore [ 13 ] Wellcome Trust Sanger Inst, Cambridge, England [ 14 ] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA [ 15 ] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA [ 16 ] Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden [ 17 ] Univ Eastern Finland, Inst Biomed, Kuopio, Finland [ 18 ] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore [ 19 ] Natl Univ Singapore, Dept Ophthalmol, Singapore 117548, Singapore [ 20 ] IRCCS, Ctr Cardiol Monzino, Milan, Italy [ 21 ] Univ Milan, Dept Pharmacol Sci, Milan, Italy [ 22 ] INSERM, Ctr Rech Epidemiol & Sante Populat CESP, U1018, Villejuif, France [ 23 ] Univ Paris 11, UMRS 1018, Villejuif, France [ 24 ] Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Dept Endocrinol & Metab, Shanghai Key Lab Diabet Mellitus,Shanghai Diabet, Shanghai 200030, Peoples R China [ 25 ] Univ Birmingham, Coll Med & Dent Sci, Birmingham, W Midlands, England [ 26 ] Heart England Natl Hlth Serv NHS Fdn Trust, Ctr Biomed Res, Birmingham, W Midlands, England [ 27 ] Univ Cambridge, Addenbrookes Hosp, Metab Res Labs, Inst Metab Sci, Cambridge CB2 2QQ, England [ 28 ] Addenbrookes Hosp, Inst Metab Sci, Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England [ 29 ] Baqai Inst Diabetol & Endocrinol, Karachi, Pakistan [ 30 ] Univ Oklahoma, Hlth Sci Ctr, Coll Med, Dept Pediat,Sect Genet, Oklahoma City, OK 73190 USA [ 31 ] Sir Charles Gairdner Hosp, Busselton Populat Med Res Inst, Nedlands, WA 6009, Australia [ 32 ] Queen Elizabeth II Med Ctr, PathWest Lab Med Western Australia, Nedlands, WA, Australia [ 33 ] Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA 6009, Australia [ 34 ] Univ Chicago, Dept Med, Chicago, IL 60637 USA [ 35 ] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA [ 36 ] Univ Iceland, Fac Med, Reykjavik, Iceland [ 37 ] Landspitali Univ Hosp, Reykjavik, Iceland [ 38 ] Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA [ 39 ] Univ Med Ctr Ulm, Div Endocrinol & Diabet, Dept Internal Med, Ulm, Germany [ 40 ] Nanyang Technol Univ, Lee Kong Chian LKC Sch Med, Singapore 639798, Singapore [ 41 ] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA [ 42 ] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA [ 43 ] NHGRI, NIH, Bethesda, MD 20892 USA [ 44 ] Broad Inst Harvard & Massachusetts Inst Technol M, Cambridge, MA USA [ 45 ] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr,Dept Med, Nashville, TN 37212 USA [ 46 ] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland [ 47 ] Univ Edinburgh, Western Gen Hosp, MRC, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland [ 48 ] CNRS, Unite Mixte Rech UMR 8199, Inst Biol, Lille, France [ 49 ] Univ Lille 2, Inst Pasteur, Lille, France [ 50 ] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, London, England [ 51 ] Queen Mary Univ London, Barts & London Sch Med, William Harvey Res Inst, Barts & London Genome Ctr, London, England [ 52 ] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China [ 53 ] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan [ 54 ] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan [ 55 ] Corbeil Essonnes Hosp, Endocrinol Diabetol Unit, Corbeil Essonnes, France [ 56 ] China Med Univ, Sch Chinese Med, Taichung, Taiwan [ 57 ] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA [ 58 ] Natl Univ Singapore, Ctr Mol Epidemiol, Singapore 117548, Singapore [ 59 ] Indian Council Med Res, Adv Ctr Genom Diabet, Madras Diabet Res Fdn, Dept Mol Genet, Madras, Tamil Nadu, India [ 60 ] Ajou Univ, Sch Med, Dept Prevent Med, Suwon 441749, South Korea [ 61 ] Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 151, South Korea [ 62 ] Natl Taiwan Univ, Sch Med, Grad Inst Clin Med, Taipei 10764, Taiwan [ 63 ] Harvard Univ, Sch Publ Hlth, Dept Nutr & Epidemiol, Boston, MA 02115 USA [ 64 ] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA [ 65 ] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore [ 66 ] Ealing Hosp NHS Trust, Southall, Middx, England [ 67 ] Karolinska Inst, Inst Environm Med, Divis Cardiovasc Epidemiol, S-10401 Stockholm, Sweden [ 68 ] Harokopio Univ, Dept Dietet Nutr, Athens, Greece [ 69 ] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland [ 70 ] Biomed Sci Res Ctr Alexander Fleming, Vari, Greece [ 71 ] INSERM, UMR 1087, Nantes, France [ 72 ] CNRS, UMR 6291, Nantes, France [ 73 ] Univ Nantes, Nantes, France [ 74 ] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Diabet Res Ctr, Dundee, Scotland [ 75 ] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Pharmacogen Ctr, Dundee, Scotland [ 76 ] Univ Oxford, Dept Stat, Oxford OX1 3TG, England [ 77 ] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands [ 78 ] Netherlands Consortium Healthy Ageing, Netherland Genom Initiat, Rotterdam, Netherlands [ 79 ] Ctr Med Syst Biol, Rotterdam, Netherlands [ 80 ] Univ London Imperial Coll Sci Technol & Med, MRC, Hlth Protect Agcy, Ctr Environm & Hlth, London, England [ 81 ] Iceland Heart Assoc, Kopavogur, Iceland [ 82 ] Univ Duisburg Essen, Univ Hosp Essen, West German Heart Ctr, Clin Cardiol, Essen, Germany [ 83 ] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland [ 84 ] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland [ 85 ] Univ Helsinki, Gen Hosp, Unit Gen Practice, Helsinki, Finland [ 86 ] Folkhalsan Res Ctr, Helsinki, Finland [ 87 ] Inst Mexicano Seguro Social, Hosp Gen Reg 1, Unidad Invest Epidemiol Clin, Mexico City, DF, Mexico [ 88 ] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia [ 89 ] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia [ 90 ] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA [ 91 ] Childrens Hosp, Div Genet & Endocrinol, Boston, MA 02115 USA [ 92 ] Harvard Univ, Sch Med, Dept Med, Boston, MA USA [ 93 ] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA [ 94 ] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA [ 95 ] Addenbrookes Hosp, Inst Metab Sci, MRC, Epidemiol Unit, Cambridge, England [ 96 ] Vaasa Hlth Care Ctr, Vaasa, Finland [ 97 ] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA [ 98 ] Harvard Univ, Sch Med, Boston, MA USA [ 99 ] Univ Exeter, Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England [ 100 ] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China [ 101 ] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden [ 102 ] Karolinska Univ, Hosp Solna, Ctr Mol Med, Stockholm, Sweden [ 103 ] Helmholtz Zentrum Muenchen, Inst Genet Epidemiol, Neuherberg, Germany [ 104 ] Helmholtz Zentrum Muenchen, Res Unit Mol Epidemiol, Neuherberg, Germany [ 105 ] Univ Munich, Clin Cooperat Grp Diabet, Munich, Germany [ 106 ] Helmholtz Zentrum Muenchen, Munich, Germany [ 107 ] Tech Univ Munich, Clin Cooperat Grp Nutrigen & Type Diabet 2, Munich, Germany [ 108 ] German Ctr Diabet Res DZD, Neuherberg, Germany [ 109 ] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England [ 110 ] Univ Tokyo, Grad Sch Med, Dept Diabet & Metab Dis, Tokyo, Japan [ 111 ] Univ Exeter, Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England [ 112 ] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany [ 113 ] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, Levanger, Norway [ 114 ] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands [ 115 ] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA [ 116 ] Univ Western Australia, Sch Populat Hlth, Nedlands, WA 6009, Australia [ 117 ] UCL, Inst Cardiovasc Sci, London, England [ 118 ] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA [ 119 ] Kinki Univ, Sch Med, Dept Diabet Endocrinol & Metab, Osaka 589, Japan [ 120 ] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany [ 121 ] Univ Uppsala Hosp, Dept Mol Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden [ 122 ] Aga Khan Univ, Dept Community Hlth Sci, Karachi, Pakistan [ 123 ] Dept Social Serv & Hlth Care, Pietarsaari, Finland [ 124 ] Aga Khan Univ, Dept Med, Karachi, Pakistan [ 125 ] Queen Elizabeth II Med Ctr, West Australian Sleep Disorders Res Inst, Dept Pulm Physiol & Sleep Med, Nedlands, WA, Australia [ 126 ] Univ Western Australia, Sch Med & Pharmacol, Nedlands, WA 6009, Australia [ 127 ] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany [ 128 ] Heart & Diabet Inst, Baker Int Diabet Inst IDI, Melbourne, Australia [ 129 ] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA [ 130 ] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA [ 131 ] Natl Ctr Global Hlth & Med, Res Inst, Shinjuku Ku, Tokyo, Japan [ 132 ] Univ Colombo, Dept Clin Med, Diabet Res Unit, Colombo, Sri Lanka [ 133 ] Univ Oulu, Inst Hlth Sci, Fac Med, Oulu, Finland [ 134 ] Oulu Univ Hosp, Unit Gen Practice, Oulu, Finland [ 135 ] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore, Singapore [ 136 ] Ewha Womans Univ, Sch Med, Dept Biochem, Seoul, South Korea [ 137 ] Soongsil Univ, Sch Syst Biomed Sci, Seoul, South Korea [ 138 ] Natl Inst Hlth & Welf, Diabet Prevent Unit, Helsinki, Finland [ 139 ] deCODE Genet, Reykjavik, Iceland [ 140 ] South Ostrobothnia Cent Hosp, Seinajoki, Finland [ 141 ] Minist Hlth, Port Louis, Mauritius [ 142 ] Univ Toronto, Dept Anthropol, Mississauga, ON L5L 1C6, Canada [ 143 ] Fdn IMSS, Mexico City, DF, Mexico [ 144 ] Univ Eastern Finland, Dept Med, Kuopio, Finland [ 145 ] Kuopio Univ Hosp, SF-70210 Kuopio, Finland [ 146 ] Kuopio Res Inst Exercise Med, Kuopio, Finland [ 147 ] Univ Western Australia, Ctr Genet Epidemiol & Biostat, Nedlands, WA 6009, Australia [ 148 ] Univ San Carlos, Off Populat Studies Fdn Inc, Cebu, Philippines [ 149 ] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Natl Heart & Lung Inst, London, England [ 150 ] Univ N Carolina, Dept Genet, Chapel Hill, NC USA [ 151 ] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA [ 152 ] Beijing Genom Inst, Shenzhen, Peoples R China [ 153 ] Uppsala Univ, Akad Sjukhuset, Dept Med Sci, Uppsala, Sweden [ 154 ] Mt Sinai Sch Med, Charles R Bronfman Inst Personalized Med, New York, NY USA [ 155 ] Mt Sinai Sch Med, Child Hlth & Dev Inst, New York, NY USA [ 156 ] Mt Sinai Sch Med, Dept Prevent Med, New York, NY USA [ 157 ] Shanghai Inst Prevent Med, Shanghai, Peoples R China [ 158 ] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA [ 159 ] Dr Mohans Diabet Specialties Ctr, Madras, Tamil Nadu, India [ 160 ] Univ Bonn, Inst Human Genet, Bonn, Germany [ 161 ] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany [ 162 ] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany [ 163 ] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany [ 164 ] Sir Charles Gairdner Hosp, Nedlands, WA 6009, Australia [ 165 ] Nagoya Univ, Grad Sch Med, Div Endocrinol & Diabet, Dept Internal Med, Nagoya, Aichi 4648601, Japan [ 166 ] Chubu Rosai Hosp, Dept Endocrinol & Diabet, Nagoya, Aichi, Japan [ 167 ] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway [ 168 ] Kyushu Univ, Grad Sch Med Sci, Dept Geriatr Med, Higashi Ku, Fukuoka 812, Japan [ 169 ] Churchill Hosp, Hlth Res Biomed Res Ctr, Oxford Natl Inst, Oxford OX3 7LJ, England [ 170 ] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA [ 171 ] Seoul Natl Univ, Grad Sch Convergence Sci & Technol, Dept Mol Med & Biopharmaceut Sci, World Class Univ Program, Seoul, South Korea [ 172 ] Seoul Natl Univ, Coll Med, Seoul, South Korea [ 173 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 174 ] Inst Mol Med Finland FIMM, Helsinki, Finland [ 175 ] Helmholtz Zentrum Muenchen, Inst Epidemiol 2, Neuherberg, Germany [ 176 ] Univ Kelaniya, Fac Med, Dept Publ Hlth, Ragama, Sri Lanka [ 177 ] Nord Trondelag Hlth Trust, Levanger Hosp, Dept Internal Med, Levanger, Norway [ 178 ] Univ Gen Hosp Attikon, Athens, Greece [ 179 ] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Biometr & Epidemiol, Dusseldorf, Germany [ 180 ] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland [ 181 ] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA [ 182 ] Partners Ctr Personalized Genom Med, Boston, MA USA [ 183 ] Univ Dusseldorf, Dept Endocrinol & Diabetol, Dusseldorf, Germany [ 184 ] Univ Dusseldorf, Dept Metab Dis, Dusseldorf, Germany [ 185 ] Harvard Univ, Hlth Sci & Technol MD Program, Boston, MA 02115 USA [ 186 ] MIT, Boston, MA USA [ 187 ] Harvard Univ, Harvard Biol & Biomed Sci Program, Boston, MA 02115 USA [ 188 ] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA [ 189 ] Finnish Diabet Assoc, Tampere, Finland [ 190 ] Pirkanmaa Hosp Dist, Tampere, Finland [ 191 ] Cent Finland Cent Hosp, Dept Med, Jyvaskyla, Finland [ 192 ] South Karelia Cent Hosp, Lappeenranta, Finland [ 193 ] UCL, Dept Genet Evolut & Environm, Genet Inst, London, England [ 194 ] Diabet Assoc Pakistan, Karachi, Pakistan [ 195 ] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA [ 196 ] Baltimore Vet Adm Med Ctr, Geriatr Res Educ & Clin Ctr, Baltimore, MD USA [ 197 ] Univ Maryland, Sch Med, Program Personalised & Genom Med, Baltimore, MD 21201 USA [ 198 ] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands [ 199 ] Univ Ulm, Dept Clin Chem, D-89069 Ulm, Germany [ 200 ] Univ Ulm, Cent Lab, D-89069 Ulm, Germany [ 201 ] Uppsala Univ, Dept Med Sci, Uppsala, Sweden [ 202 ] Kyushu Univ, Grad Sch Med Sci, Dept Internal Med & Bioregulatory Sci, Higashi Ku, Fukuoka 812, Japan [ 203 ] Univ Helsinki, Helsinki Univ Hosp, Dept Med, Helsinki, Finland [ 204 ] Hosp Univ LaPaz IdiPAZ, Inst Invest Sanitaria, Madrid, Spain [ 205 ] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria [ 206 ] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia [ 207 ] IMSS, Ctr Med Nacl Siglo 21, Hosp Especialidades, Unidad Invest Med Bioquim, Mexico City, DF, Mexico [ 208 ] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA [ 209 ] Univ Melbourne, Ctr Eye Res Australia, East Melbourne, Vic, Australia [ 210 ] Kyushu Univ, Med Inst Bioregulat, Res Ctr Genet Informat, Div Genome Anal,Higashi Ku, Fukuoka 812, Japan [ 211 ] Univ Lille 1, Math Lab, CNRS UMR 8524, MODAL Team,INRIA Lille Nord Europe, F-59655 Villeneuve Dascq, France [ 212 ] Aichi Gakuin Univ, Sch Dent, Dept Genome Sci, Nagoya, Aichi 464, Japan [ 213 ] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA [ 214 ] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA USA [ 215 ] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA [ 216 ] Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA [ 217 ] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA [ 218 ] Hallym Univ, Dept Biomed Sci, Chunchon, Gangwon Do, South Korea [ 219 ] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA [ 220 ] Imperial Coll Healthcare NHS Trust, London, England [ 221 ] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA [ 222 ] Blood Syst Res Inst, San Francisco, CA USA [ 223 ] Natl Univ Singapore, Grad Sch Integrat Sci & Engn, Singapore 117548, Singapore [ 224 ] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117548, Singapore [ 225 ] Natl Univ Singapore, Dept Med, Singapore 117548, Singapore [ 226 ] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore [ 227 ] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England, Obstetrics & Gynecology, Radiology & Nuclear Medicine, Surgery, Epidemiology, Dermatology, Internal Medicine, Medical Microbiology & Infectious Diseases, Medical Research Council (MRC), National Institute for Health Research, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, and Cardiology
Subjects: CHROMATIN, endocrine system diseases, South Asian Type 2 Diabetes (SAT2D) Consortium, SCALE ASSOCIATION ANALYSIS, Medizin, LOCI, Genome-wide association study, VARIANTS, 0302 clinical medicine, Risk Factors, IMPUTATION, Glucose homeostasis, 11 Medical and Health Sciences, Genetics & Heredity, Genetics, 0303 health sciences, IDENTIFY, Hispanic or Latino, 3. Good health, MAP, POPULATIONS, Medical genetics, Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium, Hispanic Americans, Life Sciences & Biomedicine, Asian Continental Ancestry Group, medicine.medical_specialty, European Continental Ancestry Group, TRANSETHNIC METAANALYSIS, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, Sykursýki, 03 medical and health sciences, Asian People, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Allele, Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium, Alleles, 030304 developmental biology, Genetic association, Science & Technology, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Mexican American Type 2 Diabetes (MAT2D) Consortium, 06 Biological Sciences, Arfgengi, Genetic architecture, INDIVIDUALS, Diabetes Mellitus, Type 2, Case-Control Studies, GLUCOSE-HOMEOSTASIS, ASSOCIATION ANALYSES, Imputation (genetics), Developmental Biology, Genome-Wide Association Study
Abstract: To access publisher's full text version of this article click on the hyperlink at the bottom of the page To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry. Canadian Institutes of Health Research Medical Research Council UK G0601261 Mexico Convocatoria SSA/IMMS/ISSSTE-CONACYT 2012-2 clave 150352 IMSS R-2011-785-018 CONACYT Salud-2007-C01-71068 US National Institutes of Health DK062370 HG000376 DK085584 DK085545 DK073541 DK085501 Wellcome Trust WT098017 WT090532 WT090367 WT098381 WT081682 WT085475 info:eu-repo/grantAgreement/EC/FP7/201413
Published: 2014

24. Common variants associated with plasma triglycerides and risk for coronary artery disease

Author: Richard S. Cooper, Angela Döring, Cisca Wijmenga, Jerome I. Rotter, Linda S. Adair, Tõnu Esko, Jennifer L. Bragg-Gresham, Danish Saleheen, Narisu Narisu, Xiaohui Li, Kathleen Stirrups, Ulf de Faire, Nicholas G. Martin, Dmitry Shungin, Peter Vollenweider, Yii-Der Ida Chen, Dharambir K. Sanghera, George Dedoussis, Toshiko Tanaka, Manjinder S. Sandhu, Anne U. Jackson, Nancy L. Pedersen, Maria Dimitriou, Shih-Yi Lin, David P. Strachan, Isleifur Olafsson, Ruth J. F. Loos, Kay-Tee Khaw, Antero Kesäniemi, Rainer Rauramaa, Wendy L. McArdle, Gonneke Willemsen, Dena G. Hernandez, May E. Montasser, Amy J. Swift, Colin A. McKenzie, Aaron Isaacs, Latonya F. Been, Leif Groop, Massimo Mangino, Martina Müller-Nurasyid, Karen L. Mohlke, Ci Song, Sailaja Vedantam, Anna-Liisa Hartikainen, Lori L. Bonnycastle, Ilja M. Nolte, Jaakko Kaprio, Anneli Pouta, Unnur Thorsteinsdottir, Paul Elliott, Muredach P. Reilly, Jean Ferrières, Daniel J. Rader, Elizabeth H. Young, Jaspal S. Kooner, Leena Moilanen, Markku Laakso, Albert Hofman, Kelly A. Volcik, Sekar Kathiresan, Tamara B. Harris, Eric Kim, Aimo Ruokonen, Andrea Ganna, Serena Sanna, John J.P. Kastelein, Martha L. Gravito, Ronald M. Krauss, Ken K. Ong, Paul M. Ridker, Kristian Hveem, Ayse Demirkan, Alena Stančáková, Pierre Meneton, Thomas Quertermous, John Danesh, Toby Johnson, Cornelia M. van Duijn, Samuli Ripatti, Christopher J. Groves, Jaakko Tuomilehto, Michael Boehnke, Jose M. Ordovas, Alan B. Feranil, Chao A. Hsiung, Wayne Huey-Herng Sheu, Igor Rudan, Christa Meisinger, Rebecca N. Nsubuga, Bruna Gigante, Inger Njølstad, Göran Hallmans, Aroon D. Hingorani, Jouko Saramies, Deepti Gurdasani, Fernando Rivadeneira, Andres Metspalu, Stephen E. Epstein, Gonçalo R. Abecasis, Braxton D. Mitchell, Devin Absher, Marcus E. Kleber, Sonia Shah, Pierre Fontanillas, Jeffrey R. O'Connell, Louise A. Donnelly, Jing Hua Zhao, Martin L. Buchkovich, Francis S. Collins, Gabrielle Müller, Matti Uusitupa, Evelin Mihailov, Nicholas J. Wareham, Andrew A. Hicks, Dorret I. Boomsma, Harry Campbell, Ellen M. Schmidt, Jaana Lindström, Mark I. McCarthy, Evita G. Van Den Herik, Kirsten Ohm Kyvik, Vilmundur Gudnason, Jackie F. Price, Joel N. Hirschhorn, Winfried März, Aravinda Chakravarti, Pontiano Kaleebu, James F. Wilson, Lindsay L. Waite, Leo-Pekka Lyytikäinen, Sebanti Sengupta, Mika Kivimäki, David Altshuler, Hilma Holm, Rona J. Strawbridge, Harald Grallert, Ramaiah Nagaraja, Laurence Tiret, G. Kees Hovingh, Meena Kumari, Nilesh J. Samani, Daniel F. Freitag, Nelson B. Freimer, Thomas Illig, Panos Deloukas, Bernhard O. Boehm, Nicholas W.J. Wainwright, Mark J. Daly, Mika Kähönen, Michel Burnier, Norman Klopp, L. Adrienne Cupples, Aarno Palotie, Markus Perola, Bamidele O. Tayo, Timo A. Lakka, Matthew Jones, Sarah H. Wild, Patricia B. Munroe, Antti Jula, François Mach, Peter J. Koudstaal, Pirjo Komulainen, Eric Boerwinkle, L. Joost van Pelt, Veikko Salomaa, Ann-Kristin Petersen, Ida Surakka, Andrew Wong, Caroline Hayward, Chi Gao, Cristen J. Willer, Stephen S. Rich, Yi Jen Hung, Peter P. Pramstaller, Diana Kuh, Ron Do, Dominique Arveiler, Mark O. Goodarzi, Ross M. Fraser, Ingrid B. Borecki, Steven C. Hunt, Weihua Zhang, Mary Susan Burnett, Patrik K. E. Magnusson, John C. Chambers, Benjamin M. Neale, Peter Schwarz, Jennifer L. Bolton, Murielle Bochud, Heleen M. den Hertog, Christian Gieger, Cristina Pomilla, Teresa Ferreira, Lars Wallentin, Richa Saxena, André G. Uitterlinden, Kaisa Silander, Ying Wu, Bruce M. Psaty, Jian'an Luan, Hsing-Yi Chang, Jin Chen, Daniel I. Chasman, Ulf Gyllensten, Kari Stefansson, Kauko Heikkilä, Tom Wilsgaard, Alan R. Shuldiner, Carlos Iribarren, Stavroula Kanoni, John Whitfield, Gershim Asiki, Marika Kaakinen, Georg Ehret, Elina Hyppönen, Claudia Langenberg, Gina M. Peloso, Cecilia M. Lindgren, Carlo Sidore, Gudmundur I. Eyjolfsson, Cameron D. Palmer, Jacques S. Beckmann, Hubert Scharnagl, Tanya M. Teslovich, Mary F. Feitosa, Terho Lehtimäki, Steve E. Humphries, Chris Power, Benjamin F. Voight, Stefania Bandinelli, Andrew D. Morris, Gudmar Thorleifsson, Tuomo Nieminen, Tim D. Spector, Paul W. Franks, Themistocles L. Assimes, Pascal Bovet, Luigi Ferrucci, Johannes Kettunen, Inês Barroso, Franklyn I. Bennett, Stefan Gustafsson, Paolo Brambilla, Theodore Papamarkou, Elena Tremoli, Janet Seeley, Alex S. F. Doney, Johanna Kuusisto, Giancarlo Cesana, Bruce H. R. Wolffenbuttel, Lars Lind, Stefan R. Bornstein, Åsa Johansson, Anders Hamsten, Marjo-Riitta Järvelin, Krista Fischer, Agneta Siegbahn, Samia Mora, Erik Ingelsson, Colin N. A. Palmer, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Epidemiology, Surgery, Public Health, Ophthalmology, Neurology, Medical Microbiology & Infectious Diseases, Obstetrics & Gynecology, Internal Medicine, Do, Ron, Willer, Cristen J, Schmidt, Ellen M, Sengupta, Sebanti, Hyppönen, Elina, Kathiresan, Sekar, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Do, R, Willer, C, Schmidt, E, Sengupta, S, Gao, C, Peloso, G, Gustafsson, S, Kanoni, S, Ganna, A, Chen, J, Buchkovich, M, Mora, S, Beckmann, J, Bragg Gresham, J, Chang, H, Demirkan, A, Den Hertog, H, Donnelly, L, Ehret, G, Esko, T, Feitosa, M, Ferreira, T, Fischer, K, Fontanillas, P, Fraser, R, Freitag, D, Gurdasani, D, Heikkilä, K, Hyppönen, E, Isaacs, A, Jackson, A, Johansson, A, Johnson, T, Kaakinen, M, Kettunen, J, Kleber, M, Li, X, Luan, J, Lyytikäinen, L, Magnusson, P, Mangino, M, Mihailov, E, Montasser, M, Müller Nurasyid, M, Nolte, I, O'Connell, J, Palmer, C, Perola, M, Petersen, A, Sanna, S, Saxena, R, Service, S, Shah, S, Shungin, D, Sidore, C, Song, C, Strawbridge, R, Surakka, I, Tanaka, T, Teslovich, T, Thorleifsson, G, Van den Herik, E, Voight, B, Volcik, K, Waite, L, Wong, A, Wu, Y, Zhang, W, Absher, D, Asiki, G, Barroso, I, Been, L, Bolton, J, Bonnycastle, L, Brambilla, P, Burnett, M, Cesana, G, Dimitriou, M, Doney, A, Döring, A, Elliott, P, Epstein, S, Eyjolfsson, G, Gigante, B, Goodarzi, M, Grallert, H, Gravito, M, Groves, C, Hallmans, G, Hartikainen, A, Hayward, C, Hernandez, D, Hicks, A, Holm, H, Hung, Y, Illig, T, Jones, M, Kaleebu, P, Kastelein, J, Khaw, K, Kim, E, Klopp, N, Komulainen, P, Kumari, M, Langenberg, C, Lehtimäki, T, Lin, S, Lindström, J, Loos, R, Mach, F, Mcardle, W, Meisinger, C, Mitchell, B, Müller, G, Nagaraja, R, Narisu, N, Nieminen, T, Nsubuga, R, Olafsson, I, Ong, K, Palotie, A, Papamarkou, T, Pomilla, C, Pouta, A, Rader, D, Reilly, M, Ridker, P, Rivadeneira, F, Rudan, I, Ruokonen, A, Samani, N, Scharnagl, H, Seeley, J, Silander, K, Stančáková, A, Stirrups, K, Swift, A, Tiret, L, Uitterlinden, A, van Pelt, L, Vedantam, S, Wainwright, N, Wijmenga, C, Wild, S, Willemsen, G, Wilsgaard, T, Wilson, J, Young, E, Zhao, J, Adair, L, Arveiler, D, Assimes, T, Bandinelli, S, Bennett, F, Bochud, M, Boehm, B, Boomsma, D, Borecki, I, Bornstein, S, Bovet, P, Burnier, M, Campbell, H, Chakravarti, A, Chambers, J, Chen, Y, Collins, F, Cooper, R, Danesh, J, Dedoussis, G, de Faire, U, Feranil, A, Ferrières, J, Ferrucci, L, Freimer, N, Gieger, C, Groop, L, Gudnason, V, Gyllensten, U, Hamsten, A, Harris, T, Hingorani, A, Hirschhorn, J, Hofman, A, Hovingh, G, Hsiung, C, Humphries, S, Hunt, S, Hveem, K, Iribarren, C, Järvelin, M, Jula, A, Kähönen, M, Kaprio, J, Kesäniemi, A, Kivimaki, M, Kooner, J, Koudstaal, P, Krauss, R, Kuh, D, Kuusisto, J, Kyvik, K, Laakso, M, Lakka, T, Lind, L, Lindgren, C, Martin, N, März, W, Mccarthy, M, Mckenzie, C, Meneton, P, Metspalu, A, Moilanen, L, Morris, A, Munroe, P, Njølstad, I, Pedersen, N, Power, C, Pramstaller, P, Price, J, Psaty, B, Quertermous, T, Rauramaa, R, Saleheen, D, Salomaa, V, Sanghera, D, Saramies, J, Schwarz, P, Sheu, W, Shuldiner, A, Siegbahn, A, Spector, T, Stefansson, K, Strachan, D, Tayo, B, Tremoli, E, Tuomilehto, J, Uusitupa, M, van Duijn, C, Vollenweider, P, Wallentin, L, Wareham, N, Whitfield, J, Wolffenbuttel, B, Altshuler, D, Ordovas, J, Boerwinkle, E, Thorsteinsdottir, U, Chasman, D, Rotter, J, Franks, P, Ripatti, S, Cupples, L, Sandhu, M, Rich, S, Boehnke, M, Deloukas, P, Mohlke, K, Ingelsson, E, Abecasis, G, Daly, M, Neale, B, and Kathiresan, S
Subjects: Netherlands Twin Register (NTR), BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Heart disease, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, ISCHEMIC-HEART-DISEASE, Triglyceride, Coronary artery disease, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, Polymorphism (computer science), Risk Factors, High-density-lipoprotein, Genetic epidemiology, 11 Medical and Health Sciences, Genetics & Heredity, 0303 health sciences, Cholesterol, HDL/blood, Cholesterol levels, Loci, Contribute, Single Nucleotide, LDL/blood, Triglycerides/blood, Cholesterol, Cholesterol, LDL/blood, HDL/blood, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, Human, medicine.medical_specialty, TYPE-2 DIABETES-MELLITUS, Biology, Polymorphism, Single Nucleotide, Article, HIGH-DENSITY-LIPOPROTEIN ISCHEMIC-HEART-DISEASE TYPE-2 DIABETES-MELLITUS MENDELIAN RANDOMIZATION CARDIOVASCULAR-DISEASE GENETIC EPIDEMIOLOGY CHOLESTEROL LEVELS LOCI CONTRIBUTE THERAPY, 03 medical and health sciences, Coronary Artery Disease/blood, SDG 3 - Good Health and Well-being, Cardiovascular-disease, Internal medicine, Mendelian randomization, Genetics, medicine, Humans, Polymorphism, plasma, Triglycerides, 030304 developmental biology, Science & Technology, Risk Factor, Cholesterol, HDL, Biological Transport, Cholesterol, LDL, 06 Biological Sciences, medicine.disease, Heart-disease, lipoproteins, Endocrinology, chemistry, Therapy, Developmental Biology
Abstract: Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10 -8 for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD. © 2013 Nature America, Inc. All rights reserved.
Published: 2013

25. Discovery and refinement of loci associated with lipid levels

Author: Benjamin F. Voight, Stefania Bandinelli, Pascal Bovet, Latonya F. Been, Ci Song, Luigi Ferrucci, Johannes Kettunen, Andrew D. Morris, Mary Susan Burnett, Ronald M. Krauss, Igor Rudan, Heleen M. den Hertog, Stavroula Kanoni, G. Kees Hovingh, Elina Hyppönen, Kauko Heikkilä, Richard S. Cooper, Daniel I. Chasman, Bruna Gigante, Stefan Gustafsson, Jian'an Luan, Sarah H. Wild, Patricia B. Munroe, Göran Hallmans, Jeffrey R. O'Connell, Danish Saleheen, Aarno Palotie, Leena Moilanen, Jerome I. Rotter, Caroline Hayward, Jennifer L. Bragg-Gresham, Nicholas G. Martin, Claudia Langenberg, George Dedoussis, Carlo Sidore, Ulf Gyllensten, Marika Kaakinen, Jing Hua Zhao, Aimo Ruokonen, Diana Kuh, Maria Dimitriou, Shih-Yi Lin, Gina M. Peloso, Marcus E. Kleber, Christopher J. Groves, Alena Stančáková, Michel Burnier, Patrik K. E. Magnusson, John C. Chambers, Giancarlo Cesana, Francis S. Collins, Gabrielle Müller, Angela Döring, Colin A. McKenzie, Paul Elliott, Lars Lind, Vilmundur Gudnason, Dharambir K. Sanghera, Jean Ferrières, Toshiko Tanaka, Stefan R. Bornstein, Gershim Asiki, Jacques S. Beckmann, Anneli Pouta, Timo A. Lakka, Daniel J. Rader, Elizabeth H. Young, Kelly A. Volcik, Dena G. Hernandez, Ann-Kristin Petersen, Kristian Hveem, Amy J. Swift, Murielle Bochud, Pierre Meneton, Paul M. Ridker, Kathleen Stirrups, Stephen S. Rich, Isleifur Olafsson, Ruth J. F. Loos, Serena Sanna, Markus Perola, Meena Kumari, Cameron D. Palmer, Carlos Iribarren, Nancy L. Pedersen, Mark O. Goodarzi, Panos Deloukas, Norman Klopp, Cristina Pomilla, Stephen E. Epstein, Antti Jula, Themistocles L. Assimes, Martina Müller-Nurasyid, Marjo-Riitta Järvelin, Chao A. Hsiung, Sonia Shah, Christian Gieger, Toby Johnson, Cornelia M. van Duijn, Samuli Ripatti, Nicholas J. Wareham, Krista Fischer, Wendy L. McArdle, Linda S. Adair, Kay-Tee Khaw, Bruce M. Psaty, André G. Uitterlinden, Aaron Isaacs, Tõnu Esko, Jennifer L. Bolton, Rebecca N. Nsubuga, Eric Boerwinkle, L. Joost van Pelt, Jouko Saramies, François Mach, Pierre Fontanillas, Teresa Ferreira, Lars Wallentin, Michael Boehnke, Christa Meisinger, Wayne Huey-Herng Sheu, Gonçalo R. Abecasis, Inês Barroso, Franklyn I. Bennett, Dmitry Shungin, Jaakko Kaprio, Kirsten Ohm Kyvik, Deepti Gurdasani, Anne U. Jackson, Paolo Brambilla, Georg Ehret, Cecilia M. Lindgren, Fernando Rivadeneira, Theodore Papamarkou, Jaakko Tuomilehto, Cristen J. Willer, Martin L. Buchkovich, Antero Kesäniemi, Hubert Scharnagl, Xiaohui Li, Elena Tremoli, Nelson B. Freimer, Mika Kähönen, Ron Do, Karen L. Mohlke, Thomas Illig, Gudmar Thorleifsson, Peter J. Koudstaal, Andres Metspalu, Ulf de Faire, Dominique Arveiler, Harald Grallert, Jaana Lindström, Laurence Tiret, Jaspal S. Kooner, Braxton D. Mitchell, Sebanti Sengupta, Gonneke Willemsen, Anna-Liisa Hartikainen, Terho Lehtimäki, Steve E. Humphries, Peter Schwarz, Dorret I. Boomsma, Harry Campbell, Ellen M. Schmidt, Tom Wilsgaard, Janet Seeley, Alex S. F. Doney, Alan R. Shuldiner, John Whitfield, Markku Laakso, Peter Vollenweider, Gudmundur I. Eyjolfsson, Winfried März, Mika Kivimäki, Ying Wu, Johanna Kuusisto, Andrew A. Hicks, Bruce H. R. Wolffenbuttel, May E. Montasser, Bamidele O. Tayo, Unnur Thorsteinsdottir, Muredach P. Reilly, Leo-Pekka Lyytikäinen, Eric Kim, John Danesh, Ida Surakka, Åsa Johansson, Anders Hamsten, Thomas Quertermous, Hsing-Yi Chang, Jin Chen, Agneta Siegbahn, Narisu Narisu, Samia Mora, Erik Ingelsson, Colin N. A. Palmer, Sekar Kathiresan, Manjinder S. Sandhu, Leif Groop, Jose M. Ordovas, Alan B. Feranil, Evelin Mihailov, Hilma Holm, Pontiano Kaleebu, Lindsay L. Waite, Ramaiah Nagaraja, Andrew Wong, Rona J. Strawbridge, David P. Strachan, Yii-Der Ida Chen, Tamara B. Harris, Jackie F. Price, Aravinda Chakravarti, Veikko Salomaa, Sailaja Vedantam, Albert Hofman, Devin Absher, Ross M. Fraser, Kaisa Silander, Pirjo Komulainen, Yi Jen Hung, Peter P. Pramstaller, Kari Stefansson, Aroon D. Hingorani, Tanya M. Teslovich, Matti Uusitupa, L. Adrienne Cupples, Cisca Wijmenga, Lori L. Bonnycastle, Ilja M. Nolte, Andrea Ganna, Ken K. Ong, Inger Njølstad, Bernhard O. Boehm, Nicholas W.J. Wainwright, Richa Saxena, Rainer Rauramaa, Louise A. Donnelly, James F. Wilson, Matthew Jones, Ingrid B. Borecki, Steven C. Hunt, Weihua Zhang, Massimo Mangino, John J.P. Kastelein, Martha L. Gravito, Mark I. McCarthy, Evita G. Van Den Herik, Joel N. Hirschhorn, Nilesh J. Samani, Daniel F. Freitag, Ayse Demirkan, Mary F. Feitosa, Tuomo Nieminen, Tim D. Spector, Paul W. Franks, Chris Power, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Willer, C, Schmidt, E, Sengupta, S, Peloso, G, Gustafsson, S, Kanoni, S, Ganna, A, Chen, J, Buchkovich, M, Mora, S, Beckmann, J, Bragg Gresham, J, Chang, H, Demirkan, A, Den Hertog, H, Do, R, Donnelly, L, Ehret, G, Esko, T, Feitosa, M, Ferreira, T, Fischer, K, Fontanillas, P, Fraser, R, Freitag, D, Gurdasani, D, Heikkilä, K, Hyppönen, E, Isaacs, A, Jackson, A, Johansson, A, Johnson, T, Kaakinen, M, Kettunen, J, Kleber, M, Li, X, Luan, J, Lyytikäinen, L, Magnusson, P, Mangino, M, Mihailov, E, Montasser, M, Müller Nurasyid, M, Nolte, I, O'Connell, J, Palmer, C, Perola, M, Petersen, A, Sanna, S, Saxena, R, Service, S, Shah, S, Shungin, D, Sidore, C, Song, C, Strawbridge, R, Surakka, I, Tanaka, T, Teslovich, T, Thorleifsson, G, Van den Herik, E, Voight, B, Volcik, K, Waite, L, Wong, A, Wu, Y, Zhang, W, Absher, D, Asiki, G, Barroso, I, Been, L, Bolton, J, Bonnycastle, L, Brambilla, P, Burnett, M, Cesana, G, Dimitriou, M, Doney, A, Döring, A, Elliott, P, Epstein, S, Eyjolfsson, G, Gigante, B, Goodarzi, M, Grallert, H, Gravito, M, Groves, C, Hallmans, G, Hartikainen, A, Hayward, C, Hernandez, D, Hicks, A, Holm, H, Hung, Y, Illig, T, Jones, M, Kaleebu, P, Kastelein, J, Khaw, K, Kim, E, Klopp, N, Komulainen, P, Kumari, M, Langenberg, C, Lehtimäki, T, Lin, S, Lindström, J, Loos, R, Mach, F, Mcardle, W, Meisinger, C, Mitchell, B, Müller, G, Nagaraja, R, Narisu, N, Nieminen, T, Nsubuga, R, Olafsson, I, Ong, K, Palotie, A, Papamarkou, T, Pomilla, C, Pouta, A, Rader, D, Reilly, M, Ridker, P, Rivadeneira, F, Rudan, I, Ruokonen, A, Samani, N, Scharnagl, H, Seeley, J, Silander, K, Stancáková, A, Stirrups, K, Swift, A, Tiret, L, Uitterlinden, A, van Pelt, L, Vedantam, S, Wainwright, N, Wijmenga, C, Wild, S, Willemsen, G, Wilsgaard, T, Wilson, J, Young, E, Zhao, J, Adair, L, Arveiler, D, Assimes, T, Bandinelli, S, Bennett, F, Bochud, M, Boehm, B, Boomsma, D, Borecki, I, Bornstein, S, Bovet, P, Burnier, M, Campbell, H, Chakravarti, A, Chambers, J, Chen, Y, Collins, F, Cooper, R, Danesh, J, Dedoussis, G, de Faire, U, Feranil, A, Ferrières, J, Ferrucci, L, Freimer, N, Gieger, C, Groop, L, Gudnason, V, Gyllensten, U, Hamsten, A, Harris, T, Hingorani, A, Hirschhorn, J, Hofman, A, Hovingh, G, Hsiung, C, Humphries, S, Hunt, S, Hveem, K, Iribarren, C, Järvelin, M, Jula, A, Kähönen, M, Kaprio, J, Kesäniemi, A, Kivimaki, M, Kooner, J, Koudstaal, P, Krauss, R, Kuh, D, Kuusisto, J, Kyvik, K, Laakso, M, Lakka, T, Lind, L, Lindgren, C, Martin, N, März, W, Mccarthy, M, Mckenzie, C, Meneton, P, Metspalu, A, Moilanen, L, Morris, A, Munroe, P, Njølstad, I, Pedersen, N, Power, C, Pramstaller, P, Price, J, Psaty, B, Quertermous, T, Rauramaa, R, Saleheen, D, Salomaa, V, Sanghera, D, Saramies, J, Schwarz, P, Sheu, W, Shuldiner, A, Siegbahn, A, Spector, T, Stefansson, K, Strachan, D, Tayo, B, Tremoli, E, Tuomilehto, J, Uusitupa, M, van Duijn, C, Vollenweider, P, Wallentin, L, Wareham, N, Whitfield, J, Wolffenbuttel, B, Ordovas, J, Boerwinkle, E, Thorsteinsdottir, U, Chasman, D, Rotter, J, Franks, P, Ripatti, S, Cupples, L, Sandhu, M, Rich, S, Boehnke, M, Deloukas, P, Kathiresan, S, Mohlke, K, Ingelsson, E, Abecasis, G, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Ehret, Georg Benedikt, Mach, François, Epidemiology, Surgery, Public Health, Ophthalmology, Neurology, Medical Microbiology & Infectious Diseases, Obstetrics & Gynecology, Internal Medicine, National Institute for Health Research, Global Lipids Genetics Consortium, Willer, Cristen, Sengupta, Sebanti, Peloso, Gina, Hypponen, Elina Tuulikki, and Abecasis, Gonçalo R
Subjects: Netherlands Twin Register (NTR), HOMEOSTASIS, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Blood lipids, Genome-wide association study, Type 2 diabetes, Coronary Artery Disease, 030204 cardiovascular system & hematology, Triglyceride, Coronary artery disease, chemistry.chemical_compound, 0302 clinical medicine, European Continental Ancestry Group/genetics, triglycerides, IDENTIFIES 13, 11 Medical and Health Sciences, African Continental Ancestry Group, 2. Zero hunger, Genetics, Genetics & Heredity, ddc:616, RISK, 0303 health sciences, Cholesterol, HDL/blood, PLASMA, Global Lipids Genetics Consortium, Cholesterol, HDL/blood/genetics, Lipid, Lipids, 3. Good health, LDL/blood, Triglycerides/blood, Lipids/blood/genetics, Cholesterol, Cholesterol, LDL/blood, DENSITY-LIPOPROTEIN CHOLESTEROL, CARDIOVASCULAR-DISEASE, HDL/blood, CORONARY-ARTERY-DISEASE, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, coronary artery disease, TRAITS, Human, Coronary Artery Disease/blood/genetics, Asian Continental Ancestry Group, Genotype, SUSCEPTIBILITY LOCI, European Continental Ancestry Group, Black People, HEART-DISEASE, Biology, Article, White People, lipids, 03 medical and health sciences, Coronary Artery Disease/blood, CORONARY-ARTERY-DISEASE DENSITY-LIPOPROTEIN CHOLESTEROL GENOME-WIDE ASSOCIATION HEART-DISEASE CARDIOVASCULAR-DISEASE SUSCEPTIBILITY LOCI IDENTIFIES 13 RISK GENE METAANALYSIS, Triglycerides/blood/genetics, Asian People, SDG 3 - Good Health and Well-being, Mendelian randomization, medicine, Humans, Asian Continental Ancestry Group/genetics, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Genotyping, Triglycerides, METAANALYSIS, 030304 developmental biology, Science & Technology, Lipids/blood, Cholesterol, HDL, cholesterol, African Continental Ancestry Group/genetics, Cholesterol, LDL, 06 Biological Sciences, medicine.disease, GENE, chemistry, Cholesterol, LDL/blood/genetics, Lipoprotein, Developmental Biology, Genome-Wide Association Study
Abstract: Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10 -8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research. © 2013 Nature America, Inc. All rights reserved.
Published: 2013
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26. Genome-wide associations for birth weight and correlations with adult disease

Author: Anubha Mahajan, George McMahon, Charlotta Pisinger, Timothy M. Frayling, Elisabeth M. van Leeuwen, Felix R. Day, Virpi Lindi, Allan Vaag, Debbie A Lawlor, Natalie R. van Zuydam, Peter Kovacs, David Torrents, Bjarke Feenstra, Peter Vollenweider, David P. Strachan, Krina T. Zondervan, John R. B. Perry, Jorma Viikari, Pedro Marques-Vidal, Kalliope Panoutsopoulou, Ruifang Li-Gao, Juan Fernández-Tajes, Carolina Medina-Gomez, Nicole M. Warrington, Josep M. Mercader, Antje Körner, David M. Evans, Albert Hofman, Hans Bisgaard, Amanda J. Bennett, Eleanor Davies, Linda S. Adair, Oluf Pedersen, Mustafa Atalay, Sylvain Sebert, Ying Wu, Haja N. Kadarmideen, Ronald C.W. Ma, Lawrence J. Beilin, David M. Hougaard, Diana L. Cousminer, Louise A. Diver, Jing Hua Zhao, Nilufer Rahmioglu, Peter K. Joshi, Neil R. Robertson, Johannes Waage, Hugoline G. de Haan, Jens-Christian Holm, Dale R. Nyholt, Torben Hansen, Sara M. Willems, Sílvia Bonàs-Guarch, Carol A. Wang, Rico Rueedi, Lavinia Paternoster, James F. Wilson, Cilius Esmann Fonvig, Leo-Pekka Lyytikäinen, Hanieh Yaghootkar, Momoko Horikoshi, Gonneke Willemsen, Dennis O. Mook-Kanamori, Lisbeth Carstensen, Mariona Bustamante, Emil V. R. Appel, Christian Theil Have, Rebecca M. Reynolds, Niels Grarup, Seang-Mei Saw, Yik Ying Teo, Brian R. Walker, Anke Tönjes, Christopher J. Groves, Andrew P. Morris, Katja Pahkala, Marjolein N. Kooijman, Kyle J. Gaulton, Eskil Kreiner, Michael Stumvoll, Eleftheria Zeggini, Vincent W. V. Jaddoe, Zoltán Kutalik, Scott M. MacKenzie, George Davey Smith, Christine Power, Denise M. Scholtens, Joachim Heinrich, Samuel E. Jones, William L. Lowe, Eco J. C. de Geus, Jonathan P. Bradfield, Andrew T. Hattersley, Janine F. Felix, Wing Hung Tam, Frits R. Rosendaal, Wieland Kiess, Claudia H. T. Tam, Inga Prokopenko, Terho Lehtimäki, Frank D. Mentch, Marjo-Riitta Järvelin, Struan F.A. Grant, Santhi K. Ganesh, Fernando Rivadeneira, Thorkild I. A. Sørensen, André G. Uitterlinden, Marie Standl, Jian'an Luan, Gibran Hemani, Marcus A. Tuke, Andrew R. Wood, Robert A. Scott, Cæcilie Trier, Tarunveer S. Ahluwalia, Michael Nodzenski, Jouke-Jan Hottenga, Ken K. Ong, Po-Ru Loh, Nicholas J. Timpson, George Dedoussis, Friman Sánchez, Mark I. McCarthy, Frank Geller, Harri Niinikoski, Martine Vrijheid, Hakon Hakonarson, John P. Newnham, Xu Wang, Elina Hyppönen, Johan G. Eriksson, Craig E. Pennell, Niina Pitkänen, Rachel M. Freathy, Elisabeth Widen, Judith B. Borja, Karen L. Mohlke, Mads Melbye, Carla M. T. Tiesler, Susan M. Ring, Jessica Tyrrell, Elisabeth Thiering, Timo A. Lakka, Eileen Tai-Hui Boh, Olli T. Raitakari, Nicholas J. Wareham, Mario Murcia, Natalia Vilor-Tejedor, Katherine S. Ruth, Dorret I. Boomsma, Harry Campbell, Vasiliki Lagou, Robin N Beaumont, Klaus Bønnelykke, Claudia Langenberg, Catharina E. M. van Beijsterveldt, Mika Kähönen, Mads V. Hollegaard, Frank J.A. van Rooij, Katharina E. Schraut, Ioanna Ntalla, Raimo Joro, Cornelia M. van Duijn, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Day, Felix [0000-0003-3789-7651], Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Zhao, Jing Hua [0000-0003-4930-3582], Wareham, Nicholas [0000-0003-1422-2993], Ong, Kenneth [0000-0003-4689-7530], Perry, John [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Erasmus MC other, Medical Microbiology & Infectious Diseases, Epidemiology, Medical Oncology, Child and Adolescent Psychiatry / Psychology, Public Health, Internal Medicine, Pediatrics, Horikoshi, Momoko, Beaumont, Robin N, Day, Felix R, Warrington, Nicole, Hyppönen, Elina, and Freathy, Rachel M
Subjects: Male, 0301 basic medicine, Netherlands Twin Register (NTR), Aging, Datasets as Topic, Physiology, Blood Pressure, Genome-wide association study, Coronary Artery Disease, Type 2 diabetes, Bioinformatics, CHARGE Consortium Hematology Working Group, Cohort Studies, 0302 clinical medicine, Birth Weight, Insulin, Glucose homeostasis, 030212 general & internal medicine, education.field_of_study, Multidisciplinary, Anthropometry, 3. Good health, Phenotype, Female, Glycogen, Signal Transduction, Adult, hypertension, Genotype, General Science & Technology, Birth weight, intrauterine growth, Population, Quantitative trait locus, Biology, Article, quantitative trait, Genomic Imprinting, 03 medical and health sciences, Fetus, SDG 3 - Good Health and Well-being, Early Growth Genetics (EGG) Consortium, MD Multidisciplinary, Genetic variation, medicine, Humans, metabolic disorders, Genetic Predisposition to Disease, education, genome, Genetic association, Genetic Variation, birth weight, ta3121, Chromatin Assembly and Disassembly, medicine.disease, ta3123, Glucose, 030104 developmental biology, Diabetes Mellitus, Type 2, Genetic Loci, genome-wide association studies, adult disease, Genome-Wide Association Study
Abstract: Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P&thinsp
Published: 2016

27. Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin

Author: Kathleen M. Giacomini, Adriaan Kooy, Coen D.A. Stehouwer, MetGen Investigators, Valdis Pirags, Daniel M. Rotroff, Ivan Tkáč, Huan-Chieh Chien, Michael J. Wagner, Shiro Maeda, Federico Innocenti, Joline W.J. Beulens, Monique M. Hedderson, Eric L. Seiser, Sook Wah Yee, Bruno H. Stricker, Accord Investigators, Jozef Židzik, Leen M 't Hart, Rury R. Holman, Alison A. Motsinger-Reif, Jose C. Florez, Albert Hofman, Mattijs Out, Albert M. Levin, Christopher J. Groves, Michiaki Kubo, Longyang Wu, Catherine E. de Keyser, Ewan R. Pearson, Lisa Logie, Calum Sutherland, Sabina Semiz, Tanja Dujic, John S. Witte, Amanda J. Bennett, Kathleen A. Jablonski, Linda Zaharenko, Nienke van Leeuwen, Ling Chen, Dpp Investigators, Roger Tavendale, Ruth L. Coleman, Amber A. van der Heijden, Colin N. A. Palmer, Janis Klovins, Martin Javorský, Ron H.N. van Schaik, Mark I. McCarthy, L. Keoki Williams, Kaixin Zhou, Epidemiology, Clinical Chemistry, General practice, EMGO - Lifestyle, overweight and diabetes, Epidemiology and Data Science, MUMC+: HVC Pieken Maastricht Studie (9), RS: CARIM - R3.01 - Vascular complications of diabetes and the metabolic syndrome, Interne Geneeskunde, and MUMC+: MA Interne Geneeskunde (3)
Subjects: Blood Glucose, 0301 basic medicine, medicine.medical_specialty, endocrine system diseases, Genome-wide association study, Type 2 diabetes, Polymorphism, Single Nucleotide, White People, Body Mass Index, 03 medical and health sciences, Quantitative Trait, Heritable, Internal medicine, Diabetes mellitus, Genetics, medicine, Humans, Hypoglycemic Agents, Allele, Glycemic, Glucose Transporter Type 2, Glycated Hemoglobin, biology, Glucose transporter, nutritional and metabolic diseases, medicine.disease, Metformin, 3. Good health, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, biology.protein, GLUT2, Genome-Wide Association Study, medicine.drug
Abstract: Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear(1). Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 x 10(-14)) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.
Published: 2016

28. BMI-associated alleles do not constitute risk alleles for polycystic ovary syndrome independently of BMI: a case-control study

Author: Thomas M. Barber, Nigel W. Rayner, Lisette Stolk, André G. Uitterlinden, Mark I. McCarthy, Blanca M. Herrera, Joop S.E. Laven, Christopher J. Groves, Yvonne V. Louwers, Stephen Franks, Obstetrics & Gynecology, and Internal Medicine
Subjects: endocrine system diseases, Epidemiology, lcsh:Medicine, Physiology, Genome-wide association study, Overweight, Body Mass Index, Endocrinology, Gene Frequency, Risk Factors, Genotype, lcsh:Science, Netherlands, Genetics, Multidisciplinary, Polycystic ovary, female genital diseases and pregnancy complications, Genetic Epidemiology, Medicine, Female, medicine.symptom, Research Article, Polycystic Ovary Syndrome, Clinical Research Design, Biology, Polymorphism, Single Nucleotide, Risk Assessment, medicine, Genetic predisposition, Reproductive Endocrinology, Humans, Genetic Predisposition to Disease, Obesity, Alleles, Clinical Genetics, Body Weight, lcsh:R, Case-control study, nutritional and metabolic diseases, medicine.disease, United Kingdom, Case-Control Studies, Genetics of Disease, Genetic Polymorphism, Women's Health, lcsh:Q, Body mass index, Population Genetics
Abstract: Introduction: Polycystic Ovary Syndrome (PCOS) has a strong genetic background and the majority of patients with PCOS have elevated BMI levels. The aim of this study was to determine to which extent BMI-increasing alleles contribute to risk of PCOS when contemporaneous BMI is taken into consideration. Methods: Patients with PCOS and controls were recruited from the United Kingdom (563 cases and 791 controls) and The Netherlands (510 cases and 2720 controls). Cases and controls were of similar BMI. SNPs mapping to 12 BMI-associated loci which have been extensively replicated across different ethnicities, i.e., BDNF, FAIM2, ETV5, FTO, GNPDA2, KCTD15, MC4R, MTCH2, NEGR1, SEC16B, SH2B1, and TMEM18, were studied in association with PCOS within each cohort using the additive genetic model followed by a combined analysis. A genetic allelic count risk score model was used to determine the risk of PCOS for individuals carrying increasing numbers of BMI-increasing alleles. Results: None of the genetic variants, including FTO and MC4R, was associated with PCOS independently of BMI in the meta-analysis. Moreover, no differences were observed between cases and controls in the number of BMI-risk alleles present and no overall trend across the risk score groups was observed. Conclusion: In this combined analysis of over 4,000 BMI-matched individuals from the United Kingdom and the Netherlands, we observed no association of BMI risk alleles with PCOS independent of BMI.
Published: 2016

29. Meta-analysis and functional effects of the SLC30A8 rs13266634 polymorphism on isolated human pancreatic islets

Author: Christopher J. Groves, V. D’Aleo, Roberto Lupi, Hélène Choquet, Philippe Froguel, Stéphane Cauchi, Mark I. McCarthy, Piero Marchetti, and Silvia Del Guerra
Subjects: Risk, medicine.medical_specialty, endocrine system, endocrine system diseases, Genotype, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Type 2 diabetes, Zinc Transporter 8, Arginine, Biochemistry, Glucagon, White People, Glibenclamide, Islets of Langerhans, Endocrinology, Asian People, Internal medicine, Diabetes mellitus, Glyburide, Insulin Secretion, Genetics, medicine, Humans, Insulin, Molecular Biology, Cation Transport Proteins, Polymorphism, Genetic, SLC30A8, biology, Pancreatic islets, medicine.disease, medicine.anatomical_structure, Glucose, Diabetes Mellitus, Type 2, biology.protein, Pancreas, medicine.drug
Abstract: Background The C-allele of rs13266634 located in SLC30A8 (ZNT8) has been strongly associated with decreased insulin release and with type 2 diabetes (T2D) susceptibility in some but not all studies. To shed further light on this issue, we performed a meta-analysis of the association between rs13266634 and T2D in different ethnic groups and assessed the relationships between SLC30A8 genotypes and some properties of isolated human islets. Methods From 32 original articles, a total of 77,234 control individuals and 44,945 subjects with T2D were studied in meta-analysis. To assess the relationships between SLC30A8 genotype and islet cell phenotype, insulin secretion in response to glucose, glucose plus arginine and glucose plus glibenclamide was determined in pancreatic islets isolated from 82 multiorgan donors genotyped for the rs13266634 polymorphism. Quantitative expression of SLC30A8 , Insulin and Glucagon mRNA was also measured. Results Overall, each SLC30A8 risk allele was associated with a 14% increased risk for T2D ( P =2.78×10 −34 ). The population risk of T2D attributable to this polymorphism was estimated at 9.5% in Europeans and 8.1% in East Asians. Basal and stimulated insulin secretion from human islets as well as islet expressions of SLC30A8 , Insulin and Glucagon were not affected by the presence of the polymorphism. However, SLC30A8 expression was positively correlated with Insulin ( r =0.75, P =6.43×10 −6 ) and Glucagon ( r : 0.70, P =4.89×10 −5 ) levels. Conclusions The SLC30A8 rs13266634 polymorphism is among the most confirmed genetic markers of T2D in Europeans and East Asians. In isolated human islets, the risk C-allele does not affect ex-vivo insulin secretion and SLC30A8 expression, which is correlated with that of insulin and glucagon.
Published: 2016

30. Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes

Author: Amanda J. Bennett, Lori L. Bonnycastle, Inês Barroso, Gudmar Thorleifsson, Charlotta Pisinger, Timothy M. Frayling, Laura J. Scott, Christian Herder, Mark Walker, Markku Laakso, Laura Pascoe, Beverley M. Shields, Thomas Sparsø, Ele Ferrannini, John R. B. Perry, Torsten Lauritzen, Felicity Payne, Thomas Illig, Michael N. Weedon, Beatrice Knight, Luigi Ferrucci, Giuseppe Paolisso, Claudia Langenberg, Andrew D. Morris, Torben Hansen, Ewan R. Pearson, Oluf Pedersen, Annelli Sandbæk, Peter Schwarz, Mario A. Morken, Colin N. A. Palmer, Peter Nilsson, Marcello Maggio, Narisu Narisu, Katharine R. Owen, Stefan R. Bornstein, Michael Boehnke, Mike Sampson, Leif Groop, Marjo-Riitta Järvelin, Aimo Ruokonen, Andrew T. Hattersley, Valgerdur Steinthorsdottir, Unnur Thorsteinsdottir, Ele Zeggini Magic, Mark I. McCarthy, Cecilia M. Lindgren, Christopher J. Groves, Elizabeth H. Young, Johanna Kuusisto, Harald Grallert, Valeriya Lyssenko, Anette P. Gjesing, Malin Neptin, Anne U. Jackson, Kari Stefansson, Nicholas J. Wareham, Heather M. Stringham, Perry, Jr, Weedon, Mn, Langenberg, C, Jackson, Au, Lyssenko, V, Sparsø, T, Thorleifsson, G, Grallert, H, Ferrucci, L, Maggio, M, Paolisso, Giuseppe, Walker, M, Palmer, Cn, Payne, F, Young, E, Herder, C, Narisu, N, Morken, Ma, Bonnycastle, Ll, Owen, Kr, Shields, B, Knight, B, Bennett, A, Groves, Cj, Ruokonen, A, Jarvelin, Mr, Pearson, E, Pascoe, L, Ferrannini, E, Bornstein, Sr, Stringham, Hm, Scott, Lj, Kuusisto, J, Nilsson, P, Neptin, M, Gjesing, Ap, Pisinger, C, Lauritzen, T, Sandbaek, A, Sampson, M, Zeggini, Me, Lindgren, Cm, Steinthorsdottir, V, Thorsteinsdottir, U, Hansen, T, Schwarz, P, Illig, T, Laakso, M, Stefansson, K, Morris, Ad, Groop, L, Pedersen, O, Boehnke, M, Barroso, I, Wareham, Nj, Hattersley, At, Mccarthy, Mi, and Frayling, Tm
Subjects: Male, AUGSBURG CASE-COHORT, Genome-wide association study, Type 2 diabetes, 0302 clinical medicine, Sex hormone-binding globulin, Risk Factors, Sex Hormone-Binding Globulin, polycyclic compounds, Gonadal Steroid Hormones, 11 Medical and Health Sciences, Genetics (clinical), reproductive and urinary physiology, Genetics & Heredity, 0303 health sciences, biology, INSULIN SENSITIVITY, Association Studies Articles, General Medicine, Middle Aged, PROSTATE-CANCER, 3. Good health, POSTMENOPAUSAL WOMEN, MENDELIAN RANDOMIZATION, Female, TESTOSTERONE TREATMENT, Life Sciences & Biomedicine, hormones, hormone substitutes, and hormone antagonists, Adult, Biochemistry & Molecular Biology, medicine.medical_specialty, BODY-COMPOSITION, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, STEROID-HORMONES, Polymorphism, Single Nucleotide, 03 medical and health sciences, Diabetes mellitus, Internal medicine, Mendelian randomization, Genetics, medicine, Humans, GENOME-WIDE ASSOCIATION, Molecular Biology, 030304 developmental biology, Aged, Science & Technology, Case-control study, Odds ratio, 06 Biological Sciences, medicine.disease, MAGIC, SERUM CONCENTRATIONS, Endocrinology, Diabetes Mellitus, Type 2, Case-Control Studies, biology.protein
Abstract: Udgivelsesdato: 2010-Feb-1 Epidemiological studies consistently show that circulating sex hormone binding globulin (SHBG) levels are lower in type 2 diabetes patients than non-diabetic individuals, but the causal nature of this association is controversial. Genetic studies can help dissect causal directions of epidemiological associations because genotypes are much less likely to be confounded, biased or influenced by disease processes. Using this Mendelian randomization principle, we selected a common single nucleotide polymorphism (SNP) near the SHBG gene, rs1799941, that is strongly associated with SHBG levels. We used data from this SNP, or closely correlated SNPs, in 27 657 type 2 diabetes patients and 58 481 controls from 15 studies. We then used data from additional studies to estimate the difference in SHBG levels between type 2 diabetes patients and controls. The SHBG SNP rs1799941 was associated with type 2 diabetes [odds ratio (OR) 0.94, 95% CI: 0.91, 0.97; P = 2 x 10(-5)], with the SHBG raising allele associated with reduced risk of type 2 diabetes. This effect was very similar to that expected (OR 0.92, 95% CI: 0.88, 0.96), given the SHBG-SNP versus SHBG levels association (SHBG levels are 0.2 standard deviations higher per copy of the A allele) and the SHBG levels versus type 2 diabetes association (SHBG levels are 0.23 standard deviations lower in type 2 diabetic patients compared to controls). Results were very similar in men and women. There was no evidence that this variant is associated with diabetes-related intermediate traits, including several measures of insulin secretion and resistance. Our results, together with those from another recent genetic study, strengthen evidence that SHBG and sex hormones are involved in the aetiology of type 2 diabetes.
Published: 2016

31. Low frequency variants in the exons only encoding isoform A of HNF1A do not contribute to susceptibility to type 2 diabetes

Author: Katharine R. Owen, Anna L. Gloyn, Mark I. McCarthy, Andrew T. Hattersley, Christopher J. Groves, Bahram Jafar-Mohammadi, and Timothy M. Frayling
Subjects: Nonsynonymous substitution, Adult, Male, endocrine system, lcsh:Medicine, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Genome-wide association study, Biology, Genetics and Genomics/Complex Traits, Medical sciences, Polymerase Chain Reaction, Maturity onset diabetes of the young, 03 medical and health sciences, Exon, 0302 clinical medicine, medicine, Humans, Genetic Predisposition to Disease, Diabetes and Endocrinology/Type 2 Diabetes, Hepatocyte Nuclear Factor 1-alpha, lcsh:Science, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, Genetics (medical sciences), lcsh:R, Haplotype, Diabetes, Exons, Middle Aged, medicine.disease, Penetrance, HNF1A, Genetics and Genomics/Disease Models, Diabetes Mellitus, Type 2, Mutation, lcsh:Q, Female, Research Article
Abstract: BACKGROUND: There is considerable interest in the hypothesis that low frequency, intermediate penetrance variants contribute to the proportion of Type 2 Diabetes (T2D) susceptibility not attributable to the common variants uncovered through genome-wide association approaches. Genes previously implicated in monogenic and multifactorial forms of diabetes are obvious candidates in this respect. In this study, we focussed on exons 8-10 of the HNF1A gene since rare, penetrant mutations in these exons (which are only transcribed in selected HNF1A isoforms) are associated with a later age of diagnosis of Maturity onset diabetes of the young (MODY) than mutations in exons 1-7. The age of diagnosis in the subgroup of HNF1A-MODY individuals with exon 8-10 mutations overlaps with that of early multifactorial T2D, and we set out to test the hypothesis that these exons might also harbour low-frequency coding variants of intermediate penetrance that contribute to risk of multifactorial T2D. METHODOLOGY AND PRINCIPAL FINDINGS: We performed targeted capillary resequencing of HNF1A exons 8-10 in 591 European T2D subjects enriched for genetic aetiology on the basis of an early age of diagnosis (< or =45 years) and/or family history of T2D (> or =1 affected sibling). PCR products were sequenced and compared to the published HNF1A sequence. We identified several variants (rs735396 [IVS9-24T>C], rs1169304 [IVS8+29T>C], c.1768+44C>T [IVS9+44C>T] and rs61953349 [c.1545G>A, p.T515T] but no novel non-synonymous coding variants were detected. CONCLUSIONS AND SIGNIFICANCE: We conclude that low frequency, nonsynonymous coding variants in the terminal exons of HNF1A are unlikely to contribute to T2D-susceptibility in European samples. Nevertheless, the rationale for seeking low-frequency causal variants in genes known to contain rare, penetrant mutations remains strong and should motivate efforts to screen other genes in a similar fashion.
Published: 2016

32. Prevalence and clinical characteristics of maternally inherited diabetes and deafness caused by the mt3243A > G mutation in young adult diabetic subjects in Sri Lanka

Author: Amy Barrett, Mark I. McCarthy, Prasad Katulanda, Anna L. Gloyn, Christopher J. Groves, David R. Matthews, and Rezvi Sheriff
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Deafness, DNA, Mitochondrial, Diabetes mellitus genetics, Endocrinology, Pregnancy, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Diabetes Mellitus, Humans, Family history, Young adult, Sri Lanka, business.industry, medicine.disease, Obesity, Surgery, Pedigree, Cohort, Mutation, Female, Metabolic syndrome, business, Body mass index
Abstract: AIMS: The maternally inherited mt3243A > G mutation is associated with a variable clinical phenotype including diabetes and deafness (MIDD). We aimed to determine the prevalence and clinical characteristics of MIDD in a large South Asian cohort of young adult-onset diabetic patients from Sri Lanka. METHODS: DNA was available from 994 subjects (age of diagnosis 16-40 years, age at recruitment < or = 45 years). Mutation screening was performed using a QRT-PCR method on an ABI 7900HT system using sequence-specific probes. Samples with heteroplasm > or = 5.0% were considered positive. RESULTS: Nine (four males) mutation-positive subjects were identified (prevalence 0.9%). They were diagnosed at a younger age (25.9 +/- 4.8 years vs. 31.9 +/- 5.6 years, P = 0.002) and were lean (body mass index [BMI] 18.7 +/- 2.7 kg/m(2) vs. 24.7 +/- 4.0 kg/m(2), P < 0.001) compared to NMCs. One mutation-positive subject (11.1%) had metabolic syndrome, compared to 633 (64.3%) of NMCs. Insulin therapy within 6 months of diagnosis was used in four (44.0%) carriers compared to 6.9% of NMCs (P = 0.002). Combined screening criteria of any two of maternal history of diabetes, personal history of hearing impairment and family history of hearing impairment only identified five (55%) of the carriers, with a positive predictive value of 7.4%. CONCLUSIONS: The prevalence of mt3243A > G mutation among young adult-onset diabetic subjects from Sri Lanka was 0.9%. Our study demonstrates that a maternal family history of diabetes and either a personal and/or family history of deafness only distinguish half of patients with MIDD from Sri Lankan subjects with young-onset diabetes.
Published: 2016

33. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

Author: Bo Isomaa, Anne U. Jackson, Richard N. Bergman, A Sandbaek, Yun Li, Oluf Pedersen, Thomas Edward Hughes, Mike Erdos, Christine Meisinger, Kari Kubalanza, Felicity Payne, Mark Walker, E Pettersen, William L. Duren, Kristin Ardlie, Palmer Cna., Michael Boehnke, Peter M. Nilsson, Graham A. Hitman, Rachel M. Freathy, Matthew G. Rees, Johanna Kuusisto, Finny G Kuruvilla, Kari Stefansson, P Deodhar, Knut Borch-Johnsen, Perry Jrb., Inês Barroso, Hana Lango, Richa Saxena, Augustine Kong, Gonçalo R. Abecasis, Katherine S. Elliott, Jonathan Marchini, Richard M. Watanabe, Christopher J. Groves, Niels Grarup, Unnur Thorsteinsdottir, Doney Asf., Kristina Bengtsson Boström, Peter Almgren, Cristen J. Willer, Torben Jørgensen, Lauren Gianniny, Beverley M. Shields, Christian Herder, Mario A. Morken, Lu Qi, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Nigel W. Rayner, Benjamin F. Voight, H Chen, J J Roix, Karen L. Mohlke, Heather M. Stringham, Andrew D. Morris, Mark I. McCarthy, Gudmar Thorleifsson, Frank B. Hu, Narisu Narisu, Mark J. Daly, Amanda F. Marvelle, Markku Laakso, Leif Groop, Laura J. Scott, Ding C-J., L Qin, Lori L. Bonnycastle, Thomas Illig, Noël P. Burtt, Michael N. Weedon, Valeriya Lyssenko, Amy J. Swift, Timothy M. Frayling, Nicholas J. Wareham, de Bakker Piw., Tiinamaija Tuomi, Kristian Hveem, Candace Guiducci, T Hu, Andrew T. Hattersley, David Altshuler, Harald Grallert, Peter S. Chines, Inga Prokopenko, Torsten Lauritzen, Katharine R. Owen, Eleftheria Zeggini, Carl Platou, Marketa Sjögren, Jaakko Tuomilehto, Nicholas J. Timpson, Francis S. Collins, Kristian Midthjell, Gregers S. Andersen, Claudia Langenberg, and Torben Hansen
Subjects: Genetics, 0303 health sciences, endocrine system, SLC30A8, Genome, Human, 030209 endocrinology & metabolism, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Heritability, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Diabetes Mellitus, Type 2, Meta-analysis, biology.protein, Humans, Genetic Predisposition to Disease, Human genome, CDKAL1, 030304 developmental biology
Abstract: Udgivelsesdato: 2008-May Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.
Published: 2016

34. Type 2 diabetes risk alleles are associated with reduced size at birth

Author: Nicholas J. Timpson, George Davey Smith, Andrew T. Hattersley, Timothy M. Frayling, Beverley M. Shields, John R. B. Perry, Amanda J. Bennett, Eleftheria Zeggini, Chris Power, David P. Strachan, Michael N. Weedon, Paul Elliott, Elina Hyppönen, Marjo-Riitta Järvelin, Christopher J. Groves, Rachel M. Freathy, Susan M. Ring, Anneli Pouta, Mark I. McCarthy, Aimo Ruokonen, Hana Lango, Cecilia M. Lindgren, Freathy, Rachel M, Bennett, Amanda J, Ring, Susan M, Shields, Beverly, Hypponen, Elina, and Hattersley, Andrew T
Subjects: medicine.medical_specialty, Offspring, Endocrinology, Diabetes and Metabolism, Birth weight, Mothers, Apoptosis, 030209 endocrinology & metabolism, Type 2 diabetes, Biology, risk alleles, fetal insulin, 03 medical and health sciences, Fetus, 0302 clinical medicine, Insulin resistance, Risk Factors, Insulin-Secreting Cells, Internal medicine, Insulin Secretion, Genotype, Genetics, Internal Medicine, medicine, Birth Weight, Humans, Insulin, low birth weight, CDKAL1, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, SLC30A8, Infant, Newborn, DNA, Infant, Low Birth Weight, medicine.disease, 3. Good health, Low birth weight, Endocrinology, Diabetes Mellitus, Type 2, biology.protein, Original Article, type 2 diabetes, medicine.symptom
Abstract: OBJECTIVE Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight. RESEARCH DESIGN AND METHODS We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring. RESULTS We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11–31], P = 2 × 10−5, and 14 g [4–23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39–120) lighter at birth than the 8% carrying none (Ptrend = 5 × 10−7). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus. CONCLUSIONS Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype.
Published: 2016

35. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Author: Morris J. Brown, Sanjeev S. Bhaskar, Alison J. Coffey, Suzanne Rafelt, Kirsten McLay, John Bowes, Francesca Bredin, Alastair Compston, John C. Mansfield, Elaine R. Nimmo, Kate Downes, Peter McGuffin, Neil Walker, Anthony J. Balmforth, Philip Howard, Detelina Grozeva, Helen Stevens, Kate L. Lee, Richard D. Pearson, Gerome Breen, T. Daniel Andrews, Sheila Seal, Anna Elliot, Beverley M. Shields, Andrew T. Hattersley, Sarah Edkins, Ann E. Morgan, Gil McVean, Julian Maller, Millicent A. Stone, Adam Auton, Carol Scott, Michael R. Stratton, Matthew Woodburn, John R. B. Perry, Michael Conlon O'Donovan, Nigel P. Carter, Vincent Plagnol, Stephen Sawcer, Sarah Hines, Mahim Jain, Allan H. Young, Steve Eyre, Elilan Somaskantharajah, Alexander J. Mentzer, Niall Cardin, Eleanor Howard, Inês Barroso, Stephen C. L. Gough, Toby Johnson, Deborah P M Symmons, Christopher Holmes, David St Clair, Patricia B. Munroe, Sue Shaw-Hawkins, Emma Gray, Stephen W. Scherer, Tariq Ahmad, Jaswinder Bull, Debbie Hughes, E. Russell, Timothy M. Frayling, Chris Clee, I. Nicol Ferrier, James Lee, Dominic P. Kwiatkowski, Husam Hebaishi, Anne Hinks, Simon Myers, Gareth Evans, Eleftheria Zeggini, Katarina Spanova, Michael L. Mimmack, David M. Reid, Amanda J. Bennett, Richard T. Scott, Armand Valsesia, Derek P. Jewell, Andrew P. Morris, Peter Donnelly, Mark J. Caulfield, Jake K. Byrnes, Lars Feuk, Pile Harrison, Anna F. Dominiczak, Cathryn Edwards, Andrew Dunham, Dalila Pinto, Inga Prokopenko, Ian Jones, Craig Mowat, Nigel R. Ovington, Willem H. Ouwehand, Edward Flynn, Jason D. Cooper, Louise V. Wain, Alistair Forbes, Bernadette Ebbs, Jennifer Jolley, Jonathan Marchini, Peter S. Braund, Ifejinelo Onyiah, Mark Walker, Adrian V. S. Hill, Cordelia Langford, Anne M. Phillips, George Kirov, David P. Strachan, Oliver S. Burren, Martin D. Tobin, Anthony G. Wilson, Ian N. Bruce, Hana Lango-Allen, Alistair S. Hall, Natalie J. Prescott, Charles Lee, Clare Turnbull, Cecilia M. Lindgren, John D. Isaacs, Jack Satsangi, Liz Forty, John M. C. Connell, Neelam Hassanali, Hazel E. Drummond, Matthew A. Brown, John A. Todd, Joanna M. M. Howson, Jennifer G. Sambrook, Graham A. Hitman, Michael N. Weedon, Christopher Yau, Abiodun Onipinla, Kathy Stirrups, Chris Tyler-Smith, Darshna Dudakia, G. Mark Lathrop, Katherine Gordon-Smith, Nazneen Rahman, Christopher J. Groves, William G. Newman, Kirstie Parnell, Stephen G. Ball, Tomas W Fitzgerald, Paul Gilbert, Kevin Lewis, Charlie W. Lees, Polly Gibbs, Rachel M. Freathy, Aarno Palotie, Katarzyna Blaszczyk, Matthew E. Hurles, Jonathan Stephens, Lynne J. Hocking, Nicholas A. Watkins, Christopher G. Mathew, Helen Schuilenburg, David Pernet, Eleni Giannoulatou, Kimmo Palin, Nigel W. Rayner, Donald F. Conrad, Susan M. Ring, John R. Thompson, Debbie J. Smyth, Wendy L. McArdle, B. Paul Wordsworth, David M. Evans, Dunecan Massey, Naomi Hammond, Diana Eccles, Panos Deloukas, Sian Caesar, Chris P. Barnes, Sophia Steer, Anthony Attwood, Chris Wallace, Richard Redon, Paul Burton, Anne Barton, Marcus Pembrey, Michael John Owen, Jane Worthington, Mary E. Travers, Jeremy D. Sanderson, Meeta Maisuria-Armer, Elaine K. Green, Michael A. Quail, Oliver J. Brand, Anne Farmer, Matthew J. Simmonds, Neil Robertson, Nicholas John Craddock, Zhan Su, Jan Aerts, Martin Farrall, Hazel Arbury, Damjan Vukcevic, Paul Emery, Omer Gokumen, A Hall, Wendy Thomson, Jeffrey C. Barrett, Margaret Warren-Perry, Rhian Gwilliam, Sarah E. Hunt, Samuel Robson, Paul Martin, Audrey Duncanson, Anthony Renwick, John Webster, Lisa Jones, Mark I. McCarthy, Nilesh J. Samani, Matthew Hardy, Miles Parkes, John Burton, Jayne A. Franklyn, Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Statistics [Oxford], University of Oxford, The Wellcome Trust Centre for Human Genetics [Oxford], The Wellcome Trust Case Control Consortium, Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Oxford [Oxford], and Medical Research Council (MRC)
Subjects: endocrine system diseases, [SDV]Life Sciences [q-bio], Genome-wide association study, Pilot Projects, CCL3L1, SUSCEPTIBILITY, Arthritis, Rheumatoid, Diabetes mellitus genetics, 0302 clinical medicine, Crohn Disease, Gene Frequency, DUPLICATIONS, SCHIZOPHRENIA, Disease, Copy-number variation, Oligonucleotide Array Sequence Analysis, Genetics, 0303 health sciences, Multidisciplinary, PSORIASIS, HERITABILITY, LARGE-SCALE, Nucleic Acid Hybridization, Science & Technology - Other Topics, Wellcome Trust Case Control Consortium, Quality Control, DNA Copy Number Variations, General Science & Technology, Single-nucleotide polymorphism, COPY-NUMBER VARIATION, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, MD Multidisciplinary, mental disorders, Genetic predisposition, Diabetes Mellitus, SNP, Humans, Genetic Predisposition to Disease, Allele frequency, POLYMORPHISMS, 030304 developmental biology, Genetic association, Science & Technology, MULTIDISCIPLINARY SCIENCES, DELETION, C431 Medical Genetics, Case-Control Studies, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with diseaseIRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetesalthough in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. © 2010 Macmillan Publishers Limited. All rights reserved.
Published: 2016

36. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

Author: Timo A. Lakka, Kathleen Stirrups, Jean Ferrières, Ying Wu, Gulum Kosova, Toby Johnson, Heather M. Stringham, Bruce M. Psaty, Bruna Gigante, Göran Hallmans, Cornelia M. van Duijn, Kae Woei Liang, Niclas Eriksson, N. William Rayner, Lynda M. Rose, Stavroula Kanoni, Xueling Sim, Evangelos Evangelou, Philippe Froguel, Michel Burnier, Andrew P. Morris, Olle Melander, Martin Farrall, Albert V. Smith, Brendan J. Keating, Thomas Illig, Johan Sundström, Dorret I. Boomsma, Kate Witkowska, Ellen M. Schmidt, Aki S. Havulinna, Ann-Kristin Petersen, Paul F. O'Reilly, Young Jin Kim, Kari Kuulasmaa, Tom Wilsgaard, John D. Eicher, Marcus E. Kleber, Francis S. Collins, Rona J. Strawbridge, Ronald M. Krauss, Fotios Drenos, Stuart K. Kim, Ken K. Ong, Pascal Bovet, Danish Saleheen, Jaspal S. Kooner, Karl-Heinz Herzig, Tien Yin Wong, Benjamin F. Voight, Stefania Bandinelli, Stéphane Lobbens, Colin A. McKenzie, Jing Hua Zhao, Terrence Forrester, Louise A. Donnelly, Alice Stanton, Jean Dallongeville, Kirill V. Tarasov, Narisu Narisu, Jürgen Gräßler, Luigi Ferrucci, Peter S. Sever, Paul Elliott, Tune H. Pers, Andrew J. Smith, Tomas Axelsson, Young Ah Shin, Nora Franceschini, James F. Wilson, Vilmundur Gudnason, Kati Kristiansson, Andrew A. Hicks, Kent D. Taylor, Genovefa Kolovou, Andrew D. Morris, André G. Uitterlinden, Serena Sanna, Xiuqing Guo, Honghuang Lin, Aravinda Chakravarti, Wayne Huey-Herng Sheu, Panos Deloukas, Linda S. Adair, Diana Kuh, Murielle Bochud, Eric Boerwinkle, Inger Njølstad, Meena Kumari, Norman Klopp, Leo-Pekka Lyytikäinen, Steven C. Hunt, Weihua Zhang, Tõnu Esko, Pierre Meneton, Markus Perola, Erik P A Van Iperen, Georg Ehret, Veikko Salomaa, Lars Lind, Zoltán Kutalik, Cristiano Fava, Caroline Hayward, Hugh S. Markus, Teresa Ferreira, Stefan R. Bornstein, Vasyl Pihur, Patricia B. Munroe, Anne U. Jackson, Eirini Marouli, Gabriele Müller, Damiano Baldassarre, Jacques E. Rossouw, Dan E. Arking, Maija Hassinen, Nicholas J. Wareham, Robert Roberts, Daniel I. Chasman, I. Shou Chang, Sylvain Sebert, Tove Fall, Roby Joehanes, Patrik K. E. Magnusson, John C. Chambers, Peter Vollenweider, Wen Jane Lee, Dmitry Shungin, Mathias Gorski, Christopher Newton-Cheh, Anders Franco-Cereceda, Ching-Yu Cheng, Yun Kyoung Kim, Ruth J. F. Loos, Lude Franke, Karen L. Mohlke, Yii-Der Ida Chen, Carlos Iribarren, Martina Müller-Nurasyid, Alexander Teumer, Andrew D. Johnson, Antonella Mulas, Ulf Gyllensten, Martin D. Tobin, George Dedoussis, Rainford J. Wilks, Joshua C. Bis, Beverley Balkau, Jie Yao, Frida Renström, Themistocles L. Assimes, Morris Brown, Inês Barroso, Hyun Min Kang, Loic Yengo, Mika Kähönen, Christopher J. Groves, Kirsti Kvaløy, Rainer Rauramaa, Heribert Schunkert, Satu Männistö, Marjo-Riitta Järvelin, Nancy L. Pedersen, Karl Gertow, Rick Jansen, Thomas Quertermous, Jarmo Virtamo, Lazaros Lataniotis, Serge Hercberg, Paul M. Ridker, Osorio Meirelles, Jostein Holmen, Phil Howard, G. Kees Hovingh, Jeanette Erdmann, Jong-Young Lee, Peter Schwarz, Ramaiah Nagaraja, Elizabeth Theusch, Wei Zhao, Sonia Shah, Chao A. Hsiung, Santhi K. Ganesh, Richard S. Cooper, John M. C. Connell, Jian'an Luan, Graciela E. Delgado, Eric Kim, Daniel Levy, Li Lin, Jerome I. Rotter, Andres Metspalu, Nabila Bouatia-Naji, Christopher J. O'Donnell, Roberto Elosua, Andrew Wong, Alanna C. Morrison, Juha Saltevo, Michael R. Barnes, Alan B. Weder, Kay-Tee Khaw, Leena Moilanen, Peter S. Chines, Claudia Langenberg, Marika Kaakinen, Asif Rasheed, Annette Peters, Angela Döring, Alena Stančáková, Richard A. Jensen, Jaana Lindström, Alison H. Goodall, Toshiko Tanaka, Loukianos S. Rallidis, Dabeeru C. Rao, Ann-Christine Syvänen, Alun Evans, Brenda W.J.H. Penninx, Sarah Edkins, Xiaohui Li, Neil Poulter, Jouko Saramies, Ulf de Faire, Walter Palmas, Jaakko Tuomilehto, Louise V. Wain, Cristina Menni, Stephen Bevan, Maria X. Sosa, Nanette R. Lee, Anuj Goel, Germaine C. Verwoert, Kjell Nikus, Helen R. Warren, May E. Montasser, Ren-Hua Chung, Francesco Gianfagna, Kristian Hveem, Rainer Rettig, Unnur Thorsteinsdottir, Lori L. Bonnycastle, Tim D. Spector, Paul W. Franks, Bamidele O. Tayo, Ilja M. Nolte, John Danesh, E. Shyong Tai, Mika Kivimäki, Devin Absher, Oddgeir L. Holmen, Per Eriksson, Pirjo Komulainen, Peter P. Pramstaller, Cameron D. Palmer, He Gao, Elena Tremoli, H.-Erich Wichmann, Myriam Fornage, Gyda Bjornsdottir, Afshin Parsa, Anders Hamsten, Terho Lehtimäki, Lasse Folkersen, Janine F. Felix, Anna F. Dominiczak, Hinco J. Gierman, Edward G. Lakatta, Alex S. F. Doney, Erik Ingelsson, Colin N. A. Palmer, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Vladan Mijatovic, Mark I. McCarthy, Joel N. Hirschhorn, Winfried März, Nilesh J. Samani, Stefan Enroth, Mark J. Caulfield, Gudmar Thorleifsson, Tsun-Po Yang, François Mach, Cristen J. Willer, Claudia P. Cabrera, Aline Wagner, Michael Boehnke, Elias Salfati, Sekar Kathiresan, Ramachandran S. Vasan, Franco Giulianini, Harm-Jan Westra, Harold Snieder, Mark O. Goodarzi, M. Arfan Ikram, Fred Paccaud, Johannes H. Smit, Anna-Liisa Hartikainen, Xiaofeng Zhu, Markku Laakso, Ahmad Vaez, Albert Hofman, Amy J. Swift, Maria Hughes, I. Te Lee, Aroon D. Hingorani, Matti Uusitupa, Oscar H. Franco, Kenneth Rice, Veronique Vitart, Ross M. Fraser, Jouke-Jan Hottenga, Kari Stefansson, Dhananjay Vaidya, Johns Hopkins University, School of Medicine, Hôpitaux Universitaires de Genève (HUG), Saw Swee Hock School of Public Health, National University of Singapore (NUS), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), Department of Biostatistics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Michigan System, Department of Computational Medicine and Bioinformatics (DCM&B), Queen Mary University of London (QMUL), GlaxoSmithKline, Glaxo Smith Kline, deCODE genetics [Reykjavik], University of Cambridge [UK] (CAM), University of Dundee, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Karolinska University Hospital [Stockholm], Umea University Hospital, Lund University [Lund], Queen's University [Belfast] (QUB), National Institutes of Health, Department of Genomics of Common Disease, Imperial College London, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), National Institute of Health and Welfare, Institute for Molecular Medicine Finland (FIMM), University College London Hospitals (UCLH), University Hospital of Heidelberg, Harbor UCLA Medical Center [Torrance, Ca.], University of Tampere, University of Verona (UNIVR), Uppsala University Hospital, Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Stanford University School of Medicine [CA, USA], Medical School University of Athens, Partenaires INRAE, Children's Hospital Oakland Research Institute, Boston Children's Hospital, Broad Institute of Harvard and MIT, University of Copenhagen = Københavns Universitet (KU), Statens Serum Institut [Copenhagen], Framingham Heart Dis Epidemiol Study, Department of Psychiatry, VU University Medical Center [Amsterdam], National Heart, Lung and Blood Institute, Osong Health Technology Administration Complex, University of Pennsylvania, Department of Genetics, University of North Carolina at Chapel Hill (UNC), Loyola University [Chicago], Centre Hospitalier Universitaire Vaudois (CHUV), Hudson Alpha Institute for Biotechnology, Erasmus University Rotterdam, Department of Medical Sciences, Uppsala University, Università degli Studi di Milano [Milano] (UNIMI), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Université Paris-Sud - Paris 11 (UP11), Azienda Sanitaria Firenze, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], University of Lincoln, University of Washington [Seattle], Amgen Inc., The University of Texas Health Science Center at Houston (UTHealth), VU University Amsterdam, University of Dresden Medical School, Université de Lausanne (UNIL), Healthcare NHS Trust, National Health Research Institutes, National University Health System [Singapore] (NUHS), Duke-NUS Medical School [Singapore], Singapore Eye Research Institute [Singapore] (SERI), National Human Genome Research Institute (NHGRI), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Radiology and nuclear medicine, EMGO - Mental health, Lin, Li, Mach, François, ProdInra, Migration, University of Oxford, Università degli studi di Verona = University of Verona (UNIVR), University of Copenhagen = Københavns Universitet (UCPH), Università degli Studi di Milano = University of Milan (UNIMI), Vrije Universiteit Amsterdam [Amsterdam] (VU), Université de Lausanne = University of Lausanne (UNIL), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), EMGO+ - Lifestyle, Overweight and Diabetes, Biological Psychology, APH - Amsterdam Public Health, Epidemiology and Data Science, Graduate School, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Danesh, John [0000-0003-1158-6791], Khaw, Kay-Tee [0000-0002-8802-2903], Markus, Hugh [0000-0002-9794-5996], Ong, Kenneth [0000-0003-4689-7530], Johnson, Kathleen [0000-0002-6823-3252], Wareham, Nicholas [0000-0003-1422-2993], Zhao, Jing Hua [0000-0003-4930-3582], Langenberg, Claudia [0000-0002-5017-7344], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), CHARGE-EchoGen Consortium, CHARGE-HF Consortium, Wellcome Trust Case Control Consortium, Medical Microbiology & Infectious Diseases, Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Clinical Genetics, Biochemistry, National Institute for Health Research, and Medical Research Council (MRC)
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), CHROMATIN, [SDV]Life Sciences [q-bio], LOCI, Genome-wide association study, Blood Pressure, SUSCEPTIBILITY, Bioinformatics, Cardiovascular, Genome-wide association studies, Medical and Health Sciences, single nucleotide polymorphism, CHARGE-EchoGen consortium, GWAS, 2.1 Biological and endogenous factors, Aetiology, Cells, Cultured, African Continental Ancestry Group, Genetics & Heredity, Genetics, ddc:616, Kidney, Framingham Risk Score, Cultured, COMMON VARIANTS, 11 Medical And Health Sciences, Single Nucleotide, Biological Sciences, African Continental Ancestry Group/genetics, Asian Continental Ancestry Group/genetics, Blood Pressure/genetics, Genome-Wide Association Study, Humans, Hypertension/genetics, Hypertension/pathology, Microarray Analysis, Polymorphism, Single Nucleotide, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Hypertension/genetics/pathology, Hypertension, Medical genetics, Wellcome Trust Case Control Consortium, Life Sciences & Biomedicine, TRAITS, Biotechnology, Asian Continental Ancestry Group, medicine.medical_specialty, CHARGE-EchoGen Consortium, Cells, Black People, BIOLOGY, Single-nucleotide polymorphism, Biology, Blood pressure, hypertension, genetics, single nucleotide polymorphism, GWAS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Asian People, medicine, Polymorphism, GENOME-WIDE ASSOCIATION, CELL-TYPES, METAANALYSIS, Genetic association, Science & Technology, CHARGE-HF consortium, 06 Biological Sciences, Genetic architecture, 030104 developmental biology, Blood pressure, CHARGE-HF Consortium, ARTERIAL-HYPERTENSION, Developmental Biology
Abstract: To dissect the genetic architecture of blood pressure (BP) and assess how its elevation promotes downstream cardiovascular diseases, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry. Genotypes from an additional 140,886 individuals of European ancestry were used as validation for loci reaching genome-wide significance but without prior support in the literature. We identified 66 BP loci, of which 17 were novel and 15 harbored multiple distinct association signals, and which together explain up to 3.5% of BP variation. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in BP control through modulating blood vessel tone and fluid filtration across multiple tissues, not solely the kidney. Importantly, the 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent (South-Asian, East-Asian and African), confirming that these are ancestral physiological effects that arose prior to human migration out of Africa. The 66-SNP BP risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our data expand current knowledge of BP pathways, and also, highlight that BP regulation and its effects may occur in multiple organs and tissues beyond the classic renal system.
Published: 2016

37. Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes

Author: M. Tang, S. Y. Kim, Tom Forsén, Yun Li, Q. Li, Karina Banasik, J. M. Dekker, Leif Groop, B. Balkau, N. van Leeuwen, Jacek Mokrosinski, G. Tian, Alex S. F. Doney, Thue W. Schwartz, H. Jiang, Johanna Kuusisto, Thorfinn Sand Korneliussen, S. Huang, Guillaume Charpentier, Giel Nijpels, Daniel R. Witte, Maria Lajer, Alena Stančáková, F. Xi, Oluf Pedersen, Anders Albrechtsen, Torben Jørgensen, Mozhgan Dorkhan, Torben Hansen, Amanda J. Bennett, B. Wang, Gregers S. Andersen, Chang Yu, Aneta Aleksandra Nielsen, Mark I. McCarthy, Lise Tarnow, Markku Laakso, Timothy M. Frayling, P.E. Slagboom, Olov Rolandsson, Y. Wang, Torsten Lauritzen, Christopher J. Groves, Weihua Zhang, Peter M. Nilsson, T. Jiang, Loic Yengo, Leen M 't Hart, Y. Gui, Tiinamaija Tuomi, Chao Nie, Peter Rossing, J. Zhang, Frida Renström, Andrew D. Morris, Cramer Christensen, Graham A. Hitman, Neil Robertson, H. Cao, Göran Hallmans, Allan Linneberg, Niels Grarup, Line Skotte, H. Wu, Colin N. A. Palmer, M. P. Manijak, Q. Zhang, Andrew P. Morris, Rasmus Ribel-Madsen, Yi Chen, Arne Astrup, Tibor V. Varga, Mark Walker, Y. Zhou, Jun Wang, Maria Sterner, Paul W. Franks, Lars Bolund, Andrew T. Hattersley, Johan Holmkvist, Karsten Kristiansen, David Altshuler, E. van 't Riet, Philippe Froguel, Stéphane Cauchi, R. Wu, Kunlun He, B. Mu, X. Ma, X. Liu, Weijing Li, H. Liang, Rasmus Nielsen, Olivier Lantieri, T. Ma, Xin Jin, Claes Ladenvall, Michel Marre, Nigel W. Rayner, Thomas Sparsø, Marie A. Vestmar, Johanne Marie Justesen, Ivan Brandslund, Q. Liao, Xiaoming Zhang, H. Zheng, Epidemiology and Data Science, General practice, EMGO - Lifestyle, overweight and diabetes, Massachusetts Institute of Technology. Department of Biology, and Altshuler, David
Subjects: Exome/genetics, Exome sequencing, Endocrinology, Diabetes and Metabolism, IDENTIFIES 6, EFFICIENT, Genome-wide association study, VARIANTS, 0302 clinical medicine, Gene Frequency, Glucose homeostasis, Genetic epidemiology, Exome, Polymorphism, Genetic/genetics, RISK, Genetics, 0303 health sciences, High-Throughput Nucleotide Sequencing, Type 2 diabetes, Polymorphism, Single Nucleotide/genetics, Lipids, Gene Frequency/genetics, Hypertension, Diabetes Mellitus, Type 2/genetics, Genotype, 030209 endocrinology & metabolism, Biology, Polymorphism, Single Nucleotide, DNA sequencing, Article, 03 medical and health sciences, Internal Medicine, Humans, Obesity, GENOME-WIDE ASSOCIATION, Allele frequency, METAANALYSIS, 030304 developmental biology, Polymorphism, Genetic, DIABETES SUSCEPTIBILITY LOCI, Minor allele frequency, INDIVIDUALS, Diabetes Mellitus, Type 2, DE-NOVO MUTATIONS, Next-generation sequencing, GLUCOSE-HOMEOSTASIS, Hypertension/genetics
Abstract: Aims/hypothesis Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. Methods The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m2 and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p 1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10−14), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10−11) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10−10). Conclusions/interpretation We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits. Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2756-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Published: 2012

38. Interactions of Dietary Whole-Grain Intake With Fasting Glucose– and Insulin-Related Genetic Loci in Individuals of European Descent

Author: Göran Hallmans, Josée Dupuis, Amanda J. Bennett, Ruth J. F. Loos, George Dedoussis, Emily Sonestedt, Rozenn N. Lemaitre, Toshiko Tanaka, Christopher J. Groves, André G. Uitterlinden, Stavroula Kanoni, Nita G. Forouhi, Zheng Ye, Jerome I. Rotter, Jose C. Florez, Ingegerd Johansson, Jose M. Ordovas, Julius S. Ngwa, David S. Siscovick, A. Smith, Luigi Ferrucci, Claudia Langenberg, Ingrid B. Borecki, Jennifer A. Nettleton, Stefania Bandinelli, James S. Pankow, Per Sjögren, M. C. Zillikens, Ulf Risérus, Kenneth J. Mukamal, Stephen B. Kritchevsky, Marju Orho-Melander, Georgia Saylor, van Rooij Fja., Nicholas J. Wareham, C M van Duijn, James B. Meigs, Jack L. Follis, Sijbrands Ejg., Witteman Jcm., Frida Renström, Luc Djoussé, Inga Prokopenko, Laufey Steingrimsdottir, Tamara B. Harris, Olov Rolandsson, L. J. Launer, Mike A. Nalls, Erik Ingelsson, Denise K. Houston, Dariush Mozaffarian, Mary K. Wojczynski, Kenneth Rice, Jennifer S. Anderson, Yongmei Liu, Nicola M. McKeown, Mary F. Feitosa, Melissa E. Garcia, Paul W. Franks, Albert Hofman, Frank B. Hu, Hivert M-F., Constantina Papoutsakis, and L A Cupples
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Type 2 diabetes, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Pancreatic hormone, 030304 developmental biology, 2. Zero hunger, Advanced and Specialized Nursing, 0303 health sciences, business.industry, Insulin, medicine.disease, Endocrinology, L-Glucose, chemistry, business, TCF7L2, Body mass index
Abstract: OBJECTIVE Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin. RESEARCH DESIGN AND METHODS Via meta-analysis of data from 14 cohorts comprising ∼48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value RESULTS Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: −0.009 mmol/l glucose [−0.013 to −0.005], P < 0.0001 and −0.011 pmol/l [ln] insulin [−0.015 to −0.007], P = 0.0003). No interactions met our multiple testing–adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele. CONCLUSIONS Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.
Published: 2010

39. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Author: Kenneth Rice, Amy J. Swift, Veronique Vitart, Lu Qi, Kaisa Silander, Olivier Le Bacquer, Laura Crisponi, David S. Siscovick, Bo Isomaa, Anne U. Jackson, Anke Tönjes, Richard N. Bergman, Rosa Maria Roccasecca, Luigi Ferrucci, Narisu Narisu, Kari Stefansson, Holly E. Syddall, Giuseppe Paolisso, Kim L. Ward, Paul Elliott, Scott M. Grundy, Paul Johnson, Jerome I. Rotter, Philippe Froguel, James B. Meigs, George Davey Smith, Andrew T. Hattersley, Leena Peltonen, Eric J.G. Sijbrands, Serena Sanna, María TeresaMartínez-Larrad, David Altshuler, Harald Grallert, Caroline S. Fox, Nita G. Forouhi, Dorret I. Boomsma, Harry Campbell, Jean Tichet, Angelo Scuteri, Aroon D. Hingorani, Daniel S. Pearson, Meena Kumari, Silvia Naitza, Shah Ebrahim, Manjinder S. Sandhu, Jose C. Florez, Cyrus Cooper, David M. Nathan, Joseph Hung, Fredrik Karpe, Ozren Polasek, Philip J. Barter, Ruth McPherson, Benjamin F. Voight, Wolfgang Rathmann, Abbas Dehghan, Udo Seedorf, Beverley M. Shields, Antti Jula, Pau Navarro, Josephine M. Egan, Rune R. Frants, Leif Groop, Gunnar Sigursson, Seppo Koskinen, Vincent Mooser, François Pattou, Jing Hua Zhao, Irene Pichler, John F. Peden, Göran Hallmans, Toshiko Tanaka, Ruth J. F. Loos, Peter Kovacs, Andrew D. Morris, Cécile Lecoeur, Jeffrey R. O'Connell, Massimo Mangino, Nicole Vogelzangs, Rhian Gwilliam, Gordon H. Williams, Carina Zabena, Naomi Hammond, Amélie Bonnefond, Björn Zethelius, Joachim Spranger, Nancy L. Pedersen, Christopher J. Groves, Nicholas J. Timpson, George Dedoussis, Veikko Salomaa, Peter Henneman, Andrew Walley, Serge Hercberg, Ian N. M. Day, Simon Heath, Matt Neville, Alex S. F. Doney, Robert Clarke, Olov Rolandsson, Panos Deloukas, Eric Boerwinkle, Y. AnteroKesaniemi, Mike Sampson, Gerard Waeber, Sven Bergmann, Ben A. Oostra, Manuel Serrano-Ríos, Mandy van Hoek, Christine Cavalcanti-Proença, Anna L. Gloyn, Ulla Sovio, Andrew P. Morris, Anneli Pouta, Amanda J. Bennett, Paul Scheet, Peter Schwarz, Jaakko Tuomilehto, Hugh Watkins, Johanna Kuusisto, Denis Rybin, Anna LiisaHartikainen, Maria GraziaFranzosi, Unnur Thorsteinsdottir, Rafn Benediktsson, Alan F. Wright, Colin N. Apalmer, Anuj Goel, Yavuz Ariyurek, Lars Lind, Robert Sladek, Stefan R. Bornstein, Reedik Mägi, Laila Simpson, Tim D. Spector, Paul W. Franks, Nicholas L. Smith, John R. B. Perry, Peter Vollenweider, Suzannah Bumpstead, Ruth E. Pakyz, Christa Meisinger, Alan R. Shuldiner, Josée Dupuis, Man Li, Eric J. Brunner, Francis S. Collins, Torben Hansen, James F. Wilson, Guangju Zhai, Igor Rudan, Nicole L. Glazer, Marco Orrù, Pierre Meneton, Knut Borch-Johnsen, Eleanor Wheeler, Gonçalo R. Abecasis, Mark I. McCarthy, Jouke JanHottenga, Inga Prokopenko, Ping An, Jérôme Delplanque, Albert Hofman, Andrew B. Singleton, Gabe Crawford, Thomas A. Buchanan, Avan Aihie Sayer, Richard M. Watanabe, David Schlessinger, A C Fedson, André G. Uitterlinden, Frank B. Hu, Jaqueline C. MWitteman, Dhiraj Varma, Ingrid B. Borecki, Sutapa Mukherjee, Murielle Bochud, Barbara Thorand, Christian Gieger, Lori L. Bonnycastle, Stephen J. Sharp, Markus Perola, Caroline Hayward, Kristin Ardlie, J. Graessler, Robert W. Mahley, Toby Johnson, Jian'an Luan, Joshua C. Randall, Cornelia M. van Duijn, Samuli Ripatti, Ko Willems van Dijk, Valgerdur Steinthorsdottir, Yurii S. Aulchenko, G. Mark Lathrop, Christian Dina, Eleftheria Zeggini, Cecilia M. Lindgren, Stavroula Kanoni, Timothy M. Frayling, Dawn M. Waterworth, Marika Kaakinen, Timo T. Valle, Diana Zelenika, Yii Der IdaChen, Angela Silveira, Nigel W. Rayner, Aimo Ruokonen, Yun Li, Cristian Pattaro, Annelli Sandbæk, Richa Saxena, Danielle Posthuma, Steven A. McCarroll, Niels Grarup, Samy Hadjadj, Pilar Galan, Xijing Han, Lyle J. Palmer, Ulf Gyllensten, Peter P. Pramstaller, Manuela Uda, Jarred B. McAteer, Brenda W.J.H. Penninx, Debbie A Lawlor, Torben Jørgensen, Beatrice Knight, Yvonne Böttcher, Claudia Langenberg, Nicole Soranzo, Ghislain Rocheleau, Erik Ingelsson, Mario A. Morken, Michael Roden, Felicity Payne, David R. Hillman, Michael Marmot, Karen L. Mohlke, Heather M. Stringham, Bruce M. Psaty, Gudmar Thorleifsson, Yoav Ben-Shlomo, Inês Barroso, W. H. Linda Kao, James S. Pankow, Valeriya Lyssenko, Nicholas J. Wareham, Tiinamaija Tuomi, Ann ChristineSyvänen, Braxton D. Mitchell, Alisa K. Manning, Mika Kivimäki, Peter Wagner, Praveen Sethupathy, G. BragiWalters, Jaakko Kaprio, Kijoung Song, Marjo Riitta-Järvelin, Michael A. Province, Andrew A. Hicks, Marilyn C. Cornelis, Sarah H. Wild, David Meyre, Guillaume Charpentier, Patrik K. E. Magnusson, David Melzer, Jennie Hui, Peter Shrader, Michael Stumvoll, Mark O. Goodarzi, Michael R. Erdos, Oluf Pedersen, Andreas Pfeiffer, Augustine Kong, Christian Herder, Laura J. Scott, John W. GYarnell, Kirsten Ohm Kyvik, Beverley Balkau, Antje Fischer-Rosinsky, Gonneke Willemsen, Thomas Illig, Neelam Hassanali, Markku Laakso, Michael Boehnke, John Beilby, Christopher S. Franklin, Fernando Rivadeneira, M. Carola Zillikens, Michael N. Weedon, Antonio Cao, Mark E. Cooper, Simon C. Potter, Eco J. C. de Geus, H.-Erich Wichmann, Amanda F. Elliott, Lachlan J. McOin, Sophie Visvikis-Siest, Thomas Sparsø, Laura J. McCulloch, Taina K. Lajunen, Peter S. Chines, Nabila Bouatia-Naji, Medical Research Council (MRC), Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Anxiety & Depression, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Mental Health, Ophthalmology, Epidemiology, Clinical Genetics, Dermatology, Internal Medicine, DIAGRAM Consortium, GIANT Consortium, Global BPgen Consortium, Anders Hamsten on behalf of Procardis Consortium, MAGIC investigators, Human genetics, Psychiatry, EMGO - Mental health, NCA - Attention & Cognition, and NCA - Anxiety & Depression
Subjects: Blood Glucose, Netherlands Twin Register (NTR), Candidate gene, Genome-wide association study, Type 2 diabetes, CIRCADIAN CLOCK, TRIGLYCERIDE LEVELS, 0302 clinical medicine, Delta-5 Fatty Acid Desaturase, Databases, Genetic, Homeostasis, GENETICS & HEREDITY, Anders Hamsten on behalf of Procardis Consortium, Child, Genetics, PLASMA-GLUCOSE, 0303 health sciences, Glucokinase regulatory protein, COMMON VARIANTS, 11 Medical And Health Sciences, Fasting, MAGIC investigators, 3. Good health, MODEL ASSESSMENT, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, ESSENTIAL COMPONENTS, Adolescent, DNA Copy Number Variations, Alleles, Blood Glucose/genetics, Blood Glucose/metabolism, DNA Copy Number Variations/genetics, Diabetes Mellitus, Type 2/genetics, Fasting/blood, Gene Expression Regulation, Genetic Loci/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeostasis/genetics, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide/genetics, Quantitative Trait Loci/genetics, Quantitative Trait, Heritable, Reproducibility of Results, Quantitative Trait Loci, 030209 endocrinology & metabolism, Biology, DIAGRAM Consortium, INSULIN-SECRETION, Polymorphism, Single Nucleotide, Article, Fasting glucose, 03 medical and health sciences, Insulin resistance, SDG 3 - Good Health and Well-being, Diabetes mellitus, Internal medicine, genome wide association study, glucose, diabetes type 2, medicine, GIANT Consortium, Allele, GENOME-WIDE ASSOCIATION, Global BPgen Consortium, 030304 developmental biology, Glycemic, Science & Technology, genome-wide association beta-cell dysfunction plasma-glucose insulin-secretion triglyceride levels essential components model assessment common variants circadian clock disease risk, DISEASE RISK, 06 Biological Sciences, medicine.disease, Endocrinology, Diabetes Mellitus, Type 2, Genetic Loci, biology.protein, BETA-CELL DYSFUNCTION, Developmental Biology
Abstract: Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46, 186 nondiabetic participants. Follow-up of 25 loci in up to 76, 558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
Published: 2010
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40. Management of Symptomatic Esophageal Involvement With Lichen Planus

Author: David Westaby, Emma K. Wedgeworth, Sallie Neill, Christopher J. Groves, and Panagiotis Vlavianos
Subjects: medicine.medical_specialty, Triamcinolone acetonide, medicine.drug_class, Population, Injections, Intralesional, Esophageal Diseases, Triamcinolone, Gastroenterology, Catheterization, Recurrence, Internal medicine, medicine, Humans, Esophagus, education, Glucocorticoids, education.field_of_study, Esophageal disease, business.industry, Lichen Planus, Middle Aged, medicine.disease, Combined Modality Therapy, Symptomatic relief, Dysphagia, Surgery, medicine.anatomical_structure, Esophageal stricture, Corticosteroid, Female, medicine.symptom, business, medicine.drug
Abstract: Aim: To describe the clinical features and treatment schedules of a series of 5 patients with esophageal lichen planus (LP). To review the literature on esophageal LP. Background: LP, a common papulosquamous dermatologic condition, can present to the gastroenterologist with esophageal involvement. This is rare and occurs in a distinct population of LP patients. Disease at this site is frequently refractory to conventional treatment. Case Series: Between 2001 to 2007, 5 female patients were diagnosed with esophageal LP. They all had esophageal strictures which were treated with a combination of balloon dilatation and intralesional triamcinolone. Therapeutic intervention was covered with oral steroids before and after the procedure. Symptoms tended to recur, necessitating repeat procedures. The average interval between treatments was 8.3 months. Conclusions: Intralesional triamcinolone and balloon dilatation produced good symptomatic relief in these 5 patients with esophageal LP. This was generally maintained for several months. We reviewed 35 cases of symptomatic esophageal LP in the English literature. Esophageal LP seems to have a striking predilection for middle-aged women, particularly those with disease at other mucosal sites. A range of systemic immunosuppressants and esophageal-directed therapies has been tried.
Published: 2009

41. Genome-wide association study identifies eight loci associated with blood pressure

Author: Peter Holmans, Udo Seedorf, Beverley M. Shields, Peter McGruffin, Arne Pfeufer, Steve Eyre, Nathalie J. Prescott, Michael Boehnke, Valentina Moskovina, Abiodun Onipinla, Leena Peltonen, Nadira Yuldasheva, Peter M. Nilsson, Valeria Romanazzi, Vincent Mooser, Göran Berglund, Alistair S. Hall, Dominic P. Kwiatkowski, Barry Widmer, Benjamin F. Voight, Stefania Bandinelli, Mark M. Iles, Sven Bergmann, Thomas Meitinger, James P. Boorman, Simonetta Guarrera, Nazneen Rahman, Murielle Bochud, Graham A. Hitman, Emma Keniry, Nelson B. Freimer, Richard Dobson, Francis S. Collins, Gerjan Navis, Jennifer L. Pointon, Richard N. Bergman, Ruth J. F. Loos, Roberto Lorbeer, Carolina A. Braga Marcano, Christian Gieger, Florian Ernst, Xin Yuan, Catherine Potter, Hazel E. Drummond, Allan H. Young, George Kirov, John F. Peden, Helen Stevens, David Clayton, Mattijs E. Numans, Katherine Gordon-Smith, Anne Farmer, Alastair Forbes, M. Khalid Mohiuddin, John A. Todd, Christopher G. Mathew, David A. Collier, Mark I. McCarthy, Francesca Bredin, Clive M. Onnie, Dan Davidson, Markus Perola, Pamela Whittaker, Yvonne T. van der Schouw, Rathi Ravindrarajan, I. C.A. Spencer, Teresa Ferreira, Nilesh J. Samani, Serge Hercberg, Gonçalo R. Abecasis, Christopher J. Groves, Nicholas John Craddock, Angela Döring, Edward G. Lakatta, Muminatou Jallow, Wendy L. McArdle, David Bentley, Susana Eyheramendy, Uwe Völker, Christopher Newton-Cheh, Jaspal S. Kooner, Hugh Watkins, Gavin Lucas, H. T. Leung, Marjo Ritta Jarvelin, Johanna Kuusisto, Wiek H. van Gilst, Wendy Thomson, Lou R. Cardon, Harold Snieder, Marju Orho-Melander, Patricia B. Munroe, Toshiko Tanaka, Jeffrey C. Barrett, Azhar Maqbool, Henry Völzke, John M. C. Connell, Elaine R. Nimmo, John R. B. Perry, Michael R. Stratton, Ralph McGinnis, Pekka Jousilahti, Michiel L. Bots, Ian Jones, Elizabeth Meech, Matthew A. Brown, Johannie Gungadoo, Jian'an Luan, Jilur Ghori, Richard J. Dixon, N. Charlotte Onland-Moret, Fulvio Ricceri, Anthony J. Balmforth, Catherine E. Todhunter, Inês Barroso, Sheila Bingham, Timo T. Valle, Fredrik O. Vannberg, Diana Zelenika, Stephen Sawcer, Anneli Pouta, David M. Evans, Cuno S. P. M. Uiterwaal, Pilar Galan, Georg Homuth, Hannah Donovan, David J. Conway, Paul Elliott, Alessandra Allione, Paul E. de Jong, Miles Parkes, Amy Chaney, John C. Chambers, Toby Johnson, Isaac Subirana, Vesela Gateva, Cathryn M. Lewis, Christopher J. O'Donnell, Hana Lango, David Schlessinger, Mark J. Caulfield, Thorsten Reffelmann, Jamie Barbour, Karen L. Mohlke, Sarah E. Hunt, Thilo Winzer, Frances M K Williams, Christopher Mathew, I. Wallace, Anuj Goel, Jaakko Tuomilehto, Louise V. Wain, Gabriel Crawford, Samantha L. Hider, Detelinea Grozeva, Elaine K. Green, Paul D. Gilbert, Peter S. Braund, Jaume Marrugat, Rainer Rettig, Pim van der Harst, Yik Ying Teo, Andrew P. Morris, Guiseppe Matullo, Serena Sanna, Cristen J. Willer, Suzannah Bumpstead, Niall C. Taylor, Jacques S. Beckmann, Pierre Meneton, Elin Org, Luigi Ferrucci, Doug Easton, Sheila Seal, Joanne M. Heward, Anne U. Jackson, Eleftheria Zeggini, Rachel M. Freathy, Maris Laan, Paul Wordsworth, Sarah Nutland, Kerstin Koch, Sian Ceasar, Anders Hamsten, Judith M. Hussey, Tariq Ahmad, Derek P. Jewell, Paul Scheet, Charlie W. Lees, C Farrar, Christopher Prowse, Markku Laakso, David St Clair, Kate Downes, Diederick E. Grobbee, Paul Burton, Simon C. Potter, Ian N. Bruce, Tim D. Spector, Anne Barton, H.-Erich Wichmann, Matthew J. Simmonds, David Hadley, Cecilia M. Lindgren, Gérard Waeber, Nigel W. Rayner, Melanie J. Newport, Manjinder S. Sandhu, Audrey Duncanson, Guangju Zhai, Simon Heath, Susan M. Ring, Alessandra Di Gregorio, Richard Williamson, Nicholas J. Wareham, Zhan Su, Olle Melander, John R. Thompson, Alexander Teumer, Sheila A. Fisher, Lachlan J. M. Coin, Leif Groop, Giovanni Tognoni, Amanda Elkin, Alan J. Silman, Jack Satsangi, Jane Worthington, Martin Farrall, John Webster, Niall Cardin, Neil Walker, Anna F. Dominiczak, Jeremy D. Sanderson, Damjan Vukcevic, Bryan Howie, Silvia Polidoro, Stephen G. Ball, Mark Tremelling, Stephen Newhouse, Stephen M. Schwartz, Lori L. Bonnycastle, Chris Wallace, Kijoung Song, Mario A. Morken, I. Nicol Ferrier, Beverley Barke, Paolo Vineis, Manuela Uda, Deborah P M Symmons, Emily J. Lyons, Mingzhan Xue, Timothy M. Frayling, Stephen C.L. Cough, David Withers, Adrian V. S. Hill, Suzanne Stevens, Jennifer Jolley, Marcus Dörr, Kirk A. Rockett, David B. Dunger, Mark Walker, Jayne A. Franklyn, Lisa Jones, David S. Siscovick, Ann-Christine Syvänen, Laura J. Scott, Morris J. Brown, Barbera Cant, Michael Inouye, Feng Zhang, Carlotta Sacerdote, Katherine S. Elliott, Jonathan Marchini, Peter Donnely, Michael John Owen, An Goris, Marcus Prembey, Andrew T. Hattersley, Gerome Breen, Marian L. Hamshere, Thomas Illig, Samer S. Najjar, Nicole Soranzo, Kay-Tee Khaw, Graham R. Walters, Willem H. Ouwehand, David P. Strachan, Martin D. Tobin, Alastair Compston, John C. Mansfield, David Altshuler, Salvatore Panico, Sekar Kathiresan, Dawn M. Waterworth, Michael N. Weedon, D. Timothy Bishop, Claire Bryan, Alexandra S. Knight, Kate L. Lee, Paul F. O'Reilly, Massimo Mangino, Michael Conlon O'Donovan, Jing Hua Zhao, Konstantinos A. Papadakis, Jennifer H. Barrett, Joanne Pereira-Gale, N J Timpson, Stephan B. Felix, Panos Deloukas, Nicholas A. Watkins, Anna-Liisa Hartikainen, Peter Vollenweider, Richard Jones, Anne Hinks, Fraser Cummings, Noha Lim, Linda A. Bradbury, Rhian G. William, Nita G. Forouhi, Roberto Eluosa, Ingeleif B. Hallgrimsdottir, Giorgio Sirugo, Robert Luben, Veikko Salomaa, Robert Clarke, Sally John, Ursula Everson, Emma King, Ivan Nikolov, Heather M. Stringham, Antony P. Attwood, Angelo Scuteri, Wellcome Trust Case Control Consortium, Burton, PR., Clayton, DG., Cardon, LR., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, DP., McCarthy, MI., Ouwehand, WH., Samani, NJ., Todd, JA., Donnelly, P., Barrett, JC., Davison, D., Easton, D., Evans, D., Leung, HT., Marchini, JL., Morris, AP., Spencer, IC., Tobin, MD., Attwood, AP., Boorman, JP., Cant, B., Everson, U., Hussey, JM., Jolley, JD., Knight, AS., Koch, K., Meech, E., Nutland, S., Prowse, CV., Stevens, HE., Taylor, NC., Walters, GR., Walker, NM., Watkins, NA., Winzer, T., Jones, RW., McArdle, WL., Ring, SM., Strachan, DP., Pembrey, M., Breen, G., St Clair, D., Caesar, S., Gordon-Smith, K., Jones, L., Fraser, C., Green, EK., Grozeva, D., Hamshere, ML., Holmans, PA., Jones, IR., Kirov, G., Moskvina, V., Nikolov, I., O'Donovan, MC., Owen, MJ., Collier, DA., Elkin, A., Farmer, A., Williamson, R., McGuffin, P., Young, AH., Ferrier, IN., Ball, SG., Balmforth, AJ., Barrett, JH., Bishop, DT., Iles, MM., Maqbool, A., Yuldasheva, N., Hall, AS., Braund, PS., Dixon, RJ., Mangino, M., Stevens, S., Thompson, JR., Bredin, F., Tremelling, M., Parkes, M., Drummond, H., Lees, CW., Nimmo, ER., Satsangi, J., Fisher, SA., Forbes, A., Lewis, CM., Onnie, CM., Prescott, NJ., Sanderson, J., Mathew, CG., Barbour, J., Mohiuddin, MK., Todhunter, CE., Mansfield, JC., Ahmad, T., Cummings, FR., Jewell, DP., Webster, J., Brown, MJ., Lathrop, GM., Connell, J., Dominiczak, A., Braga Marcano, CA., Burke, B., Dobson, R., Gungadoo, J., Lee, KL., Munroe, PB., Newhouse, SJ., Onipinla, A., Wallace, I., Xue, M., Caulfield, M., Farrall, M., Barton, A., Bruce, IN., Donovan, H., Eyre, S., Gilbert, PD., Hider, SL., Hinks, AM., John, SL., Potter, C., Silman, AJ., Symmons, DP., Thomson, W., Worthington, J., Dunger, DB., Widmer, B., Frayling, TM., Freathy, RM., Lango, H., Perry, JR., Shields, BM., Weedon, MN., Hattersley, AT., Hitman, GA., Walker, M., Elliott, KS., Groves, CJ., Lindgren, CM., Rayner, NW., Timpson, NJ., Zeggini, E., Newport, M., Sirugo, G., Lyons, E., Vannberg, F., Hill, AV., Bradbury, LA., Farrar, C., Pointon, JJ., Wordsworth, P., Brown, MA., Franklyn, JA., Heward, JM., Simmonds, MJ., Gough, SC., Seal, S., Stratton, MR., Rahman, N., Ban, M., Goris, A., Sawcer, SJ., Compston, A., Conway, D., Jallow, M., Rockett, KA., Bryan, C., Bumpstead, SJ., Chaney, A., Downes, K., Ghori, J., Gwilliam, R., Hunt, SE., Inouye, M., Keniry, A., King, E., McGinnis, R., Potter, S., Ravindrarajah, R., Whittaker, P., Withers, D., Cardin, NJ., Ferreira, T., Pereira-Gale, J., Hallgrimsdóttir, IB., Howie, BN., Su, Z., Teo, YY., Vukcevic, D., Bentley, D., Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), and Medical Research Council (MRC)
Subjects: Hemodynamics, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, 0302 clinical medicine, Diastole, 11 Medical and Health Sciences, POPULATION, Genetics, Genetics & Heredity, RISK, 0303 health sciences, education.field_of_study, Econometric and Statistical Methods: General, CELL-DIFFERENTIATION, biology, Intracellular Signaling Peptides and Proteins, Chromosome Mapping, Steroid 17-alpha-Hydroxylase, COMMON VARIANTS, 3. Good health, DNA-Binding Proteins, Europe, Cardiovascular Diseases, PUBLIC-HEALTH, BARTTERS-SYNDROME, Blood Pressure/genetics, Cardiovascular Diseases/genetics, Cardiovascular Diseases/physiopathology, Cytochrome P-450 CYP1A2/genetics, DNA-Binding Proteins/genetics, Diastole/genetics, European Continental Ancestry Group/genetics, Fibroblast Growth Factor 5/genetics, Genetic Variation, Genome-Wide Association Study, Humans, India, Methylenetetrahydrofolate Reductase (NADPH2)/genetics, Open Reading Frames/genetics, Phospholipase C delta/genetics, Polymorphism, Single Nucleotide, Proteins/genetics, Steroid 17-alpha-Hydroxylase/genetics, Systole/genetics, Wellcome Trust Case Control Consortium, Life Sciences & Biomedicine, hypertension, Fibroblast Growth Factor 5, Systole, Population, European Continental Ancestry Group, METHYLENETETRAHYDROFOLATE REDUCTASE GENE, Single-nucleotide polymorphism, LOW-RENIN HYPERTENSION, White People, Article, 03 medical and health sciences, Open Reading Frames, Fibroblast growth factor-5, Cytochrome P-450 CYP1A2, Geneeskunde(GENK), education, Methylenetetrahydrofolate Reductase (NADPH2), Adaptor Proteins, Signal Transducing, 030304 developmental biology, Genetic association, genome-wide association, Science & Technology, MUTATIONS, Proteins, 06 Biological Sciences, POLYMORPHISM, Blood pressure, Methylenetetrahydrofolate reductase, biology.protein, biology.gene, Phospholipase C delta, Developmental Biology
Abstract: Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
Published: 2009

42. Family-based analysis of vitamin D receptor gene polymorphisms and type 1 diabetes in the population of South Croatia

Author: Vesna Boraska, Eleftheria Zeggini, Veselin Škrabić, Maja Buljubašić, Christopher J. Groves, Marijana Peruzović, and Tatijana Zemunik
Subjects: Male, Genetics, education.field_of_study, Genotype, endocrine system diseases, Croatia, Haplotype, Population, Genetic Variation, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Calcitriol receptor, type 1 diabetes, vitamin D receptor, TDT, polymorphism, genetic epydemiology, Diabetes Mellitus, Type 1, Genetic epidemiology, Polymorphism (computer science), Vitamin D and neurology, Humans, Receptors, Calcitriol, Female, Allele, education, Genetics (clinical)
Abstract: Type 1 diabetes mellitus (T1DM) is a disease characterised by the autoimmune destruction of insulin-producing pancreatic beta cells. Vitamin D is a known immune system modulator and its effects are exerted via the vitamin D receptor (VDR). Several VDR gene single nucleotide polymorphisms (SNPs) have been commonly studied in relation to T1DM. The aim of this study was to evaluate the role of VDR gene variation in T1DM susceptibility by genotyping four SNPs (FokI-rs10735810, TaqI-rs731236, BsmI-rs1544410, and Tru9I-rs757343) in 160 case-parent trio samples from the population of South Croatia. We observed overtransmission of Tru9I allele G and undertransmission of the Tru9I-BsmI A-A haplotype from parents to affected children (P = 0.032, P = 0.002, respectively). These results indicate a possible role of the VDR gene in T1DM aetiology. In conclusion, this family-based study presents some evidence of association of specific VDR gene variants with T1DM in the population of South Croatia.
Published: 2007

43. Common Variation in the LMNA Gene (Encoding Lamin A/C) and Type 2 Diabetes

Author: Mark I. McCarthy, Graham A. Hitman, Andrew T. Hattersley, Philippe Froguel, Panos Deloukas, Juliana C.N. Chan, Alan R. Shuldiner, Steven C. Elbein, Eleftheria Zeggini, Mark Walker, Katharine R. Owen, Braxton D. Mitchell, Robert L. Hanson, Weiping Jia, Christopher J. Groves, William C. Knowler, Maggie C.Y. Ng, and Timothy M. Frayling
Subjects: Genetics, Diabetes risk, Endocrinology, Diabetes and Metabolism, Haplotype, Single-nucleotide polymorphism, Type 2 diabetes, Biology, medicine.disease, LMNA, Minor allele frequency, Genotype, Internal Medicine, medicine, Allele
Abstract: Mutations in the LMNA gene (encoding lamin A/C) underlie familial partial lipodystrophy, a syndrome of monogenic insulin resistance and diabetes. LMNA maps to the well-replicated diabetes-linkage region on chromosome 1q, and there are reported associations between LMNA single nucleotide polymorphisms (SNPs) (particularly rs4641; H566H) and metabolic syndrome components. We examined the relationship between LMNA variation and type 2 diabetes (using six tag SNPs capturing >90% of common variation) in several large datasets. Analysis of 2,490 U.K. diabetic case and 2,556 control subjects revealed no significant associations at either genotype or haplotype level: the minor allele at rs4641 was no more frequent in case subjects (allelic odds ratio [OR] 1.07 [95% CI 0.98–1.17], P = 0.15). In 390 U.K. trios, family-based association analyses revealed nominally significant overtransmission of the major allele at rs12063564 (P = 0.01), which was not corroborated in other samples. Finally, genotypes for 2,817 additional subjects from the International 1q Consortium revealed no consistent case-control or family-based associations with LMNA variants. Across all our data, the OR for the rs4641 minor allele approached but did not attain significance (1.07 [0.99–1.15], P = 0.08). Our data do not therefore support a major effect of LMNA variation on diabetes risk. However, in a meta-analysis including other available data, there is evidence that rs4641 has a modest effect on diabetes susceptibility (1.10 [1.04–1.16], P = 0.001).
Published: 2007

44. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Author: Laura J. Scott, Neil Robertson, Anders Hamsten, Domenico Palli, Susanne Moebus, Bernhard O. Boehm, Gunnar Sigurðsson, Paul W. Franks, C. N. A. Palmer, Sonali Pechlivanis, Katharine R. Owen, Michael E. Reschen, Sarah Edkins, Jason Carey, Christopher A. O’Callaghan, Norman Klopp, Caroline S. Fox, Petter Storm, N. William Rayner, Johan G. Eriksson, Thomas Illig, Anubha Mahajan, Erik Ingelsson, Allan Linneberg, Andrew R. Wood, Oddgeir L. Holmen, Nicola L. Beer, Mark I. McCarthy, Frank B. Hu, Peter Almgren, Heiner Boeing, Peter Donnelly, Carl Platou, Veikko Salomaa, Karl-Heinz Jöcke, Wen-Hong L. Kao, Lori L. Bonnycastle, Denis Rybin, Benjamin F. Voight, Peter Kraft, Inês Barroso, Claudia Langenberg, Teresa Ferreira, Peter Kovacs, Anne Raimondo, Christian Theil Have, Ulf de Faire, Torben Hansen, Han Chen, James B. Meigs, Timothy M. Frayling, Noël P. Burtt, Gerald Steinbach, Eric Boerwinkle, Michael Stumvoll, Stefan Gustafsson, Lars Lind, Andrew D. Morris, Alena Stančáková, Panagiotis Deloukas, Kari Stefansson, Augustine Kong, Hans A. Kestler, Andrew T. Hattersley, Beverley Balkau, Lorenzo Pasquali, Yingchang Lu, Nicola D. Kerrison, George B. Grant, Eeva Korpi-Hyövälti, Steven Wiltshire, Karl Gertow, Jorge Ferrer, Barbara Thorand, Inga Prokopenko, Matthias Blüher, Yvonne T. van der Schouw, Olga McLeod, Oluf Pedersen, Leena Peltonen, Anil Chalisey, Eleftheria Zeggini, Joseph Trakalo, Eric J.G. Sijbrands, Rainer Rauramaa, Guillaume Charpentier, Satu Männistö, Cordelia Langford, Lewin Eisele, Damiano Baldassarre, Lennart C. Karssen, Rona J. Strawbridge, Ghazala Mirza, Peter S. Chines, Roman Wennauer, Sara M. Willems, Erwin P. Bottinger, Timo Saaristo, Stéphane Cauchi, Ching-Ti Liu, Martijn van de Bunt, Valgerdur Steinthorsdottir, David Altshuler, Hyun Min Kang, Michael Boehnke, Jaakko Tuomilehto, Peter M. Nilsson, Kyle J. Gaulton, Jian'an Luan, Loic Yengo, David Couper, Reedik Mägi, Harald Grallert, Simone Wahl, Juha Saltevo, Phoenix Kwan, Cecilia M. Lindgren, Peter Lichtner, Richard N. Bergman, Andrew Crenshaw, João Fadista, Michael Roden, Annette Peters, Robert A. Scott, Unnur Thorsteinsdottir, James S. Pankow, Yeji Lee, Cornelia M. van Duijn, Samuli Ripatti, Francis S. Collins, Stéphane Lobbens, Niels Grarup, Ruth J. F. Loos, Julia Meyer, Marit E. Jørgensen, Christian Herder, Inger Njølstad, John R. B. Perry, Markus M. Nöthen, Man Li, Martina Müller-Nurasyid, Valeriya Lyssenko, Pierre Fontanillas, Michael D. Linderman, Leena Kinnunen, Jana K. Rundle, Elena Tremoli, Marilyn C. Cornelis, Tanya M. Teslovich, Todd Green, Raimund Erbel, Elisabeth M. van Leeuwen, Bengt Sennblad, Olle Melander, Sirkka Keinänen-Kiukaanniemi, Markku Laakso, Eero Lindholm, Alex S. F. Doney, Anke Tönjes, Maija Hassinen, Thomas W. Mühleisen, Gonçalo R. Abecasis, Nancy L. Pedersen, Thomas Sparsø, Johanna Kuusisto, Dorothée Thuillier, Qi Sun, Ian Dunham, Himanshu Chheda, Adam E. Locke, Philippe Froguel, Nicholas J. Wareham, Bruna Gigante, Jose C. Florez, Mozhgan Dorkhan, Omri Gottesman, Liming Liang, Anna Jonsson, Tiinamaija Tuomi, Leif Groop, Steve E. Humphries, Heikki A. Koistinen, Kristian Hveem, Astradur B. Hreidarsson, Jason Flannick, Torben Jørgensen, Clement Ma, Mattias Frånberg, Ewan Birney, Andrew P. Morris, Timo A. Lakka, Rob M. van Dam, Heather M. Stringham, Christian Gieger, Elodie Eury, Konstantin Strauch, Anna L. Gloyn, Rafn Benediktsson, Andres Metspalu, David J. Hunter, Karen L. Mohlke, Gudmar Thorleifsson, Josée Dupuis, Emmi Tikkanen, Christian Fuchsberger, Evelin Mihailov, Christopher J. Groves, Soren K. Thomsen, Tõnu Esko, Anne U. Jackson, Karin Leander, Douglas M. Ruderfer, Nikolay Oskolkov, Sekar Kathiresan, Robert Sladek, Lu Qi, Jasmina Kravic, Carmen Navarro, Epidemiology, Dermatology, Internal Medicine, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Cardiology, Wellcome Trust, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), [ 1 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 2 ] Stanford Univ, Dept Genet, Stanford, CA 94305 USA [ 3 ] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA [ 4 ] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England [ 5 ] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia [ 6 ] Univ Oxford, Nuffield Dept Med, Ctr Cellular & Mol Physiol, Oxford, England [ 7 ] Wellcome Trust Sanger Inst, Hinxton, England [ 8 ] Univ Cambridge, Sch Clin Med, Inst Metab Sci, Med Res Council MRC Epidemiol Unit, Cambridge, England [ 9 ] Univ London Imperial Coll Sci Technol & Med, Genom Common Dis, London, England [ 10 ] Broad Inst Harvard & MIT, Cambridge, MA USA [ 11 ] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark [ 12 ] European Genom Inst Diabet, Lille Inst Biol, Lille, France [ 13 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany [ 14 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany [ 15 ] German Ctr Diabet Res, Neuherberg, Germany [ 16 ] Karolinska Inst, Dept Med Solna, Atherosclerosis Res Unit, Stockholm, Sweden [ 17 ] Sci Life Lab, Stockholm, Sweden [ 18 ] Stockholm Univ, Dept Numer Anal & Comp Sci, S-10691 Stockholm, Sweden [ 19 ] Fritz Lipmann Inst, Leibniz Inst Age Res, Jena, Germany [ 20 ] Univ Ulm, Med Syst Biol, D-89069 Ulm, Germany [ 21 ] Finnish Inst Mol Med, Helsinki, Finland [ 22 ] Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany [ 23 ] Uppsala Univ, Dept Med Sci, Mol Epidemiol & Sci Life Lab, Uppsala, Sweden [ 24 ] deCODE Genet Amgen Inc, Reykjavik, Iceland [ 25 ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA [ 26 ] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA [ 27 ] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA [ 28 ] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA [ 29 ] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA [ 30 ] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands [ 31 ] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA [ 32 ] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA [ 33 ] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA [ 34 ] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA [ 35 ] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA [ 36 ] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA [ 37 ] Lund Univ, Scania Univ Hosp, Dept Clin Sci Malmo, Ctr Diabet, Malmo, Sweden [ 38 ] IRCCS, Ctr Cardiol Monzino, Milan, Italy [ 39 ] Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy [ 40 ] Ctr Rech Epidemiol & Sante Populat CESP, INSERM, U1018, Villejuif, France [ 41 ] Univ Paris 11, UMRS 1018, Villejuif, France [ 42 ] Univ Iceland, Fac Med, Reykjavik, Iceland [ 43 ] Landspitali Univ Hosp, Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital [ 44 ] Univ Leipzig, Integrated Treatment & Res IFB Ctr Adipos Dis, D-04109 Leipzig, Germany [ 45 ] Univ Leipzig, Dept Med, D-04109 Leipzig, Germany [ 46 ] German Inst Human Nutr, Potsdam, Germany [ 47 ] NHGRI, US NIH, Bethesda, MD 20892 USA [ 48 ] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA [ 49 ] Corbeil Essonnes Hosp, Endocrinol Diabetol Unit, Corbeil Essonnes, France [ 50 ] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA [ 51 ] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA [ 52 ] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore [ 53 ] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Ctr Diabet Res, Dundee, Scotland [ 54 ] Univ Dundee, Ninewells Hosp, Biomed Res Inst, Pharmacogen Ctr, Dundee, Scotland [ 55 ] Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, Novo Nordisk Scandinavia, Malmo, Sweden [ 56 ] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland [ 57 ] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland [ 58 ] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland [ 59 ] Folkhalsan Res Ctr, Helsinki, Finland [ 60 ] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA [ 61 ] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA [ 62 ] CNRS, UMR 8199, Inst Biol, Lille, France [ 63 ] Univ Lille 2, Inst Pasteur, Lille, France [ 64 ] NHLBI, Framingham Heart Study, Framingham, MA USA [ 65 ] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA [ 66 ] Harvard Univ, Sch Med, Boston, MA USA [ 67 ] Lund Univ, Dept Clin Sci, Malmo, Sweden [ 68 ] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden [ 69 ] Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, S-10401 Stockholm, Sweden [ 70 ] Kuopio Res Inst Exercise Med, Kuopio, Finland [ 71 ] Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany [ 72 ] Partner Site Dusseldorf, German Ctr Diabet Res, Dusseldorf, Germany [ 73 ] Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, Nord Trondelag Hlth Study HUNT Res Ctr, Levanger, Norway [ 74 ] UCL, Inst Cardiovasc Sci, British Heart Fdn BHF Labs, Cardiovasc Genet, London, England [ 75 ] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA [ 76 ] Steno Diabet Ctr, DK-2820 Gentofte, Denmark [ 77 ] Capital Reg Denmark, Res Ctr Prevent & Hlth, Copenhagen, Denmark [ 78 ] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark [ 79 ] Aalborg Univ, Fac Med, Aalborg, Denmark [ 80 ] Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany [ 81 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany [ 82 ] Rigshosp, Copenhagen Univ Hosp, DK-2100 Copenhagen, Denmark [ 83 ] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark [ 84 ] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany [ 85 ] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Guys & St Thomas Hosp, Genom Core Facil, Biomed Res Ctr, London, England [ 86 ] Univ Bonn, Inst Human Genet, Bonn, Germany [ 87 ] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany [ 88 ] Res Ctr Julich, Inst Neurosci & Med INM 1, Julich, Germany [ 89 ] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany [ 90 ] Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Neuherberg, Germany [ 91 ] Partner Site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany [ 92 ] Inst Murciano Invest Biosanitaria Virgen de la Ar, Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain [ 93 ] CIBERESP, Madrid, Spain [ 94 ] Univ Murcia, Dept Hlth & Social Sci, Murcia, Spain [ 95 ] Churchill Hosp, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford OX3 7LJ, England [ 96 ] Canc Res & Prevent Inst ISPO, Florence, Italy [ 97 ] Nord Trondelag Hlth Trust, Levanger Hosp, Dept Internal Med, Levanger, Norway [ 98 ] Univ Hosp Dusseldorf, Dept Endocrinol & Diabetol, Dusseldorf, Germany [ 99 ] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY 10029 USA [ 100 ] Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA [ 101 ] Univ Med Ctr Utrecht, Utrecht, Netherlands [ 102 ] Iceland Heart Assoc, Kopavogur, Iceland [ 103 ] Univ Eastern Finland, Dept Med, Kuopio, Finland [ 104 ] Kuopio Univ Hosp, SF-70210 Kuopio, Finland [ 105 ] Univ Ulm, Dept Clin Chem & Cent Lab, D-89069 Ulm, Germany [ 106 ] Univ Helsinki, Dept Publ Hlth, Hjelt Inst, Helsinki, Finland [ 107 ] Helsinki Univ Hosp, Abdominal Ctr, Dept Endocrinol, Helsinki, Finland [ 108 ] Univ Helsinki, Res Program Diabet & Obes, Helsinki, Finland [ 109 ] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands [ 110 ] Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England [ 111 ] European Mol Biol Lab, EBI, Hinxton, England [ 112 ] Germans Trias & Pujol Univ Hosp & Res Inst, Div Endocrinol, Badalona, Spain [ 113 ] Josep Carreras Leukaemia Res Inst, Badalona, Spain [ 114 ] CIBERDEM, Barcelona, Spain [ 115 ] Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England [ 116 ] Inst Invest Biomed August Pi & Sunyer, Ctr Esther Koplowitz, Barcelona, Spain [ 117 ] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA [ 118 ] Harvard Univ, Sch Med, Dept Med, Boston, MA USA [ 119 ] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA [ 120 ] Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA [ 121 ] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX 77030 USA [ 122 ] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA [ 123 ] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA [ 124 ] Netherlands Consortium Hlth Ageing, Netherlands Genom Initiat, Rotterdam, Netherlands [ 125 ] Ctr Med Syst Biol, Rotterdam, Netherlands [ 126 ] Massachusetts Gen Hosp, Gen Med Div, Boston, MA 02114 USA [ 127 ] Univ Eastern Finland, Inst Biomed Physiol, Kuopio, Finland [ 128 ] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland [ 129 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 130 ] Univ Uppsala Hosp, Dept Med Sci, Uppsala, Sweden [ 131 ] Univ Oulu, Inst Hlth Sci, Fac Med, Oulu, Finland [ 132 ] Oulu Univ Hosp, Unit Gen Practice, Oulu, Finland [ 133 ] South Ostrobothnia Cent Hosp, Seinajoki, Finland [ 134 ] Finnish Diabet Assoc, Tampere, Finland [ 135 ] Pirkanmaa Dist Hosp, Tampere, Finland [ 136 ] Cent Finland Cent Hosp, Dept Med, Jyvasklya, Finland [ 137 ] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia [ 138 ] Univ Duisdurg Essen, Univ Hosp Essen, West German Heart Ctr, Clin Cardiol, Essen, Germany [ 139 ] Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland [ 140 ] Univ Med Ctr Ulm, Dept Internal Med, Div Endocrinol & Diabet, Ulm, Germany [ 141 ] Univ London Imperial Coll Sci Technol & Med, Lee Kong Chian Sch Med, London SW7 2AZ, England [ 142 ] Nanyang Technol Univ, Singapore 639798, Singapore [ 143 ] Cedars Sinai Med Ctr, Diabet & Obes Res Inst, Los Angeles, CA 90048 USA [ 144 ] Univ N Carolina, Dept Genet, Chapel Hill, NC USA [ 145 ] Univ Helsinki, Cent Hosp, Dept Med, Div Endocrinol, Helsinki, Finland [ 146 ] Minerva Fdn, Helsinki, Finland [ 147 ] Hosp Univ La Paz, Inst Invest Sanitaria, Madrid, Spain [ 148 ] Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria [ 149 ] King Abdulaziz Univ, Diabet Res Grp, Jeddah 21413, Saudi Arabia [ 150 ] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway [ 151 ] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England [ 152 ] Univ Oxford, Dept Stat, Oxford OX1 3TG, England [ 153 ] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England [ 154 ] Ctr Hosp Univ Montreal, Ctr Rech, Montreal Diabet Res Ctr, Montreal, PQ, Canada [ 155 ] McGill Univ, Montreal, PQ, Canada [ 156 ] Genome Quebec Innovat Ctr, Montreal, PQ, Canada [ 157 ] Univ Southern Denmark, Fac Hlth Sci, Odense, Denmark [ 158 ] Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland [ 159 ] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA [ 160 ] Univ Cambridge, Metab Res Labs, Wellcome Trust MRC Inst Metab Sci, Cambridge, England [ 161 ] Cambridge Biomed Res Ctr, Natl Inst Hlth Res, Cambridge, England [ 162 ] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA [ 163 ] Harvard Univ, Sch Med, Dept Mol Biol, Boston, MA USA [ 164 ] Univ Liverpool, Dept Biostat, Liverpool L69 3BX, Merseyside, England [ 165 ] Univ Liverpool, Dept Mol & Clin Pharmacol, Liverpool L69 3BX, Merseyside, England, Luan, Jian'an [0000-0003-3137-6337], Perry, John [0000-0001-6483-3771], Barroso, Ines [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository
Subjects: endocrine system diseases, Medizin, Genome-wide association study, Glucose homeostasis, WIDE ASSOCIATION, Association mapping, Non-U.S. Gov't, Genome-Wide Association Study, Regulation of gene expression, Genetics, Genetics & Heredity, LARGE-SCALE ASSOCIATION, Research Support, Non-U.S. Gov't, COMMON VARIANTS, Chromosome Mapping, 11 Medical And Health Sciences, Genomics, 3. Good health, TRANSCRIPTION FACTORS, Liver, Hepatocyte Nuclear Factor 3-beta, Medical Genetics, Life Sciences & Biomedicine, Chromatin Immunoprecipitation, endocrine system, European Continental Ancestry Group/genetics, Biology, GENOTYPE IMPUTATION, Research Support, INSULIN-SECRETION, Polymorphism, Single Nucleotide, Article, N.I.H, Sykursýki, Islets of Langerhans, SDG 3 - Good Health and Well-being, Research Support, N.I.H., Extramural, HUMAN PANCREATIC-ISLETS, GLYCEMIC TRAITS, Journal Article, SNP, Humans, Genetic Predisposition to Disease, Comparative Study, Enhancer, Medicinsk genetik, Science & Technology, Binding Sites, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Receptor, Melatonin, MT2, Extramural, Molecular Sequence Annotation, Arfgengi, 06 Biological Sciences, Genetic Predisposition to Disease/genetics, BETA-CELL, Diabetes Mellitus, Type 2/genetics, Diabetes Mellitus, Type 2, Gene Expression Regulation, Genetic Loci, Case-Control Studies, Gene-Environment Interaction, GLUCOSE-HOMEOSTASIS, Chromatin immunoprecipitation, Developmental Biology
Abstract: To access publisher's full text version of this article click on the hyperlink at the bottom of the page We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease. cademy of Finland 77299 102318 10493 118065 123885 124243 129293 129680 136895 139635 211119 213506 251217 263836 Agence National de la Recherche Association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques Association Diabeete Risque Vasculaire Association Francaise des Diabetiques Association of Danish Pharmacies Augustinus Foundation Becket Foundation British Diabetes Association (BDA) Research British Heart Foundation Central Norway Health Authority Central Finland Hospital District Center for Inherited Disease Research (CIDR) City of Kuopio City of Leutkirch Copenhagen County Danish Centre for Evaluation and Health Technology Assessment Danish Council for Independent Research Danish Heart Foundation Danish Research Councils Deutsche Forschungsgemeinschaft ER 155/6-2 Diabetes Research Foundation Diabetes UK Doris Duke Charitable Foundation Erasmus Medical Center Erasmus University Estonian government SF0180142s08 European Commission ENGAGE HEALTH-F4-2007-201413 FP7-201413 FP7-245536 EXGENESIS LSHM-CT-2004-005272 FP6 LSHM_CT_2006_037197 LSHM-CT-2007-037273 C-Public Health 2004310 European Regional Development Fund Federal Ministry of Education and Research, Germany FKZ 01GI1128 FKZ 01EO1001 Federal Ministry of Health, Germany Finnish Diabetes Association Finnish Diabetes Research Foundation Finnish Foundation for Cardiovascular Research Finnish Medical Society Folkhalsan Research Foundation Foundation for Life and Health in Finland Foundation for Old Servants Fredrick och Ingrid Thuring Foundation French region of Nord-Pas-de-Calais (Contrat de Projets Etat-Region) German Center for Diabetes Research German Research Council GRK1041 German National Genome Research Network Groupe d'Etude des Maladies Metaboliques et Systemiques Health Care Centers in Vasa, Narpes and Korsholm, Finland Health Foundation Heinz Nixdorf Foundation Helmholtz Zentrum Munchen Helsinki University Central Hospital Research Foundation Hospital District of Southwest Finland Ib Henriksens Foundation IngaBritt and Arne Lundberg's Research Foundation 359 Karolinska Institutet Knut and Alice Wallenberg Foundation KAW 2009.0243 Kuopio University Hospital Lundbeck Foundation Magnus Bergvall Foundation Medical Faculty of University Duisburg-Essen Medical Research Council, UK G0000649 G0601261 Ministry for Health, Welfare and Sports, the Netherlands Ministry of Education and Culture, Finland 722 627 Ministry of Education, Culture and Science, the Netherlands Ministry of Health and Prevention, Denmark Ministry of Social Affairs and Health, Finland Ministry of Innovation, Science, Research and Technology of North Rhine-Westphalia, Germany Munich Center of Health Sciences Municipal Health Care Center and Hospital in Jakobstad, Finland municipality of Rotterdam, the Netherlands Narpes Health Care Foundation National Health Screening Service of Norway National Heart, Lung, and Blood Institute, USA HHSN268201100005C HHSN268201100006C HHSN268201100007C HHSN268201100008C HHSN268201100009C HHSN268201100010C HHSN268201100011C HHSN268201100012C N01HC25195 N02HL64278 R01HL087641 R01HL59367 R01HL086694 National Human Genome Research Institute, USA U01HG004402 N01HG65403 National Institute for Diabetes and Digestive and Kidney Diseases, USA R01DK078616 U01DK085526 K24DK080140 R01DK073490 National Institute for Health and Welfare, Finland National Institutes of Health, USA HHSN268200625226C UL1RR025005 R01DK062370 R01DK072193 1Z01HG000024 AG028555 AG08724 AG04563 AG10175 AG08861 U01HG004399 DK58845 CA055075 DK085545 DK098032 Netherlands Genomics Initiative Netherlands Organisation for Health Research and Development Netherlands Organisation of Scientific Research NOW Investments 175.010.2005.011 911-03-012 050-060-810 Nord-Trondelag County Council Nordic Center of Excellence in Disease Genetics Norwegian Institute of Public Health Norwegian Research Council Novo Nordisk Foundation Ollquist Foundation Oxford National Institute for Health Research (NIHR) Biomedical Research Centre Paavo Nurmi Foundation Paivikki and Sakari Sohlberg Foundation Perklen Foundation Pirkanmaa Hospital District, Finland Programme Hospitalier de Recherche Clinique Programme National de Recherche sur la Diabete Research Institute for Diseases in the Elderly 014-93-015 Robert Dawson Evans Endowment, Department of Medicine, Boston University School of Medicine and Boston Medical Center Royal Swedish Academy of Sciences Sarstedt, Germany Signe and Ane Gyllenberg Foundation Sigrid Juselius Foundation Slottery Machine Association, Finland Social Insurance Institution of Finland South OstroBothnia Hospital District state of Baden-Wurttemberg, Germany Stockholm County Council 560183 Swedish Cultural Foundation, Finland Swedish Diabetes Foundation Swedish e-science Research Center Swedish Foundation for Strategic Research Swedish Heart-Lung Foundation Swedish Research Council SFO EXODIAB 2009-1039 521-2010-3490 521-2007-4037 521-2008-2974 ANDIS 825-2010-5983 LUDC 349-2008-6589 8691 Swedish Society of Medicine Tore Nilsson Foundation Torsten and Ragnar Soderbergs Stiftelser MT33/09 University Hospital Essen University of Tromso University College London NIHR Biomedical Research Centre UK NIHR Cambridge Biomedical Research Centre Uppsala University Uppsala University Hospital Vaasa Hospital District Velux Foundation Wellcome Trust GR072960 076113 083948 090367 090532 083270 086596 098017 095101 098051 098381
Published: 2015

45. Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High- Density Imputation

Author: Letizia Marullo, Jouke-Jan Hottenga, Kari Stefansson, Antti Jula, Johan Rung, Kyle J. Gaulton, Claes Ladenvall, Marian Beekman, Jeanine J. Houwing-Duistermaat, Anton J. M. de Craen, Nancy L. Pedersen, Teresa Ferreira, Jeanette Erdmann, Terho Lehtimӓki, Valgerdur Steinthorsdottir, Antti-Pekka Sarin, Christopher J. Groves, Anders Hamsten, Cecilia M. Lindgren, Veikko Salomaa, Unnur Thorsteinsdottir, Lennart C. Karssen, Valeriya Lyssenko, Cornelia M. van Duijn, Samuli Ripatti, Patrik K. E. Magnusson, Anubha Mahajan, Evelin Mihailov, Eco J. C. de Geus, P. Eline Slagboom, Martijn van de Bunt, Tõnu Esko, Andrew P. Morris, Aaron Isaacs, Sara Hӓgg, Jaakko Kaprio, Aki S. Havulinna, S Wiltshire, Sara M. Willems, Neil R. Robertson, Juan Fernandez, Momoko Horikoshi, Heribert Schunkert, Lars Lind, Erik Ingelsson, Yuri Milaneschi, Dorret I. Boomsma, Harald Grallert, Martina Müller-Nurasyid, Janina S. Ried, Gudmar Thorleifsson, Ida Surakka, Leif Groop, Joris Deelen, Martin D. Tobin, Jorma Viikari, Christian Gieger, Christian Herder, Natalia Pervjakova, Amanda J. Bennett, Matthew Blades, Annette Peters, Johannes H. Smit, Gonneke Willemsen, Markus Perola, Christina Willenborg, Thomas W. Winkler, Reedik Mӓgi, Iris M. Heid, Brenda W.J.H. Penninx, Michael Roden, Chris Power, Inga Prokopenko, Christopher P. Nelson, Elisabeth M. van Leeuwen, Mark I. McCarthy, Nilesh J. Samani, Johan G. Eriksson, Andres Metspalu, Olli T. Raitakari, Elina Hyppönen, Christian Hengstenberg, Gibson, Greg, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Institute for Molecular Medicine Finland, Clinicum, Jaakko Kaprio / Principal Investigator, Department of Public Health, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Leif Groop Research Group, Samuli Olli Ripatti / Principal Investigator, Biostatistics Helsinki, Quantitative Genetics, Complex Disease Genetics, Genetic Epidemiology, Psychiatry, NCA - Neurobiology of mental health, EMGO - Lifestyle, overweight and diabetes, Epidemiology, General Practice, Dermatology, Immunology, Horikoshi, Momoko, Mägi, Reedik, van de Bunt, Martijn, Surakka, Ida, Hypponen, Elina, Morris, Andrew P, and ENGAGE Consortium
Subjects: Netherlands Twin Register (NTR), Cancer Research, RARE GENETIC-VARIATION, Obesity/genetics, Genome-wide association study, Body Mass Index, Germinal Center Kinases, 0302 clinical medicine, quantitative trait locus, Gene Frequency, genetic variability, 2.1 Biological and endogenous factors, Aetiology, Association mapping, Genetics (clinical), 2. Zero hunger, Genetics, G6PC2 gene, Genetics & Heredity, 0303 health sciences, INSULIN-RESISTANCE, Glycemic Index/genetics, Chromosome Mapping, Single Nucleotide, ENGAGE Consortium, Protein-Serine-Threonine Kinases, Polymorphism, Single Nucleotide/genetics, ddc, 3. Good health, fine-mapping, Gene Frequency/genetics, Glucose-6-Phosphatase, LOW-FREQUENCY, RSPO3 gene, Life Sciences & Biomedicine, Single Nucleotide/genetics, Medical Genetics, Research Article, Biotechnology, lcsh:QH426-470, Protein-Serine-Threonine Kinases/genetics, Thrombospondins/genetics, Quantitative Trait Loci, Locus (genetics), Biology, Endocrinology and Diabetes, Protein Serine-Threonine Kinases, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, ASIAN POPULATIONS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Humans, Genetic Predisposition to Disease, Obesity, 1000 Genomes Project, GENOME-WIDE ASSOCIATION, Polymorphism, Molecular Biology, Allele frequency, Ecology, Evolution, Behavior and Systematics, Metabolic and endocrine, 030304 developmental biology, Genetic association, Medicinsk genetik, Nutrition, Science & Technology, Body mass index, Molecular genetics, Quantitative trait loci, Genome-wide association studies, Quality control, Genomic signal processing, Meta-analysis, Human Genome, gene mapping, ta3121, Minor allele frequency, BODY-MASS INDEX, lcsh:Genetics, Glucose-6-Phosphatase/genetics, Glycemic Index, glycemic control, TYPE-2 DIABETES RISK, 3111 Biomedicine, GCK gene, WAIST-HIP RATIO, Quantitative Trait Loci/genetics, Thrombospondins, 030217 neurology & neurosurgery, Imputation (genetics), FASTING GLUCOSE, Genome-Wide Association Study, Developmental Biology
Abstract: Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated., Author Summary Human genetic studies have demonstrated that quantitative human anthropometric and metabolic traits, including body mass index, waist-hip ratio, and plasma concentrations of glucose and insulin, are highly heritable, and are established risk factors for type 2 diabetes and cardiovascular diseases. Although many regions of the genome have been associated with these traits, the specific genes responsible have not yet been identified. By making use of advanced statistical “imputation” techniques applied to more than 87,000 individuals of European ancestry, and publicly available “reference panels” of more than 37 million genetic variants, we have been able to identify novel regions of the genome associated with these glycaemic and obesity-related traits and localise genes within these regions that are most likely to be causal. This improved understanding of the biological mechanisms underlying glycaemic and obesity-related traits is extremely important because it may advance drug development for downstream disease endpoints, ultimately leading to public health benefits.
Published: 2015

46. Leveraging cross-species transcription factor binding site patterns: from diabetes risk loci to disease mechanisms

Author: Melina Claussnitzer, Simon N. Dankel, Bernward Klocke, Harald Grallert, Viktoria Glunk, Tea Berulava, Heekyoung Lee, Nikolay Oskolkov, Joao Fadista, Kerstin Ehlers, Simone Wahl, Christoph Hoffmann, Kun Qian, Tina Rönn, Helene Riess, Martina Müller-Nurasyid, Nancy Bretschneider, Timm Schroeder, Thomas Skurk, Bernhard Horsthemke, Derek Spieler, Martin Klingenspor, Martin Seifert, Michael J. Kern, Niklas Mejhert, Ingrid Dahlman, Ola Hansson, Stefanie M. Hauck, Matthias Blüher, Peter Arner, Leif Groop, Thomas Illig, Karsten Suhre, Yi-Hsiang Hsu, Gunnar Mellgren, Hans Hauner, Helmut Laumen, Benjamin F. Voight, Laura J. Scott, Valgerdur Steinthorsdottir, Andrew P. Morris, Christian Dina, Ryan P. Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S. Aulchenko, Gudmar Thorleifsson, Laura J. McCulloch, Teresa Ferreira, Najaf Amin, Guanming Wu, Cristen J. Willer, Soumya Raychaudhuri, Steve A. McCarroll, Claudia Langenberg, Oliver M. Hofmann, Josée Dupuis, Lu Qi, Ayellet V. Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J. Bennett, Roza Blagieva, Eric Boerwinkle, Lori L. Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noël P. Burtt, Guillaume Charpentier, Peter S. Chines, Marilyn Cornelis, David J. Couper, Gabe Crawford, Alex S.F. Doney, Katherine S. Elliott, Amanda L. Elliott, Michael R. Erdos, Caroline S. Fox, Christopher S. Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J. Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U. Jackson, Paul R.V. Johnson, Torben Jørgensen, Wen H.L. Kao, Norman Klopp, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M. Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A. Morken, Narisu Narisu, Peter Nilsson, Katharine R. Owen, Felicity Payne, John R.B. Perry, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N. William Rayner, Neil R. Robertson, Ghislain Rocheleau, Michael Roden, Michael J. Sampson, Richa Saxena, Beverley M. Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M. Stringham, Qi Sun, Amy J. Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M. van Dam, Timon W. van Haeften, Thijs van Herpt, Jana V. van Vliet-Ostaptchouk, G. Bragi Walters, Michael N. Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N. Bergman, Stephane Cauchi, Francis S. Collins, Anna L. Gloyn, Ulf Gyllensten, Torben Hansen, Winston A. Hide, Graham A. Hitman, Albert Hofman, David J. Hunter, Kristian Hveem, Markku Laakso, Karen L. Mohlke, Andrew D. Morris, Colin N.A. Palmer, Peter P. Pramstaller, Igor Rudan, Eric Sijbrands, Lincoln D. Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Nicholas J. Wareham, Richard M. Watanabe, Goncalo R. Abecasis, Bernhard O. Boehm, Harry Campbell, Mark J. Daly, Andrew T. Hattersley, Frank B. Hu, James B. Meigs, James S. Pankow, Oluf Pedersen, H.-Erich Wichmann, Inês Barroso, Jose C. Florez, Timothy M. Frayling, Rob Sladek, Unnur Thorsteinsdottir, James F. Wilson, Philippe Froguel, Cornelia M. van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I. McCarthy, Clinical sciences, Johnson, P, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Center for Liver, Digestive and Metabolic Diseases (CLDM)
Subjects: Diabetes risk, SUSCEPTIBILITY LOCI, Medizin, Genome-wide association study, Regulatory Sequences, Nucleic Acid, Endocrinology and Diabetes, Biology, PHOSPHOENOLPYRUVATE CARBOXYKINASE, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, 0302 clinical medicine, insulin resistance, Animals, Humans, EPIGENOMIC ANALYSIS, GENOME-WIDE ASSOCIATION, genome, Gene, Transcription factor, IN-VIVO, Cells, Cultured, Conserved Sequence, 030304 developmental biology, Genetic association, Homeodomain Proteins, Regulation of gene expression, Genetics, 0303 health sciences, Biochemistry, Genetics and Molecular Biology(all), INSULIN SENSITIVITY, Research Support, Non-U.S. Gov't, LARGE-SCALE, GENE, PPAR gamma, DNA binding site, ADIPOSE-TISSUE, Diabetes Mellitus, Type 2, Gene Expression Regulation, transcription factor binding sites, Homeobox, PPAR-GAMMA, type 2 diabetes, 030217 neurology & neurosurgery, Genome-Wide Association Study, Transcription Factors
Abstract: SummaryGenome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.
Published: 2014

47. Higher Magnesium Intake Is Associated with Lower Fasting Glucose and Insulin, with No Evidence of Interaction with Select Genetic Loci, in a Meta-Analysis of 15 CHARGE Consortium Studies

Author: Kenneth J. Mukamal, Stephen B. Kritchevsky, Kurt Lohman, W. H. Linda Kao, James S. Pankow, Julius S. Ngwa, Oscar H. Franco, Yongmei Liu, Ani Manichaikul, Nicola M. McKeown, L. Adrienne Cupples, Kari E. North, Christopher J. Groves, David S. Siscovick, Mika Kähönen, Frank J. A. van Rooij, Inga Prokopenko, Emily Sonestedt, James B. Meigs, Stavroula Kanoni, Frida Renström, Rozenn N. Lemaitre, Ingrid B. Borecki, Ioanna Ntalla, Dariush Mozaffarian, Jerome I. Rotter, Ingegerd Johansson, Adela Hruby, M. Carola Zillikens, Terho Lehtimäki, Toshiko Tanaka, Stefania Bandinelli, Vera Mikkilä, George Dedoussis, Albert Hofman, Mary K. Wojczynski, Luc Djoussé, Jacqueline C.M. Witteman, Mary Yannakoulia, Marju Orho-Melander, Efi Grigoriou, Denise K. Houston, Neelam Hassanali, Jorma Viikari, Göran Hallmans, André G. Uitterlinden, Luigi Ferrucci, Jennifer A. Nettleton, Lars Lind, Ulf Risérus, Olli T. Raitakari, Paul F. Jacques, Mark I. McCarthy, Frank B. Hu, Paul W. Franks, Erik Ingelsson, Andrea Ganna, Ann-Christine Syvänen, Constantina Papoutsakis, Epidemiology, and Internal Medicine
Subjects: Blood Glucose, Male, medicine.medical_specialty, medicine.medical_treatment, TRPM Cation Channels, Medicine (miscellaneous), chemistry.chemical_element, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Diabetes mellitus, medicine, Humans, Insulin, Nutritional Epidemiology, Magnesium, 030212 general & internal medicine, Glycemic, Nutrition and Dietetics, SLC30A8, Type 2 Diabetes Mellitus, medicine.disease, Trace Elements, Endocrinology, chemistry, Genetic Loci, biology.protein, Female, Metabolic syndrome
Abstract: Favorable associations between magnesium intake and glycemic traits, such as fasting glucose and insulin, are observed in observational and clinical studies, but whether genetic variation affects these associations is largely unknown. We hypothesized that single nucleotide polymorphisms (SNPs) associated with either glycemic traits or magnesium metabolism affect the association between magnesium intake and fasting glucose and insulin. Fifteen studies from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided data from up to 52,684 participants of European descent without known diabetes. In fixed-effects meta-analyses, we quantified 1) cross-sectional associations of dietary magnesium intake with fasting glucose (mmol/L) and insulin (ln-pmol/L) and 2) interactions between magnesium intake and SNPs related to fasting glucose (16 SNPs), insulin (2 SNPs), or magnesium (8 SNPs) on fasting glucose and insulin. After adjustment for age, sex, energy intake, BMI, and behavioral risk factors, magnesium (per 50-mg/d increment) was inversely associated with fasting glucose [β = -0.009 mmol/L (95% CI: -0.013, -0.005), P < 0.0001] and insulin [-0.020 ln-pmol/L (95% CI: -0.024, -0.017), P < 0.0001]. No magnesium-related SNP or interaction between any SNP and magnesium reached significance after correction for multiple testing. However, rs2274924 in magnesium transporter-encoding TRPM6 showed a nominal association (uncorrected P = 0.03) with glucose, and rs11558471 in SLC30A8 and rs3740393 near CNNM2 showed a nominal interaction (uncorrected, both P = 0.02) with magnesium on glucose. Consistent with other studies, a higher magnesium intake was associated with lower fasting glucose and insulin. Nominal evidence of TRPM6 influence and magnesium interaction with select loci suggests that further investigation is warranted.
Published: 2013

48. The plasma cell signature in autoimmune disease

Author: Katie, Streicher, Christopher A, Morehouse, Christopher J, Groves, Bhargavi, Rajan, Fernanda, Pilataxi, Kim P, Lehmann, Philip Z, Brohawn, Brandon W, Higgs, Kathleen, McKeever, Steven A, Greenberg, David, Fiorentino, Laura K, Richman, Bahija, Jallal, Ronald, Herbst, Yihong, Yao, and Koustubh, Ranade
Subjects: Immunoglobulin kappa-Chains, Scleroderma, Systemic, Tissue Array Analysis, Immunoglobulin J-Chains, Plasma Cells, Humans, Immunoglobulins, B-Cell Maturation Antigen, Transcriptome, Autoantibodies, Autoimmune Diseases
Abstract: Production of pathogenic autoantibodies by self-reactive plasma cells (PCs) is a hallmark of autoimmune diseases. We undertook this study to investigate the prevalence of PCs and their relationship to known pathogenic pathways to increase our understanding of the role of PCs in disease progression and treatment response.We developed a sensitive gene expression-based method to overcome the challenges of measuring PCs using flow cytometry. Whole-genome microarray analysis of sorted cellular fractions identified a panel of genes, IGHA1, IGJ, IGKC, IGKV4-1, and TNFRSF17, expressed predominantly in PCs. The sensitivity of the PC signature score created from the combined expression levels of these genes was assessed through ex vivo experiments with sorted cells. This PC gene expression signature was used for monitoring changes in PC levels following anti-CD19 therapy, for evaluating the relationship between PCs and other autoimmune disease-related genes, and for estimating PC levels in affected blood and tissue from patients with multiple autoimmune diseases.The PC signature was highly sensitive and capable of detecting a change in as few as 360 PCs. The PC signature was reduced more than 90% in scleroderma patients following anti-CD19 treatment, and this reduction was highly correlated (r = 0.80) with inhibition of collagen gene expression. Evaluation of multiple autoimmune diseases revealed that 30-35% of lupus and rheumatoid arthritis patients had increased levels of PCs.This newly developed PC signature provides a robust and accurate method of measuring PC levels in the clinic. Our results highlight subsets of patients across multiple autoimmune diseases who may benefit from PC-depleting therapy.
Published: 2012

49. New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism

Author: Keith M. Godfrey, Aline Meirhaeghe, Jing Hua Zhao, Elina Hyppönen, Luis A. Moreno, Torben Hansen, James F. Wilson, Virpi Lindi, Eco J. C. de Geus, Ben A. Oostra, Karen A. Jameson, Liang Kee Goh, Philippe Froguel, Antje Körner, Ali Al-Odaib, H. Rob Taal, Dorret I. Boomsma, Craig E. Pennell, Terho Lehtimäki, Nicholas J. Timpson, George Dedoussis, Jorma Viikari, Haitao Zhang, Maiju Saarinen, Frédéric Gottrand, Daniel R. Witte, Vasiliki Lagou, Michael Stumvoll, Chris Power, Linda S. Adair, Anubha Mahajan, Karen L. Mohlke, Marcel den Hoed, Amanda J. Bennett, Dorota Monies, George McMahon, Zoltán Kutalik, Fowzan S. Alkuraya, Ewan R. Pearson, Marjan Kerkhof, Oluf Pedersen, Torben Jørgensen, Rachel M. Freathy, Albert Hofman, Elisabeth Widen, Bjarke Feenstra, Peter Vollenweider, Shikta Das, Frank Geller, Timo A. Lakka, Timothy M. Frayling, Seang-Mei Saw, Nadja Hawwa Vissing, Tuomas O. Kilpeläinen, Elisabeth Thiering, Jean Dallongeville, Hans Bisgaard, Eskil Kreiner-Møller, Sylvain Sebert, Mònica Guxens, Fernando Rivadeneira, Christina Kanaka-Gantenbein, Mads Melbye, Carla M. T. Tiesler, Susan M. Ring, Brian F. Meyer, Anke Tönjes, Nicholas J. Wareham, Ulla Sovio, Hazel Inskip, Nicole M. Warrington, Mirna Kirin, Claudia Flexeder, Marie Neergaard Harder, Berthold Hocher, Ehm A. Andersson, Andrew M. Prentice, Philippe Amouyel, Jouke-Jan Hottenga, Momoko Horikoshi, Jessica L. Buxton, Struan F.A. Grant, Ken K. Ong, Mariona Bustamante, Torsten Slowinski, Hakon Hakonarson, Marika Kaakinen, Jani Heikkinen, Gonneke Willemsen, Anneli Pouta, John P. Newnham, Allan Vaag, Christopher J. Groves, Thiemo Pfab, Debbie A Lawlor, Joachim Heinrich, Beverley M. Shields, Jianhua Zhao, Wieland Kiess, Olli Simell, Xavier Estivill, George Davey Smith, Andrew T. Hattersley, Colin Boreham, Bridget A. Knight, Ying Wu, Klaus Bønnelykke, Aaron Isaacs, Louise Pedersen, Kaixin Zhou, André G. Uitterlinden, Elisabeth M. van Leeuwen, John W. Holloway, Inga Prokopenko, Neil R. Robertson, Rany M. Salem, Alexandra I. F. Blakemore, Ruth J. F. Loos, Marjo-Riitta Järvelin, Sheila J. Barton, Beate St Pourcain, Jacqueline M. Vink, Norman Klopp, Anthony J. C. Fulford, David M. Evans, Gerard H. Koppelman, Hanieh Yaghootkar, Dennis O. Mook-Kanamori, David M. Hougaard, Christopher W. Kuzawa, Cyrus Cooper, Vincent W. V. Jaddoe, Diana L. Cousminer, Dirkje S. Postma, Matthew W. Gillman, Jonathan P. Bradfield, Pimphen Charoen, John P. Kemp, Ioanna Ntalla, Branwen J. Hennig, Cornelia M. van Duijn, Diane J. Berry, Mads V. Hollegaard, Johan G. Eriksson, Olli T. Raitakari, Mark I. McCarthy, Joel N. Hirschhorn, Harri Niinikoski, Faculty of Behavioural and Movement Sciences, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Medical Research Council (MRC), Erasmus MC other, Epidemiology, Medical Microbiology & Infectious Diseases, Clinical Genetics, Internal Medicine, Medical Oncology, Pediatrics, Groningen Research Institute of Pharmacy, Faculteit Medische Wetenschappen/UMCG, Groningen Research Institute for Asthma and COPD (GRIAC), Meta-Analyses of Glucose and Insulin related traits Consortium (MAGIC), Early Growth Genetics (EGG) Consortium, Horikoshi, Momoko, Yaghootkar, Hanieh, Mook-Kanamori, Dennis O, Sovio, Ulla, Hypponen, Elina Tuulikki, Freathy, Rachel M, Insulin-related traits Consortium (MAGIC), Meta-Analyses of, Glucose, Gastroenterology & Hepatology, Hematology, and Public Health
Subjects: Type 2/genetics, Netherlands Twin Register (NTR), Male, Genetic Linkage, Birth Weight/genetics, Physiology, Genome-wide association study, BLOOD-PRESSURE, Blood Pressure, Type 2 diabetes, Head circumference, Genome-wide association studies, Fetal Development, GLUCOKINASE GENE, 0302 clinical medicine, Birth Weight, GENETICS & HEREDITY, Genetics & Heredity, 0303 health sciences, ADCY5, Body Height/genetics, COMMON VARIANTS, 11 Medical And Health Sciences, Single Nucleotide, Glucokinase gene, Metaanalysis, 3. Good health, HEAD CIRCUMFERENCE, Adult Birth Weight/*genetics Blood Pressure/genetics Body Height/*genetics Diabetes Mellitus, Type 2/genetics Female Fetal Development/*genetics *Genetic Linkage Genetic Predisposition to Disease Genome-Wide Association Study Humans Infant, Newborn Male Meta-Analysis as Topic Polymorphism, Single Nucleotide *Quantitative Trait Loci, Diabetes Mellitus, Type 2/genetics, Female, Life Sciences & Biomedicine, Blood-pressure, Adult, SUSCEPTIBILITY LOCI, Blood Pressure/genetics, Birth weight, Meta-Analyses of Glucose- and Insulin-related traits Consortium (MAGIC), Quantitative Trait Loci, 030209 endocrinology & metabolism, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, Genetic linkage, Early Growth Genetics (EGG) Consortium, Genetics, medicine, Diabetes Mellitus, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Polymorphism, Fetal Development/genetics, Genome-Wide Association Study, Infant, Newborn, CDKAL1, METAANALYSIS, 030304 developmental biology, Genetic association, Fasting glucose, Science & Technology, Infant, ta3121, 06 Biological Sciences, medicine.disease, Newborn, Body Height, INDIVIDUALS, Diabetes Mellitus, Type 2, Institut für Ernährungswissenschaft, TYPE-2 DIABETES RISK, FASTING GLUCOSE, Developmental Biology
Abstract: Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood1. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits2. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism. Major funding for the research in this paper is provided by the Academy of Finland (project grants 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), 41071 (Skidi), 209072, 129255, 104781, 120315, 129269, 1114194, 206374, 251360, 139900/24300796, Center of Excellence in Complex Disease Genetics and SALVE) and Biocentrum Helsinki; Arthritis Research UK; the Augustinus Foundation; the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL); the Biomedical Research Council, Singapore (BMRC 06/1/21/19/466); BIF: Boehringer Ingelheim Fonds (travel grant to A.T.); the British Heart Foundation; the C.G. Sundell Foundation; the Canadian Institutes of Health Research (grant MOP-82893); Cancer Research UK; the Chief Scientist Office of the Scottish Government; the Children’s Hospital of Philadelphia (Institute Development Award); Conselleria de Sanitat Generalitat Valenciana; the Copenhagen Graduate School of Health Sciences; the Cotswold Foundation (Research Development Award); the Curtin University and Women and Infants Research Foundation; the Danish Health Insurance Societies (Health Fund); the Danish Medical Research Council; the Danish National Research Foundation; the Danish Pediatric Asthma Centre; the Danish Pharmacists’ Fund; the Danish Strategic Research Council; the Darlington Trust; the Department of Health and Social Services in Northern Ireland; Deutsche Forschungsgemeinschaft (DFG); Diabetes Hilfs- und Forschungsfonds Deutschland (DHFD; travel grant to M. Stumvoll); Diabetes UK (grants RD08/0003704 and RD08/0003692); the Dunhill Medical Trust; the Dutch Asthma Foundation (grants 3.4.01.26, 3.2.06.022, 3.4.09.081 and 3.2.10.085CO); the Dutch Ministry of the Environment (EFRE): Europäische Fonds für Regionale Entwicklung (LIFE Child Obesity); the Egmont Foundation; the Else Kröner-Fresenius Foundation; the Emil Aaltonen Foundation (T.L.); the ENGAGE project and grant agreement HEALTH-F4-2007-201413; the Erasmus Medical Center; Erasmus University, Rotterdam; the European Commission (EURO-BLCS, Beta-JUDO, Framework 5 award QLG1-CT-2000-01643, GABRIEL (Integrated Program LSH-2004-1.2.5-1 contract 018996), framework programme 6 EUROSPAN project (contract LSHG-CT-2006-018947), Sixth Research, Technological Development (RTD) Framework Programme (Contract FOOD-CT-2005-007034) and Seventh Framework Programme (FP7/2007-2013)); the European Research Council (ERC Advanced; 230374); the European Science Foundation (ESF; EU/QLRT-2001-01254); the Exeter NHS Research and Development; Faculty of Biology and Medicine of Lausanne; the Finnish Foundation of Cardiovascular Research; the Finnish Cultural Foundation; the Finnish Innovation Fund Sitra; the Finnish Ministry of Education and Culture; the Finnish Ministry of Social Affairs and Health; the Finnish Social Insurance Institution; the Foundation for Paediatric Research; Fundació La Marató de TV3; Fundación Roger Torné; Generalitat de Catalunya–Interminesterial Council for Research and Technological Innovation (CIRIT; 1999SGR) 00241; the German Diabetes Association (A.T.); the German Bundesministerium fuer Forschung und Technology (grants 01 AK 803 A-H and 01 IG 07015 G); the German Research Foundation for the Clinical Research Group Atherobesity KFO 152 (KO3512/1 to A.K.); GlaxoSmithKline; the Hagedorn Research Institute; Instituto de Salud Carlos III (CB06/02/0041, FIS PI041436, PI081151, PI041705 and PS09/00432 and FIS-FEDER 03/1615, 04/1509, 04/1112, 04/1931, 05/1079, 05/1052, 06/1213, 07/0314 and 09/02647); the Interdisciplinary Centre for Clinical Research at the University of Leipzig (B27 to A.T. and M. Stumvoll); the Integrated Research and Treatment Centre (IFB) Adiposity Diseases; the Jackstädt-Foundation; the Juho Vainio Foundation; the Juvenile Diabetes Research Foundation International (JDRF); Kuopio, Tampere and Turku University Hospital Medical Funds (grant 5031343 to T.A. Lakka and grant 9M048 to T.L.); The Lundbeck Foundation; the Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention and Care (LuCAMP); the March of Dimes Birth Defects Foundation (6-FY09-507); the MRC, UK (grants 74882, G0000934, G0601653, G0500539, G0600705, G0601261, G0600331, PrevMetSyn/SALVE PS0476 and MC-A760-5QX00); the Munich Center of Health Sciences (MC Health); the National Health and Medical Research Council of Australia (grants 403981 and 003209); the US National Human Genome Research Institute; the US National Institute of Allergy and Infectious Diseases; the US National Institute of Child Health and Human Development; the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); the US National Institutes of Health (grants U01DK062418, U01HG004423, U01HG004446, U01HG004438, R01DK075787, 1R01HD056465-01A, R01D0042157-01A, DK078150, TW05596, HL085144, HD054501, RR20649, ES10126, DK56350 and Biomedical Research Centers funding); the Netherlands Bioinformatics Centre (NBIC) BioAssist (RK/2008.024); a National Heart, Lung, and Blood Institute (NHLBI) grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01); the NIH Genetic Association Information Network (GAIN); the NIH/National Institute of Mental Health (NIMH) (5R01MH63706:02 and MH081802); the Rutgers University Cell and DNA Repository cooperative agreement (NIMH U24 MH068457-06); the Novo Nordisk Foundation Center for Basic Metabolic Research; the Center for Medical Systems Biology (CMSB; NWO Genomics); the Netherlands Organization for Scientific Research (NWO: Social Sciences (MaGW) and the Netherlands Organization for Health Research and Development (ZonMw) (Middelgroot-911-09-032, Spinozapremie 56-464-14192, 904-61-090, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 985-10-002, 40-0056-98-9032 and 912-03-031); the Paavo Nurmi Foundation; the Peninsula NIHR Clinical Research Facility; the Pharmacy Foundation of 1991; the PhD School of Molecular Metabolism University of Southern Denmark; the Raine Medical Research Foundation; the Royal Society; the Sigrid Juselius Foundation; South West NHS Research and Development; the Spanish Ministry of Science and Innovation (SAF2008-00357), Turku University Hospital; the Swiss National Science Foundation (33CSCO-122661); the Tampere Tuberculosis Foundation; the Telethon Institute for Child Health Research; the Turku University Foundation; the US Centers for Disease Control and Prevention; University Hospital Oulu, Biocenter, the University of Oulu (75617); the University of Bristol; the University of Potsdam; the University of Southampton; the University of Western Australia (UWA); the VU Institute for Health and Care Research (EMGO+) and the Neuroscience Campus Amsterdam (NCA); the Wellcome Trust (grants GR069224, WT088806, 068545/Z/02, 076467, 085301, 090532, 083270, 083948, 085541/Z/08/Z, WT089549 and WT083431MA); and the Yrjö Jahnsson Foundation.
Published: 2012

50. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

Author: Sarah Edkins, Anubha Mahajan, Nita G. Forouhi, Danish Saleheen, Lori L. Bonnycastle, Jackie F. Price, Lu Qi, Jasmina Kravic, Laura J. Scott, Susanne Moebus, Timothy M. Frayling, Stéphane Cauchi, Ching-Ti Liu, Michael Boehnke, Peter M. Nilsson, Lars Lind, James F. Wilson, John Beilby, Emil Rehnberg, Veikko Salomaa, Richard N. Bergman, Thomas Illig, Ruth J. F. Loos, Martina Müller-Nurasyid, Andrew Crenshaw, Karl-Heinz Jöckel, Krista Fischer, James B. Meigs, Rob M. van Dam, George Dedoussis, Christopher J. Groves, Julia Meyer, Valur Emilsson, Timo Saaristo, Kees Hovingh, Joseph Trakalo, Peter Kraft, André G. Uitterlinden, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Denis Rybin, Gonçalo R. Abecasis, Andrew T. Hattersley, Sonia Shah, Bruna Gigante, Jaakko Tuomilehto, Pierre Fontanillas, Kay-Tee Khaw, Annette Peters, Andrew D. Johnson, Rafn Benediktsson, Candace Guiducci, Andrew P. Morris, Tõnu Esko, Bo Isomaa, Anne U. Jackson, Beverley Balkau, Peter Donnelly, Thomas W. Mühleisen, Barbara Thorand, Tom Wilsgaard, Alan R. Shuldiner, David J. Hunter, Roman Wennauer, Karl Gertow, Wen Hong L. Kao, Alan James, Cordelia Langford, Christian Herder, Timo A. Lakka, Soumya Raychaudhuri, Jian'an Luan, Katharine R. Owen, Jennie Hui, Francis S. Collins, Juha Saltevo, David Couper, Bernhard O. Boehm, Sonali Pechlivanis, Raimund Erbel, Suthesh Sivapalaratnam, Markku Laakso, Augustine Kong, Heather M. Stringham, Leena Kinnunen, Kathleen Stirrups, Markus M. Nöthen, Ashok Kumar, Andrew R. Wood, Delilah Zabaneh, Rona J. Strawbridge, Bill Musk, Noël P. Burtt, Eeva Korpi-Hyövälti, Oddgeir L. Holmen, Inga Prokopenko, Marilyn C. Cornelis, Elodie Eury, Angela Silveira, Inês Barroso, Michael Roden, Unnur Thorsteinsdottir, Josée Dupuis, Han Chen, Cornelia M. van Duijn, Samuli Ripatti, Anna Jonsson, Gerald Steinbach, George B. Grant, Kristian Hveem, Andres Metspalu, Astradur B. Hreidarsson, Guillaume Charpentier, John Danesh, Claudia Langenberg, Sirkka Keinänen-Kiukaanniemi, Christian Dina, James S. Pankow, Panos Deloukas, Rainer Rauramaa, Satu Männistö, Kaarel Krjutškov, Eric Boerwinkle, Wendy Winckler, Valeriya Lyssenko, Anders Hamsten, Philippe Froguel, Nancy L. Pedersen, Harry Campbell, Sailaja Vedantam, Nicholas J. Wareham, Hassan Khan, Simon C. Potter, Damiano Baldassarre, Tiinamaija Tuomi, Vasiliki Lagou, Mozhgan Dorkhan, Stavroula Kanoni, Benjamin F. Voight, Wolfgang Rathmann, Tanya M. Teslovich, Antigone S. Dimas, Bengt Sennblad, Olle Melander, Albert Hofman, Mark I. McCarthy, Andrew D. Morris, Fabrizio Veglia, Karen L. Mohlke, Melissa Parkin, Sarah E. Hunt, Frank B. Hu, Elena Tremoli, Gudmar Thorleifsson, Steve E. Humphries, Jason Carey, Eero Lindholm, Alex S. F. Doney, Peter Almgren, Erik Ingelsson, Colin N. A. Palmer, Johanna Kuusisto, Inger Njølstad, Ann-Christine Syvänen, Leena Peltonen, Eric J.G. Sijbrands, Ross M. Fraser, Mieke D. Trip, Ghazala Mirza, Robert W. Lawrence, Neil Robertson, David Altshuler, Harald Grallert, Gunnar Sigurðsson, Kari Stefansson, N. William Rayner, Johan G. Eriksson, Christian Gieger, Emmi Tikkanen, Mustafa Atalay, S Wiltshire, Eleftheria Zeggini, Alena Stančáková, Loukianos S. Rallidis, Jouko Saramies, Stéphane Lobbens, Man Li, Hyun Min Kang, Loic Yengo, Norman Klopp, Ayellet V. Segrè, Carl G. P. Platou, Tom Forsén, Qi Sun, Karin Leander, Caroline S. Fox, Sekar Kathiresan, Jose C. Florez, Leif Groop, Teresa Ferreira, John R. B. Perry, Ulf de Faire, Peter S. Chines, Elizabeth J. Rossin, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Surgery, Dermatology, Epidemiology, and Internal Medicine
Subjects: Male, Linkage disequilibrium, Medizin, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Genome-wide association study, Type 2 diabetes, Biology, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Genetics, medicine, Humans, Genetic Predisposition to Disease, Pakistan, Gene, 030304 developmental biology, Genetic association, 0303 health sciences, Case-control study, medicine.disease, Genetic architecture, 3. Good health, Diabetes Mellitus, Type 2, Genes, Evolutionary biology, Case-Control Studies, Female, Genome-Wide Association Study
Abstract: To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis. © 2012 Nature America, Inc. All rights reserved.
Published: 2012

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