112 results on '"MANUELA UDA"'
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2. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.
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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
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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
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- 2012
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3. A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation.
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Silvia Naitza, Eleonora Porcu, Maristella Steri, Dennis D Taub, Antonella Mulas, Xiang Xiao, James Strait, Mariano Dei, Sandra Lai, Fabio Busonero, Andrea Maschio, Gianluca Usala, Magdalena Zoledziewska, Carlo Sidore, Ilenia Zara, Maristella Pitzalis, Alessia Loi, Francesca Virdis, Roberta Piras, Francesca Deidda, Michael B Whalen, Laura Crisponi, Antonio Concas, Carlo Podda, Sergio Uzzau, Paul Scheet, Dan L Longo, Edward Lakatta, Gonçalo R Abecasis, Antonio Cao, David Schlessinger, Manuela Uda, Serena Sanna, and Francesco Cucca
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Genetics ,QH426-470 - Abstract
Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional ∼1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals-5 of which were identified only with the custom arrays-and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p = 2.13×10(-29)); for ESR, at the HBB (rs4910472, p = 2.31×10(-11)) and UCN119B/SPPL3 (rs11829037, p = 8.91×10(-10)) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53×10(-13)) and in CADM3 (rs3026968, p = 7.63×10(-13)); for hsCRP, within the CRP gene (rs3093077, p = 5.73×10(-21)), near DARC (rs3845624, p = 1.43×10(-10)), UNC119B/SPPL3 (rs11829037, p = 1.50×10(-14)), and ICOSLG/AIRE (rs113459440, p = 1.54×10(-08)) loci. Confirmatory evidence was found for IL-6 in the IL-6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process.
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- 2012
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4. A genome-wide association search for type 2 diabetes genes in African Americans.
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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
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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
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- 2012
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5. Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability.
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Serena Sanna, Bingshan Li, Antonella Mulas, Carlo Sidore, Hyun M Kang, Anne U Jackson, Maria Grazia Piras, Gianluca Usala, Giuseppe Maninchedda, Alessandro Sassu, Fabrizio Serra, Maria Antonietta Palmas, William H Wood, Inger Njølstad, Markku Laakso, Kristian Hveem, Jaakko Tuomilehto, Timo A Lakka, Rainer Rauramaa, Michael Boehnke, Francesco Cucca, Manuela Uda, David Schlessinger, Ramaiah Nagaraja, and Gonçalo R Abecasis
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Genetics ,QH426-470 - Abstract
Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ∼10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci.
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- 2011
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6. Correction: Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution.
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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, 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 for the 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, and Mark I. McCarthy for the GIANT consortium
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Genetics ,QH426-470 - Published
- 2009
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7. Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.
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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
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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.
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- 2009
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8. Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations.
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Melanie Kolz, Toby Johnson, Serena Sanna, Alexander Teumer, Veronique Vitart, Markus Perola, Massimo Mangino, Eva Albrecht, Chris Wallace, Martin Farrall, Asa Johansson, Dale R Nyholt, Yurii Aulchenko, Jacques S Beckmann, Sven Bergmann, Murielle Bochud, Morris Brown, Harry Campbell, EUROSPAN Consortium, John Connell, Anna Dominiczak, Georg Homuth, Claudia Lamina, Mark I McCarthy, ENGAGE Consortium, Thomas Meitinger, Vincent Mooser, Patricia Munroe, Matthias Nauck, John Peden, Holger Prokisch, Perttu Salo, Veikko Salomaa, Nilesh J Samani, David Schlessinger, Manuela Uda, Uwe Völker, Gérard Waeber, Dawn Waterworth, Rui Wang-Sattler, Alan F Wright, Jerzy Adamski, John B Whitfield, Ulf Gyllensten, James F Wilson, Igor Rudan, Peter Pramstaller, Hugh Watkins, PROCARDIS Consortium, Angela Doering, H-Erich Wichmann, KORA Study, Tim D Spector, Leena Peltonen, Henry Völzke, Ramaiah Nagaraja, Peter Vollenweider, Mark Caulfield, WTCCC, Thomas Illig, and Christian Gieger
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Genetics ,QH426-470 - Abstract
Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2x10(-201)), ABCG2 (p = 3.1x10(-26)), SLC17A1 (p = 3.0x10(-14)), SLC22A11 (p = 6.7x10(-14)), SLC22A12 (p = 2.0x10(-9)), SLC16A9 (p = 1.1x10(-8)), GCKR (p = 1.4x10(-9)), LRRC16A (p = 8.5x10(-9)), and near PDZK1 (p = 2.7x10(-9)). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0x10(-26)) and propionyl-L-carnitine (p = 5.0x10(-8)) concentrations, which in turn were associated with serum UA levels (p = 1.4x10(-57) and p = 8.1x10(-54), respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels.
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- 2009
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9. The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts.
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Siguang Li, Serena Sanna, Andrea Maschio, Fabio Busonero, Gianluca Usala, Antonella Mulas, Sandra Lai, Mariano Dei, Marco Orrù, Giuseppe Albai, Stefania Bandinelli, David Schlessinger, Edward Lakatta, Angelo Scuteri, Samer S Najjar, Jack Guralnik, Silvia Naitza, Laura Crisponi, Antonio Cao, Gonçalo Abecasis, Luigi Ferrucci, Manuela Uda, Wei-Min Chen, and Ramaiah Nagaraja
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Genetics ,QH426-470 - Abstract
High serum uric acid levels elevate pro-inflammatory-state gout crystal arthropathy and place individuals at high risk for cardiovascular morbidity and mortality. Genome-wide scans in the genetically isolated Sardinian population identified variants associated with serum uric acid levels as a quantitative trait. They mapped within GLUT9, a Chromosome 4 glucose transporter gene predominantly expressed in liver and kidney. SNP rs6855911 showed the strongest association (p = 1.84 x 10(-16)), along with eight others (p = 7.75 x 10(-16) to 6.05 x 10(-11)). Individuals homozygous for the rare allele of rs6855911 (minor allele frequency = 0.26) had 0.6 mg/dl less uric acid than those homozygous for the common allele; the results were replicated in an unrelated cohort from Tuscany. Our results suggest that polymorphisms in GLUT9 could affect glucose metabolism and uric acid synthesis and/or renal reabsorption, influencing serum uric acid levels over a wide range of values.
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- 2007
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10. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits.
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Angelo Scuteri, Serena Sanna, Wei-Min Chen, Manuela Uda, Giuseppe Albai, James Strait, Samer Najjar, Ramaiah Nagaraja, Marco Orrú, Gianluca Usala, Mariano Dei, Sandra Lai, Andrea Maschio, Fabio Busonero, Antonella Mulas, Georg B Ehret, Ashley A Fink, Alan B Weder, Richard S Cooper, Pilar Galan, Aravinda Chakravarti, David Schlessinger, Antonio Cao, Edward Lakatta, and Gonçalo R Abecasis
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Genetics ,QH426-470 - Abstract
The obesity epidemic is responsible for a substantial economic burden in developed countries and is a major risk factor for type 2 diabetes and cardiovascular disease. The disease is the result not only of several environmental risk factors, but also of genetic predisposition. To take advantage of recent advances in gene-mapping technology, we executed a genome-wide association scan to identify genetic variants associated with obesity-related quantitative traits in the genetically isolated population of Sardinia. Initial analysis suggested that several SNPs in the FTO and PFKP genes were associated with increased BMI, hip circumference, and weight. Within the FTO gene, rs9930506 showed the strongest association with BMI (p = 8.6 x10(-7)), hip circumference (p = 3.4 x 10(-8)), and weight (p = 9.1 x 10(-7)). In Sardinia, homozygotes for the rare "G" allele of this SNP (minor allele frequency = 0.46) were 1.3 BMI units heavier than homozygotes for the common "A" allele. Within the PFKP gene, rs6602024 showed very strong association with BMI (p = 4.9 x 10(-6)). Homozygotes for the rare "A" allele of this SNP (minor allele frequency = 0.12) were 1.8 BMI units heavier than homozygotes for the common "G" allele. To replicate our findings, we genotyped these two SNPs in the GenNet study. In European Americans (N = 1,496) and in Hispanic Americans (N = 839), we replicated significant association between rs9930506 in the FTO gene and BMI (p-value for meta-analysis of European American and Hispanic American follow-up samples, p = 0.001), weight (p = 0.001), and hip circumference (p = 0.0005). We did not replicate association between rs6602024 and obesity-related traits in the GenNet sample, although we found that in European Americans, Hispanic Americans, and African Americans, homozygotes for the rare "A" allele were, on average, 1.0-3.0 BMI units heavier than homozygotes for the more common "G" allele. In summary, we have completed a whole genome-association scan for three obesity-related quantitative traits and report that common genetic variants in the FTO gene are associated with substantial changes in BMI, hip circumference, and body weight. These changes could have a significant impact on the risk of obesity-related morbidity in the general population.
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- 2007
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11. Editorial: Female Infertility: Genetics of Reproductive Ageing, Menopause and Primary Ovarian Insufficiency
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Mara Marongiu, Laura Crisponi, Manuela Uda, and Emanuele Pelosi
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Genetics ,Molecular Medicine ,Genetics (clinical) - Published
- 2021
12. Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci
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Paul, Ds, Albers, Ca, Rendon, A, Voss, K, Stephens, J, Akkerman, Jan Willem N., Albers, Cornelis A., Ale, Algra, Abtehale Al Hussani, Hooman, Allayee, Franco, Anni, Asselbergs, Folkert W., Antony, Attwood, Beverley, Balkau, Stefania, Bandinelli, François, Bastardot, Saonli, Basu, Baumeister, Sebastian E., Jacques, Beckmann, Beben, Benyamin, Ginevra, Biino, Bis, Joshua C., Lorenzo, Bomba, Amélie, Bonnefond, Boomsma, Dorret I., Bradley, John R., François, Cambien, Chambers, John C., Marina, Ciullo, Cookson, William O., Francesco, Cucca, Ana, Cvejic, D'Adamo, ADAMO PIO, John, Danesh, Fabrice, Danjou, Debashish, Das, Gail, Davies, Paul IW de Bakker, de Boer, Rudolf A., Eco JC de Geus, Deary, Ian J., Dedoussis, George V., Panos, Deloukas, Maria, Dimitriou, Christian, Dina, Angela, Döring, Ulrich, Elling, David, Ellinghaus, Paul, Elliott, Gunnar, Engström, Jeanette, Erdmann, Tõnu, Esko, Evans, David M., Eyjolfsson, Gudmundur I., Mario, Falchi, Wei, Feng, Ferreira, Manuel A., Luigi, Ferrucci, Krista, Fischer, Folsom, Aaron R., Paolo, Fortina, Andre, Franke, Lude, Franke, Frazer, Ian H., Philippe, Froguel, Renzo, Galanello, Ganesh, Santhi K., Garner, Stephen F., Gasparini, Paolo, Bernd, Genser, Gibson, Quince D., Christian, Gieger, Girotto, Giorgia, Glazer, Nicole L., Martin, Gögele, Goodall, Alison H., Andreas, Greinacher, Gudbjartsson, Daniel F., Chris, Hammond, Harris, Sarah E., Jaana, Hartiala, Anna Liisa Hartikainen, Hazen, Stanley L., Heckbert, Susan R., Hedblad, Bo, Christian, Hengstenberg, Micha, Hersch, Hicks, Andrew A., Hilma, Holm, Jouke Jan Hottenga, Thomas, Illig, Marjo Riitta Jarvelin, Jennifer, Jolley, Steve, Jupe, Mika, Kähönen, Naoyuki, Kamatani, Stavroula, Kanoni, Kema, Ido P., Kemp, John P., Jyoti, Khadake, Kay Tee Khaw, Kleber, Marcus E., Kooner, Jaspal S., Peter, Kovacs, Brigitte, Kühnel, Marie Christine Kyrtsonis, Yann, Labrune, Vasiliki, Lagou, Claudia, Langenberg, Terho, Lehtimäki, Xinzhong, Li, Liming, Liang, Lifelines Cohort Study, Heather Lloyd Jones, Ruth JF Loos, Lopez, Lorna M., Thomas, Lumley, Leo Pekka Lyytikäinen, Winfried, Maerz, Reedik, Mägi, Massimo, Mangino, Martin, Nicholas G., Andrea, Maschio, Irene Mateo Leach, Barbara, Mcknight, Stuart, Meacham, Medland, Sarah E., Christa, Meisinger, Olle, Melander, Yasin, Memari, Andres, Metspalu, Kathy, Miller, Mitchell, Braxton D., Moffatt, Miriam F., Montgomery, Grant W., Carmel, Moore, Federico, Murgia, Yusuke, Nakamura, Matthias, Nauck, Gerjan, Navis, Nolte, Ilja M., Ute, Nöthlings, Teresa, Nutile, Yukinori, Okada, Isleifur, Olafsson, Onundarson, Pall T., O’Reilly, Paul F., Ouwehand, Willem H., Debora, Parracciani, Afshin, Parsa, Paul, Dirk S., Penninger, Josef M., Penninx, Brenda W., Mario, Pirastu, Pirastu, Nicola, Giorgio, Pistis, Eleonora, Porcu, Laura, Portas, David, Porteous, Anneli, Pouta, Pramstaller, Peter P., Inga, Prokopenko, Psaty, Bruce M., Janne, Pullat, Aparna, Radhakrishnan, Olli, Raitakari, Ramiro Ramirez Solis, Augusto, Rendon, Ried, Janina S., Ring, Susan M., Robino, Antonietta, Rotter, Jerome I., Daniela, Ruggiero, Aimo, Ruokonen, Cinzia, Sala, Andres, Saluments, Samani, Nilesh J., Jennifer, Sambrook, Serena, Sanna, David, Schlessinger, Schmidt, Carsten O., Stefan, Schreiber, Heribert, Schunkert, James, Scott, Joban, Sehmi, Jovana Serbanovic Canic, So Youn Shin, Shuldiner, Alan R., Rob, Sladek, Smit, Johannes H., George Davey Smith, Gustav Smith, J., Smith, Nicholas L., Harold, Snieder, Nicole, Soranzo, Rossella, Sorice, Spector, Timothy D., Starr, John M., Kari, Stefansson, Derek, Stemple, Jonathan, Stephens, Michael, Stumvoll, Patrick, Sulem, Atsushi, Takahashi, Sian Tsung Tan, Toshiko, Tanaka, Clara, Tang, Weihong, Tang, WH Wilson Tang, Kent, Taylor, Albert, Tenesa, Alexander, Teumer, Swee Lay Thein, Unnur, Thorsteinsdottir, Daniela, Toniolo, Anke, Tönjes, Traglia, Michela, Manuela, Uda, Sheila, Ulivi, Pim van der Harst, Ellen van der Schoot, C., van Gilst, Wiek H., Joost van Pelt, L., van Veldhuisen, Dirk J., Niek, Verweij, Visscher, Peter M., Uwe, Völker, Peter, Vollenweider, Katrin, Voss, Wareham, Nicholas J., Lorenz, Wernisch, Harm Jan Westra, Whitfield, John B., Herich, Wichmann, Wiggins, Kerri L., Gonneke, Willemsen, Winkelmann, Bernhard R., Gerald, Wirnsberger, Bruce HR Wolffenbuttel, Jian, Yang, Tsun Po Yang, Weihua, Zhang, Jing Hua Zhao, Paavo, Zitting, Jaap Jan Zwaginga, van der Harst, P, Chambers, Jc, Soranzo, N, Ouwehand, Wh, Deloukas, P., Paul, D, Albers, Ca, Rendon, A, Voss, K, Stephens, J, Jan Willem N., Akkerman, Cornelis A., Alber, Ale, Algra, Abtehale Al, Hussani, Hooman, Allayee, Franco, Anni, Folkert W., Asselberg, Antony, Attwood, Beverley, Balkau, Stefania, Bandinelli, François, Bastardot, Saonli, Basu, Sebastian E., Baumeister, Jacques, Beckmann, Beben, Benyamin, Ginevra, Biino, Joshua C., Bi, Lorenzo, Bomba, Amélie, Bonnefond, Dorret I., Boomsma, John R., Bradley, François, Cambien, John C., Chamber, Marina, Ciullo, William O., Cookson, Francesco, Cucca, Ana, Cvejic, D'Adamo, ADAMO PIO, John, Danesh, Fabrice, Danjou, Debashish, Da, Gail, Davie, Paul IW de, Bakker, Rudolf A., de Boer, Eco JC de, Geu, Ian J., Deary, George V., Dedoussi, Panos, Delouka, Maria, Dimitriou, Christian, Dina, Angela, Döring, Ulrich, Elling, David, Ellinghau, Paul, Elliott, Gunnar, Engström, Jeanette, Erdmann, Tõnu, Esko, David M., Evan, Gudmundur I., Eyjolfsson, Mario, Falchi, Wei, Feng, Manuel A., Ferreira, Luigi, Ferrucci, Krista, Fischer, Aaron R., Folsom, Paolo, Fortina, Andre, Franke, Lude, Franke, Ian H., Frazer, Philippe, Froguel, Renzo, Galanello, Santhi K., Ganesh, Stephen F., Garner, Gasparini, Paolo, Bernd, Genser, Quince D., Gibson, Christian, Gieger, Girotto, Giorgia, Nicole L., Glazer, Martin, Gögele, Alison H., Goodall, Andreas, Greinacher, Daniel F., Gudbjartsson, Chris, Hammond, Sarah E., Harri, Jaana, Hartiala, Anna Liisa, Hartikainen, Stanley L., Hazen, Susan R., Heckbert, Bo, Hedblad, Christian, Hengstenberg, Micha, Hersch, Andrew A., Hick, Hilma, Holm, Jouke Jan, Hottenga, Thomas, Illig, Marjo Riitta, Jarvelin, Jennifer, Jolley, Steve, Jupe, Mika, Kähönen, Naoyuki, Kamatani, Stavroula, Kanoni, Ido P., Kema, John P., Kemp, Jyoti, Khadake, Kay Tee, Khaw, Marcus E., Kleber, Jaspal S., Kooner, Peter, Kovac, Brigitte, Kühnel, Marie Christine, Kyrtsoni, Yann, Labrune, Vasiliki, Lagou, Claudia, Langenberg, Terho, Lehtimäki, Xinzhong, Li, Liming, Liang, Lifelines Cohort, Study, Heather Lloyd, Jone, Ruth JF, Loo, Lorna M., Lopez, Thomas, Lumley, Leo Pekka, Lyytikäinen, Winfried, Maerz, Reedik, Mägi, Massimo, Mangino, Nicholas G., Martin, Andrea, Maschio, Irene Mateo, Leach, Barbara, Mcknight, Stuart, Meacham, Sarah E., Medland, Christa, Meisinger, Olle, Melander, Yasin, Memari, Andres, Metspalu, Kathy, Miller, Braxton D., Mitchell, Miriam F., Moffatt, Grant W., Montgomery, Carmel, Moore, Federico, Murgia, Yusuke, Nakamura, Matthias, Nauck, Gerjan, Navi, Ilja M., Nolte, Ute, Nöthling, Teresa, Nutile, Yukinori, Okada, Isleifur, Olafsson, Pall T., Onundarson, Paul F., O’Reilly, Willem H., Ouwehand, Debora, Parracciani, Afshin, Parsa, Dirk S., Paul, Josef M., Penninger, Brenda W., Penninx, Mario, Pirastu, Pirastu, Nicola, Giorgio, Pisti, Eleonora, Porcu, Laura, Porta, David, Porteou, Anneli, Pouta, Peter P., Pramstaller, Inga, Prokopenko, Bruce M., Psaty, Janne, Pullat, Aparna, Radhakrishnan, Olli, Raitakari, Ramiro Ramirez, Soli, Augusto, Rendon, Janina S., Ried, Susan M., Ring, Robino, Antonietta, Jerome I., Rotter, Daniela, Ruggiero, Aimo, Ruokonen, Cinzia, Sala, Andres, Salument, Nilesh J., Samani, Jennifer, Sambrook, Serena, Sanna, David, Schlessinger, Carsten O., Schmidt, Stefan, Schreiber, Heribert, Schunkert, James, Scott, Joban, Sehmi, Jovana Serbanovic, Canic, So Youn, Shin, Alan R., Shuldiner, Rob, Sladek, Johannes H., Smit, George Davey, Smith, J., Gustav Smith, Nicholas L., Smith, Harold, Snieder, Nicole, Soranzo, Rossella, Sorice, Timothy D., Spector, John M., Starr, Kari, Stefansson, Derek, Stemple, Jonathan, Stephen, Michael, Stumvoll, Patrick, Sulem, Atsushi, Takahashi, Sian Tsung, Tan, Toshiko, Tanaka, Clara, Tang, Weihong, Tang, WH Wilson, Tang, Kent, Taylor, Albert, Tenesa, Alexander, Teumer, Swee Lay, Thein, Unnur, Thorsteinsdottir, Daniela, Toniolo, Anke, Tönje, Traglia, Michela, Manuela, Uda, Sheila, Ulivi, Pim van der, Harst, C., Ellen van der Schoot, Wiek H., van Gilst, L., Joost van Pelt, Dirk J., van Veldhuisen, Niek, Verweij, Peter M., Visscher, Uwe, Völker, Peter, Vollenweider, Katrin, Vo, Nicholas J., Wareham, Lorenz, Wernisch, Harm Jan, Westra, John B., Whitfield, Herich, Wichmann, Kerri L., Wiggin, Gonneke, Willemsen, Bernhard R., Winkelmann, Gerald, Wirnsberger, Bruce HR, Wolffenbuttel, Jian, Yang, Tsun Po, Yang, Weihua, Zhang, Jing Hua, Zhao, Paavo, Zitting, Jaap Jan, Zwaginga, van der Harst, P, Chambers, Jc, Soranzo, N, Ouwehand, Wh, Deloukas, P., Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England, UCL, UCL Canc Inst, London WC1E 6BT, England, Univ Cambridge, Dept Haematol, Cambridge CB2 0PT, England, Natl Hlth Serv NHS Blood & Transplant, Cambridge CB2 0PT, England, Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands, Inst Publ Hlth, MRC Biostat Unit, Cambridge CB2 0SR, England, NIHR Biomed Res Ctr, Cambridge CB2 0PT, England, Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9713 GZ Groningen, Netherlands, Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9713 GZ Groningen, Netherlands, Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1NY, England, Hammersmith Hosp, Imperial Coll Healthcare NHS Trust, London W12 0HS, England, Royal Brompton & Harefield Hosp NHS Trust, London SW3 6NP, England, Ealing Hosp NHS Trust, Southall UB1 3HW, Middx, England, Psychiatry, Epidemiology and Data Science, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, and Cardiovascular Centre (CVC)
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Netherlands Twin Register (NTR) ,Erythrocytes ,Genome-wide association study ,UNCERTAINTY ,Regulatory Sequences, Nucleic Acid ,VARIANTS ,ANNOTATION ,COLORECTAL-CANCER ,Histones ,0302 clinical medicine ,BINDING ,Cluster Analysis ,Myeloid Cells ,Genetics (clinical) ,Genetics ,hematological trait ,0303 health sciences ,Chromosome Mapping ,MRP4 ABCC4 ,Chromatin ,Nucleosomes ,Phenotype ,Organ Specificity ,030220 oncology & carcinogenesis ,Blood Platelets ,Quantitative Trait Loci ,Biology ,Quantitative trait locus ,Polymorphism, Single Nucleotide ,DYNAMIN 3 ,03 medical and health sciences ,Quantitative Trait, Heritable ,MEGAKARYOCYTES ,Humans ,Cell Lineage ,ddc:610 ,GENOME-WIDE ASSOCIATION ,Enhancer ,Transcription factor ,Gene ,ChIA-PET ,030304 developmental biology ,Research ,Genetic Variation ,DNA ,Chromatin Assembly and Disassembly ,Genetic architecture ,Gene Expression Regulation ,Genome-Wide Association Study - Abstract
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits. Marie-Curie Initial Training Network NETSIM British Heart Foundation RG/09/12/28096 National Institutes for Health RP-PG-0310-1002 Wellcome Trust 098051 info:eu-repo/grantAgreement/EC/FP7/282510
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- 2013
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13. GENOME-WIDE ASSOCIATION ANALYSES BASED ON WHOLE-GENOME SEQUENCING IN SARDINIA PROVIDE INSIGHTS INTO REGULATION OF HEMOGLOBIN LEVELS
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Eleonora Porcu, Fabio Busonero, Andrea Angius, Swee Lay Thein, Antonella Mulas, Maristella Steri, Giorgio Pistis, Mauro Pala, Paolo Moi, Lucia Perseu, Stephan Menzel, Carlo Sidore, Magdalena Zoledziewska, Serena Sanna, Lidia Leoni, Sarah Metrustry, Manuela Uda, Andrea Maschio, Susanna Barella, Gonçalo R. Abecasis, David Schlessinger, Renzo Galanello, Maristella Pitzalis, Fabrice Danjou, Francesco Cucca, and Tim D. Spector
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Adult ,Male ,Genotype ,Genotyping Techniques ,Genome-wide association study ,beta-Globins ,Polymorphism, Single Nucleotide ,Article ,Hemoglobins ,alpha-Globins ,Genetic variation ,Genetics ,Humans ,Genotyping ,Whole genome sequencing ,Islands ,biology ,Genome, Human ,Genetic Variation ,Sequence Analysis, DNA ,Middle Aged ,NFIX ,Italy ,Multigene Family ,biology.protein ,Human genome ,Female ,Genome-Wide Association Study - Abstract
We report genome-wide association study results for the levels of A1, A2 and fetal hemoglobins, analyzed for the first time concurrently. Integrating high-density array genotyping and whole-genome sequencing in a large general population cohort from Sardinia, we detected 23 associations at 10 loci. Five signals are due to variants at previously undetected loci: MPHOSPH9, PLTP-PCIF1, ZFPM1 (FOG1), NFIX and CCND3. Among the signals at known loci, ten are new lead variants and four are new independent signals. Half of all variants also showed pleiotropic associations with different hemoglobins, which further corroborated some of the detected associations and identified features of coordinated hemoglobin species production.
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- 2015
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14. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
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Yuki Bradford, Toshiko Tanaka, Jeffrey R. O'Connell, Florence Kyndt, Unnur Thorsteinsdottir, Ivana Kolcic, Xiaoyan Yin, Vincent Probst, Manolis Kellis, Christopher Newton-Cheh, Stefan Kääb, Argelia Medeiros-Domingo, Markus M. Nöthen, Paolo Gasparini, Jean-Jacques Schott, Ruth J. F. Loos, Thomas W. Mühleisen, Annukka Marjamaa, Morris Brown, Igor Rudan, Runjun D. Kumar, Peter J. Schwartz, Lars Lind, Martina Müller-Nurasyid, Xinchen Wang, Joshua C. Denny, Roberto Insolia, Soumya Raychaudhuri, Stephen W. Scherer, Bruno H. Stricker, Alexander Kluttig, Adamo Pio D'Adamo, Laurie A. Boyer, Moritz F. Sinner, Norbert Frey, Nour Eddine El Mokhtari, Thomas Meitinger, Jesper V. Olsen, Gerjan Navis, Steven R. Cummings, Richard W Morris, Nynke Hofman, Marcel den Hoed, Rudolf A. de Boer, Gonçalo R. Abecasis, Mark J. Daly, Dan M. Roden, Christian Gieger, Lyudmyla Kedenko, Marcus Dörr, Thomas P. Cappola, Afshin Parsa, Kari Stefansson, Markus Perola, Mark Eijgelsheim, Fredrik Nyberg, Robert M. Hamilton, Yalda Jamshidi, W. H. Linda Kao, Terho Lehtimäki, Annette Peters, David Schlessinger, Peter P. Pramstaller, James F. Wilson, Vilmundur Gudnason, Florian Kronenberg, Aroon D. Hingorani, Connie R. Bezzina, Abdennasser Bardai, Marylyn D. Ritchie, Andrew S. Plump, Johan Sundström, Daryl Waggott, Chrysoula Dalageorgou, Paul I.W. de Bakker, Uwe Völker, Aaron Isaacs, Oscar H. Franco, Yongmei Liu, Andrew N. Nicolaides, Lia Crotti, Cornelia M. van Duijn, Ben A. Oostra, Arne Pfeufer, Karl Werdan, Michael Morley, Jan A. Kors, Julien Barc, Lewin Eisele, Siegfried Perz, Stéphanie Chatel, Pieter A. van der Vleuten, Sara L. Pulit, Anna F. Dominiczak, Harry Campbell, Alice Ghidoni, Irene Mateo Leach, Nona Sotoodehnia, Nina Mononen, Henriette E. Meyer zu Schwabedissen, Alvaro Alonso, Fabiola Del Greco M, Dan E. Arking, Vera Adamkova, Mike A. Nalls, Valur Emilsson, Edward G. Lakatta, Kirill Tarasov, Alan F. Wright, Lenore J. Launer, Erik Ingelsson, Karin Halina Greiser, Ozren Polasek, Massimo Carella, Daniel F. Gudbjartsson, Bouwe P. Krijthe, Hanna Prucha, Per Hoffmann, Maura Griffin, Stefan Kiechl, Angel Carracedo, Ilja M. Nolte, Christine E. Moravec, Johann Willeit, Joshua C. Bis, Patricia B. Munroe, Marcello Ricardo Paulista Markus, Hailiang Huang, Mika Kähönen, Albert Hofman, Peter H. Whincup, Dirk J. van Veldhuisen, Michael Knoflach, Alicia Lundby, Serena Sanna, Hagen Kälsch, Bernhard Paulweber, Kamil Slowikowski, Luigi Ferrucci, Melanie Waldenberger, Marco Bobbo, Annukka M. Lahtinen, Ann-Christine Syvänen, J. Gustav Smith, Åsa Torinsson Naluai, Jaroslav A. Hubacek, Jeffrey Brandimarto, Wendy S. Post, Lude Franke, Mark J. Caulfield, Folkert W. Asselbergs, André G. Uitterlinden, Stefan Gustafsson, Pim van der Harst, David J. Tester, David S. Siscovick, David O. Arnar, Sarah H Wild, Elizabeth J. Rossin, Albert V. Smith, Bruce M. Psaty, Georg Ehret, Alan R. Shuldiner, Stephen Newhouse, Kimmo Kontula, Maria Brion, Andre Franke, Peter W. Macfarlane, Mika Kivimäki, Tamara B. Harris, Lasse Oikarinen, Tamara T. Koopmann, Kenneth B. Margulies, Aravinda Chakravarti, Gianfranco Sinagra, Maarten P. van den Berg, Veikko Salomaa, Karl-Heinz Jöckel, Daniel S. Evans, Caroline Hayward, Kimmo Porthan, Michael J. Ackerman, Jacqueline C.M. Witteman, Arthur A.M. Wilde, Martin G. Larson, Kasper Lage, Manuela Uda, Susan R. Heckbert, Joel S. Bader, Graham Watt, María Dolores Torres, Stephan B. Felix, Jerome I. Rotter, Pau Navarro, Meena Kumari, Johan Ärnlöv, Andrew D. Paterson, Antti Jula, Olli T. Raitakari, Raimund Erbel, Christopher J. O'Donnell, Britt M. Beckmann, Peter A. Noseworthy, Tim D. Spector, Wai K. Lee, Leopoldo Zelante, Nilesh J. Samani, John R. Giudicessi, Harold Snieder, Dag S. Thelle, David Ellinghaus, Eimo Martens, James B. Strait, Jorma S. A. Viikari, Andrew D. Johnson, Antonella Mulas, Hilma Holm, Johannes Haerting, Annamaria Iorio, Rebecca L. Zuvich, Sheila Ulivi, Andrew A. Hicks, Elijah R. Behr, Leo-Pekka Lyytikäinen, Bernhard Strohmer, Marco Orru, Claudia Lamina, Sandosh Padmanabhan, Christian Fuchsberger, Andrie G. Panayiotou, Ehret, Georg Benedikt, Internal Medicine, Public Health, Epidemiology, Rehabilitation Medicine, Medical Informatics, Clinical Genetics, Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Ethical, Legal, Social Issues in Genetics (ELSI), Stem Cell Aging Leukemia and Lymphoma (SALL), Arking, D, Pulit, S, Crotti, L, van der Harst, P, Munroe, P, Koopmann, T, Sotoodehnia, N, Rossin, E, Morley, M, Wang, X, Johnson, A, Lundby, A, Gudbjartsson, D, Noseworthy, P, Eijgelsheim, M, Bradford, Y, Tarasov, K, Dörr, M, Müller-Nurasyid, M, Lahtinen, A, Nolte, I, Smith, A, Bis, J, Isaacs, A, Newhouse, S, Evans, D, Post, W, Waggott, D, Lyytikäinen, L, Hicks, A, Eisele, L, Ellinghaus, D, Hayward, C, Navarro, P, Ulivi, S, Tanaka, T, Tester, D, Chatel, S, Gustafsson, S, Kumari, M, Morris, R, Naluai, A, Padmanabhan, S, Kluttig, A, Strohmer, B, Panayiotou, A, Torres, M, Knoflach, M, Hubacek, J, Slowikowski, K, Raychaudhuri, S, Kumar, R, Harris, T, Launer, L, Shuldiner, A, Alonso, A, Bader, J, Ehret, G, Huang, H, Kao, W, Strait, J, Macfarlane, P, Brown, M, Caulfield, M, Samani, N, Kronenberg, F, Willeit, J, Smith, J, Greiser, K, Meyer Zu Schwabedissen, H, Werdan, K, Carella, M, Zelante, L, Heckbert, S, Psaty, B, Rotter, J, Kolcic, I, Polašek, O, Wright, A, Griffin, M, Daly, M, Arnar, D, Hólm, H, Thorsteinsdottir, U, Denny, J, Roden, D, Zuvich, R, Emilsson, V, Plump, A, Larson, M, O'Donnell, C, Yin, X, Bobbo, M, D'Adamo, A, Iorio, A, Sinagra, G, Carracedo, A, Cummings, S, Nalls, M, Jula, A, Kontula, K, Marjamaa, A, Oikarinen, L, Perola, M, Porthan, K, Erbel, R, Hoffmann, P, Jöckel, K, Kälsch, H, Nöthen, M, den Hoed, M, Loos, R, Thelle, D, Gieger, C, Meitinger, T, Perz, S, Peters, A, Prucha, H, Sinner, M, Waldenberger, M, de Boer, R, Franke, L, van der Vleuten, P, Beckmann, B, Martens, E, Bardai, A, Hofman, N, Wilde, A, Behr, E, Dalageorgou, C, Giudicessi, J, Medeiros-Domingo, A, Kyndt, F, Probst, V, Ghidoni, A, Insolia, R, Hamilton, R, Scherer, S, Brandimarto, J, Margulies, K, Moravec, C, Greco, M, Fuchsberger, C, O'Connell, J, Lee, W, Watt, G, Campbell, H, Wild, S, El Mokhtari, N, Frey, N, Asselbergs, F, Mateo Leach, I, Navis, G, van den Berg, M, van Veldhuisen, D, Kellis, M, Krijthe, B, Franco, O, Hofman, A, Kors, J, Uitterlinden, A, Witteman, J, Kedenko, L, Lamina, C, Oostra, B, Abecasis, G, Lakatta, E, Mulas, A, Orrú, M, Schlessinger, D, Uda, M, Markus, M, Völker, U, Snieder, H, Spector, T, Arnlöv, J, Lind, L, Sundström, J, Syvänen, A, Kivimaki, M, Kähönen, M, Mononen, N, Raitakari, O, Viikari, J, Adamkova, V, Kiechl, S, Brion, M, Nicolaides, A, Paulweber, B, Haerting, J, Dominiczak, A, Nyberg, F, Whincup, P, Hingorani, A, Schott, J, Bezzina, C, Ingelsson, E, Ferrucci, L, Gasparini, P, Wilson, J, Rudan, I, Franke, A, Mühleisen, T, Pramstaller, P, Lehtimäki, T, Paterson, A, Parsa, A, Liu, Y, van Duijn, C, Siscovick, D, Gudnason, V, Jamshidi, Y, Salomaa, V, Felix, S, Sanna, S, Ritchie, M, Stricker, B, Stefansson, K, Boyer, L, Cappola, T, Olsen, J, Lage, K, Schwartz, P, Kääb, S, Chakravarti, A, Ackerman, M, Pfeufer, A, de Bakker, P, Newton-Cheh, C, Arking, Dan E., Pulit, Sara L., Crotti, Lia, Van Der Harst, Pim, Munroe, Patricia B., Koopmann, Tamara T., Sotoodehnia, Nona, Rossin, Elizabeth J., Morley, Michael, Wang, Xinchen, Johnson, Andrew D., Lundby, Alicia, Gudbjartsson, Daníel F., Noseworthy, Peter A., Eijgelsheim, Mark, Bradford, Yuki, Tarasov, Kirill V., Dörr, Marcu, Müller Nurasyid, Martina, Lahtinen, Annukka M., Nolte, Ilja M., Smith, Albert Vernon, Bis, Joshua C., Isaacs, Aaron, Newhouse, Stephen J., Evans, Daniel S., Post, Wendy S., Waggott, Daryl, Lyytikäinen, Leo Pekka, Hicks, Andrew A., Eisele, Lewin, Ellinghaus, David, Hayward, Caroline, Navarro, Pau, Ulivi, Sheila, Tanaka, Toshiko, Tester, David J., Chatel, Stéphanie, Gustafsson, Stefan, Kumari, Meena, Morris, Richard W., Naluai, Asa T., Padmanabhan, Sandosh, Kluttig, Alexander, Strohmer, Bernhard, Panayiotou, Andrie G., Torres, Maria, Knoflach, Michael, Hubacek, Jaroslav A., Slowikowski, Kamil, Raychaudhuri, Soumya, Kumar, Runjun D., Harris, Tamara B., Launer, Lenore J., Shuldiner, Alan R., Alonso, Alvaro, Bader, Joel S., Ehret, Georg, Huang, Hailiang, Kao, W. H. Linda, Strait, James B., Macfarlane, Peter W., Brown, Morri, Caulfield, Mark J., Samani, Nilesh J., Kronenberg, Florian, Willeit, Johann, Smith, J. Gustav, Greiser, Karin H., Zu Schwabedissen, Henriette Meyer, Werdan, Karl, Carella, Massimo, Zelante, Leopoldo, Heckbert, Susan R., Psaty, Bruce M., Rotter, Jerome I., Kolcic, Ivana, Polašek, Ozren, Wright, Alan F., Griffin, Maura, Daly, Mark J., Arnar, David O., Hólm, Hilma, Thorsteinsdottir, Unnur, Denny, Joshua C., Roden, Dan M., Zuvich, Rebecca L., Emilsson, Valur, Plump, Andrew S., Larson, Martin G., O'Donnell, Christopher J., Yin, Xiaoyan, Bobbo, Marco, D'Adamo, ADAMO PIO, Iorio, Annamaria, Sinagra, Gianfranco, Carracedo, Angel, Cummings, Steven R., Nalls, Michael A., Jula, Antti, Kontula, Kimmo K., Marjamaa, Annukka, Oikarinen, Lasse, Perola, Marku, Porthan, Kimmo, Erbel, Raimund, Hoffmann, Per, Jöckel, Karl Heinz, Kälsch, Hagen, Nöthen, Markus M., Den Hoed, Marcel, Loos, Ruth J. F., Thelle, Dag S., Gieger, Christian, Meitinger, Thoma, Perz, Siegfried, Peters, Annette, Prucha, Hanna, Sinner, Moritz F., Waldenberger, Melanie, De Boer, Rudolf A., Franke, Lude, Van Der Vleuten, Pieter A., Beckmann, Britt Maria, Martens, Eimo, Bardai, Abdennasser, Hofman, Nynke, Wilde, Arthur A. M., Behr, Elijah R., Dalageorgou, Chrysoula, Giudicessi, John R., Medeiros Domingo, Argelia, Barc, Julien, Kyndt, Florence, Probst, Vincent, Ghidoni, Alice, Insolia, Roberto, Hamilton, Robert M., Scherer, Stephen W., Brandimarto, Jeffrey, Margulies, Kenneth, Moravec, Christine E., Del Greco M, Fabiola, Fuchsberger, Christian, O'Connell, Jeffrey R., Lee, Wai K., Watt, Graham C. M., Campbell, Harry, Wild, Sarah H., El Mokhtari, Nour E., Frey, Norbert, Asselbergs, Folkert W., Leach, Irene Mateo, Navis, Gerjan, Van Den Berg, Maarten P., Van Veldhuisen, Dirk J., Kellis, Manoli, Krijthe, Bouwe P., Franco, Oscar H., Hofman, Albert, Kors, Jan A., Uitterlinden, André G., Witteman, Jacqueline C. M., Kedenko, Lyudmyla, Lamina, Claudia, Oostra, Ben A., Abecasis, Gonçalo R., Lakatta, Edward G., Mulas, Antonella, Orrú, Marco, Schlessinger, David, Uda, Manuela, Markus, Marcello R. P., Völker, Uwe, Snieder, Harold, Spector, Timothy D., Ärnlöv, Johan, Lind, Lar, Sundström, Johan, Syvänen, Ann Christine, Kivimaki, Mika, Kähönen, Mika, Mononen, Nina, Raitakari, Olli T., Viikari, Jorma S., Adamkova, Vera, Kiechl, Stefan, Brion, Maria, Nicolaides, Andrew N., Paulweber, Bernhard, Haerting, Johanne, Dominiczak, Anna F., Nyberg, Fredrik, Whincup, Peter H., Hingorani, Aroon D., Schott, Jean Jacque, Bezzina, Connie R., Ingelsson, Erik, Ferrucci, Luigi, Gasparini, Paolo, Wilson, James F., Rudan, Igor, Franke, Andre, Mühleisen, Thomas W., Pramstaller, Peter P., Lehtimäki, Terho J., Paterson, Andrew D., Parsa, Afshin, Liu, Yongmei, Van Duijn, Cornelia M., Siscovick, David S., Gudnason, Vilmundur, Jamshidi, Yalda, Salomaa, Veikko, Felix, Stephan B., Sanna, Serena, Ritchie, Marylyn D., Stricker, Bruno H., Stefansson, Kari, Boyer, Laurie A., Cappola, Thomas P., Olsen, Jesper V., Lage, Kasper, Schwartz, Peter J., Kääb, Stefan, Chakravarti, Aravinda, Ackerman, Michael J., Pfeufer, Arne, De Bakker, Paul I. W., Newton Cheh, Christopher, Cardiology, ACS - Amsterdam Cardiovascular Sciences, and Human Genetics
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Male ,Candidate gene ,Myocardium/metabolism ,LOCI ,Medizin ,Heart electrophysiology ,Genome-wide association study ,Arrhythmias ,Bioinformatics ,Medical and Health Sciences ,Heart Ventricle ,Sudden cardiac death ,Electrocardiography ,PR INTERVAL ,Arrhythmias, Cardiac/genetics ,Death, Sudden, Cardiac/etiology ,Genetics ,ddc:616 ,Cardiac electrophysiology ,Adult ,Aged ,Arrhythmias, Cardiac ,Calcium Signaling ,Death, Sudden, Cardiac ,Female ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genotype ,Heart Ventricles ,Humans ,Long QT Syndrome ,Middle Aged ,Myocardium ,Polymorphism, Single Nucleotide ,COMMON VARIANTS ,Heart Ventricles/metabolism ,Single Nucleotide ,Long QT Syndrome/genetics ,CHRONIC HEART-FAILURE ,Death ,Heart ventricle arrhythmia ,genetic association study ,gene ,SNP ,heart ,Genome-Wide Association Study/methods ,Long QT syndrome ,QRS DURATION ,Cardiac ,Cardiac/etiology ,Human ,QT interval ,congenital, hereditary, and neonatal diseases and abnormalities ,Electrocardiography/methods ,TRPM7 ,BIO/18 - GENETICA ,Cardiac/genetics ,Biology ,Article ,sudden cardiac death ,QRS complex ,CARDIAC REPOLARIZATION ,medicine ,Repolarization ,cardiovascular diseases ,GENOME-WIDE ASSOCIATION ,Polymorphism ,MED/01 - STATISTICA MEDICA ,calcium ,ta1184 ,Calcium signaling ,Calcium Signaling/genetics ,MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE ,ta3121 ,Cardiovascular risk ,medicine.disease ,SARCOPLASMIC-RETICULUM ,Sudden ,MODEL ,Genetic association ,myocardial repolarization ,Genetic variability ,Gene expression ,Clinical Medicine ,genetic ,Controlled study - Abstract
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain similar to 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
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- 2014
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15. Impulsivity is Associated with Uric Acid: Evidence from Humans and Mice
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Luigi Ferrucci, Roy G. Cutler, Neil H. Feldman, David Schlessinger, Manuela Uda, Alan B. Zonderman, Angelina R. Sutin, Antonio Terracciano, Mark P. Mattson, Francesco Cucca, and Simonetta Camandola
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Adult ,Male ,medicine.medical_specialty ,Time Factors ,Personality Inventory ,Urate Oxidase ,Transgene ,Mice, Transgenic ,Impulsivity ,Article ,Revised NEO Personality Inventory ,Cohort Studies ,Mice ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Humans ,Bipolar disorder ,Maze Learning ,Psychiatry ,Biological Psychiatry ,Aged ,Mental Disorders ,Middle Aged ,medicine.disease ,Uric Acid ,Genetically modified organism ,Disease Models, Animal ,Normal variation ,Endocrinology ,chemistry ,Impulsive Behavior ,Exploratory Behavior ,Uric acid ,Female ,medicine.symptom ,Personality Assessment Inventory ,Psychology - Abstract
Background The ability to control impulses varies greatly, and difficulty with impulse control can have severe consequences; in the extreme, it is the defining feature of many psychiatric disorders. Evidence from disparate lines of research suggests that uric acid is elevated in psychiatric disorders characterized by high impulsivity, such as attention-deficit/hyperactivity disorder and bipolar disorder. The present research tests the hypothesis that impulsivity is associated with higher uric acid in humans and mice. Methods Using two longitudinal, nonclinical community samples (total n = 6883), we tested whether there is an association between uric acid and normal variation in trait impulsivity measured with the Revised NEO Personality Inventory. We also examined the effect of uric acid on behavior by comparing wild-type mice, which naturally have low levels of uric acid, with mice genetically modified to accumulate high levels of uric acid. Results In both human samples, the emotional aspects of trait impulsivity, specifically impulsiveness and excitement seeking, were associated with higher levels of uric acid concurrently and when uric acid was measured 3 to 5 years later. Consistent with the human data, the genetically modified mice displayed significantly more exploratory and novelty-seeking behavior than the wild-type mice. Conclusions Higher uric acid was associated with impulsivity in both humans and mice. The identification of biological markers of impulsivity may lead to a better understanding of the physiological mechanisms involved in impulsivity and may suggest potential targets for therapeutic intervention.
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- 2014
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16. Multi-ethnic fine-mapping of 14 central adiposity loci
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Eco De Geus, Michael Weedon, Joyce Van Meurs, Torben Jørgensen, Kirsi Pietiläinen, Patricia Munroe, Amanda Bennett, Michael Stumvoll, Andrew Hattersley, Vilmundur Gudnason, Dale Nyholt, Mary Feitosa, Mariano Dei, Marcus Dörr, Terho Lehtimäki, Anette P Gjesing, Daniel Witte, Adebowale Adeyemo, Eleanor Wheeler, Peter Kovacs, Hana Lango Allen, Philippe Froguel, Panos Deloukas, Cornelia Van Duijn, Tiinamaija Tuomi, Daniel Shriner, Struan Grant, Tonu Esko, Reedik Mägi, Lyle John Palmer, L. Adrienne Cupples, Claes Ohlsson, Krina Zondervan, Thomas Meitinger, Sarah Nyante, Lina Zgaga, Themistocles Assimes, Paul Elliott, Robert Luben, Albert Vernon Smith, MANUELA UDA, Rona Strawbridge, Richard Bergman, Gonneke Willemsen, Igor Rudan, Maris Teder-Laving, Liesbeth Vandenput, Mary Cushman, Allan Linneberg, Biological Psychology, and EMGO+ - Lifestyle, Overweight and Diabetes
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Netherlands Twin Register (NTR) ,Linkage disequilibrium ,Ethnic group ,Churg-strauss syndrome ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,waist-to-hip ratio ,multi-ethnic fine-mapping ,Genetics ,medicine ,Ethnicity ,Humans ,Molecular Biology ,Genetics (clinical) ,Adiposity ,Anthropometry ,Association Studies Articles ,Physical Chromosome Mapping ,Computational Biology ,Molecular Sequence Annotation ,General Medicine ,medicine.disease ,Carotid sinus syncope ,Genetic Loci ,Central Adiposity ,Allelic heterogeneity - Abstract
The Genetic Investigation of Anthropometric Traits (GIANT) consortium identified 14 loci in European Ancestry (EA) individuals associated with waist-to-hip ratio (WHR) adjusted for body mass index. These loci are wide and narrowingthe signalsremains necessary. Twelve of 14 loci identified inGIANTEA samples retained strong associations with WHR in our joint EA/individuals of African Ancestry (AA) analysis (log-Bayes factor >6.1). Transethnic analysesatfiveloci (TBX15-WARS2, LYPLAL1, ADAMTS9, LY86andITPR2-SSPN)substantially narrowed the signals to smaller sets of variants, some of which are in regions that have evidence of regulatory activity. By leveraging varying linkage disequilibrium structures across different populations, single-nucleotide polymorphisms (SNPs) with strong signals and narrower credible sets from trans-ethnic meta-analysis of central obesity provide more precise localizations of potential functional variants and suggest a possible regulatory role. Meta-analysis results for WHR were obtained from 77 167 EA participants from GIANT and 23 564 AA participants from the AfricanAncestry Anthropometry Genetics Consortium. For fine mapping we interrogatedSNPs within ±250 kbflanking regionsof 14 previously reported indexSNPsfrom loci discovered in EApopulations by performing trans-ethnic meta-analysis of results from the EA and AA meta-analyses. We applied a Bayesian approach that leverages allelic heterogeneity across populations to combine meta-analysis results and aids in fine-mapping shared variants at these locations. We annotated variants using information from the ENCODE Consortium and Roadmap Epigenomics Project to prioritize variants for possible functionality. © The Author 2014. Published by Oxford University Press. All rights reserved.
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- 2014
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17. Personality Traits and Leptin
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Antonio Terracciano, Luigi Ferrucci, Angelina R. Sutin, Barbara Deiana, Francesco Cucca, Manuela Uda, Dennis D. Taub, David Schlessinger, Dan L. Longo, and Alan B. Zonderman
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Adult ,Leptin ,Male ,medicine.medical_specialty ,Adolescent ,Personality Inventory ,media_common.quotation_subject ,Enzyme-Linked Immunosorbent Assay ,Models, Psychological ,Article ,Body Mass Index ,Leukocyte Count ,Young Adult ,Internal medicine ,medicine ,Humans ,Personality ,Obesity ,Big Five personality traits ,Applied Psychology ,Adiposity ,Aged ,media_common ,Aged, 80 and over ,Neuroticism ,Analysis of Variance ,Interleukin-6 ,digestive, oral, and skin physiology ,Conscientiousness ,Appetite ,Middle Aged ,medicine.disease ,Anxiety Disorders ,Psychiatry and Mental health ,C-Reactive Protein ,Endocrinology ,Italy ,Impulsive Behavior ,Female ,Waist Circumference ,Personality Assessment Inventory ,Psychology ,hormones, hormone substitutes, and hormone antagonists - Abstract
Leptin is an adipose-derived hormone that plays a significant role in food intake and energy storage by relaying information between peripheral tissue and the central nervous system. When functioning normally, leptin acts as a signal to the brain to stop eating. Higher levels of leptin typically reduce appetite, but the elevated level found in obese individuals is thought to be due to reduced sensitivity to leptin signaling (i.e., leptin resistance). In addition to its association with physiological factors such as obesity and inflammation (1), leptin has been implicated in a number of cognitive and psychological processes. Although leptin may have neuroprotective effects (2), elevated levels have been associated with poor psychological outcomes, including subjective stress (3) and post-traumatic stress disorder (4), although the findings are mixed on the association between leptin and depression (5, 6). There is reason to suspect that other psychological factors, specifically personality traits, may be related to circulating levels of leptin. Individuals high in Neuroticism and low in Conscientiousness are more prone to being overweight or obese (7-10), are more likely to experience weight fluctuations (10), have higher levels of inflammation (11, 12), and are more vulnerable to depression (13). The present study examines the association between personality and leptin in a large sample of community-dwelling adults. Given their association with obesity, inflammation, and psychological distress, we hypothesized that high Neuroticism and low Conscientiousness would be associated with higher levels of leptin. In addition to the five broad domains, we examine the association with more specific aspects, or facets of personality. We hypothesize that facets that have previously been linked to obesity (higher impulsiveness, higher assertiveness, lower activity, lower order, lower self-discipline, and lower deliberation) will be associated with higher leptin; we present the results for the remaining facets as exploratory analyses. We also examine whether the associations between personality and leptin are independent of body mass index (BMI), waist circumference, and inflammatory markers associated with both leptin and personality (interleukin-6 [IL-6], c-reactive protein [CRP], white blood cells [WBC]). Because the association between personality and leptin may depend on age and it may differ between the sexes, we examine whether these associations vary by age and sex. Finally, we hypothesize that the association between personality traits and adiposity will be partially mediated by higher levels of leptin.
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- 2013
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18. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation
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Angelo Scuteri, Chris Wallace, Rachel Hackett, Sonja I. Berndt, Richard B. Hayes, Peter Vollenweider, Susan M. Ring, Lauren Gianniny, Alistair S. Hall, Christopher J. Gillson, Karani Santhanakrishnan Vimaleswaran, Karol Estrada, Thomas Meitinger, Kay-Tee Khaw, Nicholas J. Timpson, Willem H. Ouwehand, Cristen J. Willer, Andy R Ness, Peter S. Chines, Wendy L. McArdle, I. Sadaf Farooqi, Eleftheria Zeggini, Jouko Saramies, Amanda J. Bennett, Matthew A. Sims, Richard M. Watanabe, David M. Evans, Patricia B. Munroe, Toshiko Tanaka, Francis S. Collins, Peter Kraft, Morris Brown, Inês Barroso, Sheila Bingham, John M. C. Connell, Jian'an Luan, Pekka Jousilahti, Amanda F. Elliott, Lachlan J. M. Coin, Parimal Deodhar, Kijoung Song, Ruth J. F. Loos, Eleanor Wheeler, George Davey Smith, Kate Northstone, Joshua C. Randall, Claudia Lamina, André G. Uitterlinden, Dawn M. Waterworth, Tim D. Spector, Robert Luben, Veikko Salomaa, Vincent Mooser, Candace Guiducci, Andrew T. Hattersley, Guillaume Lettre, Guangju Zhai, Gonçalo R. Abecasis, Jaana Laitinen, Cyrus Cooper, David J. Hunter, Noël P. Burtt, Timo T. Valle, Carolin Purmann, Narisu Narisu, Lori L. Bonnycastle, Steven A. McCarroll, Christian Gieger, Albert Hofman, Laura J. Scott, Iris M. Heid, Lu Qi, Kevin B. Jacobs, Toby Johnson, Cornelia M. van Duijn, David Altshuler, David Hadley, Marjo-Riitta Järvelin, Johannes Hebebrand, Stephen J. Chanock, Stephen O'Rahilly, Jaakko Tuomilehto, Cecilia M. Lindgren, Y. C. Loraine Tung, Panagiotis Deloukas, Manjinder S. Sandhu, H-Erich Wichmann, Antonella Mulas, Matthew G. Rees, Jack M. Guralnik, Elaine M. Dennison, Timothy M. Frayling, David P. Strachan, Jonathan Stephens, Inga Prokopenko, Mikko Kuokkanen, Shengxu Li, Leif Groop, Jing Hua Zhao, Paul Elliott, David Schlessinger, Ken K. Ong, Peter Almgren, Massimo Mangino, Manuela Uda, Zorica Jovanovic, Karen L. Mohlke, Leena Peltonen, Michael N. Weedon, Elizabeth K. Speliotes, Markku Laakso, Bo Isomaa, Serena Sanna, Mark J. Caulfield, Gérard Waeber, Martin Ridderstråle, Luigi Ferrucci, Anne U. Jackson, Suzanne Stevens, Aimo Ruokonen, Jacqueline C. M. Witteman, Nicole Soranzo, Kaisa Silander, Mark I. McCarthy, Joel N. Hirschhorn, Nilesh J. Samani, Frank B. Hu, Michael R. Erdos, Paul Scheet, Leonie C. Jacobs, Rosa Maria Roccasecca, Heather M. Stringham, Helen N. Lyon, Konstantinos A. Papadakis, Aki S. Havulinna, Michael Boehnke, Richard N. Bergman, Nicholas J. Wareham, M. Carola Zillikens, Nicholas A. Watkins, Tiinamaija Tuomi, Fernando Rivadeneira, Noha Lim, Edward G. Lakatta, and Johanna Kuusisto
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Central Nervous System ,medicine.medical_specialty ,Quantitative Trait Loci ,Medizin ,Gene Dosage ,030209 endocrinology & metabolism ,Genome-wide association study ,Locus (genetics) ,Biology ,FTO gene ,Polymorphism, Single Nucleotide ,Article ,Body Mass Index ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Quantitative Trait, Heritable ,SH2B1 ,Meta-Analysis as Topic ,Internal medicine ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Obesity ,Alleles ,030304 developmental biology ,2. Zero hunger ,0303 health sciences ,Neuronal growth regulator 1 ,Anthropometry ,Genetics of obesity ,Body Weight ,3. Good health ,Endocrinology ,Alpha-Ketoglutarate-Dependent Dioxygenase FTO ,Genome-Wide Association Study ,Colaus Study ,Body mass index - Abstract
Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 × 10⁻⁸): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity. © 2009 Nature America, Inc. All rights reserved.
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- 2016
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19. Common variants at 30 loci contribute to polygenic dyslipidemia
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Michael Boehnke, Luigi Ferrucci, Aarti Surti, Jaakko Tuomilehto, Karen L. Mohlke, Candace Guiducci, Lee M. Kaplan, Rory Collins, Leena Peltonen, Qiong Yang, Cristen J. Willer, Francis S. Collins, Angelo Scuteri, Christopher J. O'Donnell, Edward G. Lakatta, Serkalem Demissie, Johanna Kuusisto, John C. Chambers, Amy J. Swift, Leif Groop, Markku Laakso, Gina M. Peloso, Sekar Kathiresan, Jouko Sundvall, G. Mark Lathrop, Gonçalo R. Abecasis, Benjamin F. Voight, Jose M. Ordovas, Veikko Salomaa, Eric E. Schadt, Robert Clarke, David Altshuler, David Schlessinger, Diana Zelenika, Pilar Galan, Serge Hercberg, Derrick A Bennett, Kari Kubalanza, Laura J. Scott, Kiran Musunuru, Kathryn L. Lunetta, Serena Sanna, Marju Orho-Melander, L. Adrienne Cupples, Toshiko Tanaka, Gabriel Crawford, Pierre Meneton, Josée Dupuis, Anne U. Jackson, Sarah Parish, Paul I.W. de Bakker, Yun Li, Olle Melander, Mario A. Morken, Manuela Uda, Heather M. Stringham, Lori L. Bonnycastle, Noël P. Burtt, Paul Scheet, Richard N. Bergman, and Jaspal S. Kooner
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Adult ,Male ,Multifactorial Inheritance ,medicine.medical_specialty ,Quantitative Trait Loci ,Blood lipids ,Genome-wide association study ,030204 cardiovascular system & hematology ,Biology ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Delta-5 Fatty Acid Desaturase ,0302 clinical medicine ,Meta-Analysis as Topic ,ANGPTL4 ,Internal medicine ,Genetics ,medicine ,Humans ,RNA, Messenger ,Allele ,Alleles ,Triglycerides ,Dyslipidemias ,030304 developmental biology ,0303 health sciences ,Triglyceride ,Cholesterol ,Cholesterol, HDL ,Reproducibility of Results ,Cholesterol, LDL ,Syndrome ,Middle Aged ,medicine.disease ,3. Good health ,Phenotype ,Endocrinology ,Gene Expression Regulation ,Liver ,chemistry ,Female ,lipids (amino acids, peptides, and proteins) ,Dyslipidemia ,Genome-Wide Association Study ,Lipoprotein - Abstract
Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.
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- 2016
20. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
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Peter Kovacs, Alan F. Wright, Stephen Turner, Michèle M. Sale, Siim Sõber, Janoš Terzić, Elin Org, Richard S. Cooper, Alena Stančáková, Jerome I. Rotter, W. H. Linda Kao, Albert Hofman, Andrew B. Singleton, Florian Kronenberg, Jianjun Liu, Nicole L. Glazer, Christopher W. Knouff, Jennifer L. Bragg-Gresham, Juha Karjalainen, Li Ching Chang, Benjamin J. Wright, Jacqueline C.M. Witteman, Martin G. Larson, Klaus Stark, Richard J. Rodeheffer, Sharon L.R. Kardia, Douglas M. Ruderfer, Sheila Ulivi, Madhumathi Rao, Andrew A. Hicks, Eva Brand, Viviane Nicaud, Stephen G. Ball, Anna Köttgen, Germaine C. Verwoert, Anders Hamsten, Nick Shrine, Uwe Völker, Stefan Kloiber, Stephen Hancock, Emelia J. Benjamin, Bok Ghee Han, Kenneth Rice, Mark Woodward, Veronique Vitart, Karl Andersen, Nicholas J. Wareham, Robert Roberts, Maja Barbalić, David Couper, Yukinori Okada, André G. Uitterlinden, Sekar Kathiresan, Leo-Pekka Lyytikäinen, Pankaj Arora, Tatijana Zemunik, David S. Siscovick, Simonetta Guarrera, Dawn M. Waterworth, Tatjana Stojakovic, Braxton D. Mitchell, Devin Absher, Carmen A. Peralta, Mika Kivimäki, Xueling Sim, Norihiro Kato, Philippe Froguel, Keith L. Keene, Donna K. Arnett, Naoyuki Kamatani, Tazeen H. Jafar, Idris Guessous, Gunnar Jacobs, Michael M. Hoffmann, Kari Stefansson, Christian Hengstenberg, Tomonori Okamura, Inga Prokopenko, Christina Willenborg, Peter S. Braund, Rainer Rettig, Francesco U.S. Mattace-Raso, Vikal Tripathy, F. Gerald R. Fowkes, Laura R. Loehr, Harry Campbell, Margherita Cavalieri, Olle Melander, Hao Mei, I. Mateo Leach, Nicholette D. Palmer, Eva Albrecht, Naoharu Iwai, Stefan Martin Brand, Toshiko Tanaka, Jackie A. Cooper, Omri Gottesman, Manuela Uda, Angelo Scuteri, Aroon D. Hingorani, Cristiano Fava, Yusuke Nakamura, Jiang He, Min Jin Go, Serge Hercberg, Wendy L. McArdle, Philipp S. Wild, Florian Ernst, Paul Mitchell, Wolfgang Koenig, Caroline S. Fox, S. J.Cathy Fann, Janine F. Felix, Anna F. Dominiczak, Mike A. Nalls, Erik Ingelsson, Mario A. Morken, Susana Eyheramendy, Christopher Newton-Cheh, Igor Rudan, D. G. Vinay, Christopher P. Nelson, Ervin R. Fox, Xiuqing Guo, Jing Hua Zhao, Rick Twee-Hee Ong, Margaret M. Redfield, Oscar H. Franco, Yongmei Liu, Fulvio Ricceri, Mark A. Hlatky, Bernhard Paulweber, Mingyao Li, Themistocles L. Assimes, Karl Winkler, Inês Barroso, Sylvia E. Rosas, M Walker, Richard W Morris, Bo Hedblad, Hakon Hakonarson, Sonny Dandona, Peter H. Whincup, Martin Adam, Vilmundur Gudnason, Daniel Ackermann, Qiong Yang, Cuno S. P. M. Uiterwaal, Paul M. Ridker, George Davey Smith, Li Chen, C. Sinning, Terri L. Young, Jer-Yuarn Wu, Walter Palmas, Will Longstreth, Joe Devaney, Pavel Hamet, Xiaofeng Zhu, Fredrik Nyberg, Wilfried Renner, Anuj Goel, L. Adrienne Cupples, Nish Chaturvedi, Iftikhar J. Kullo, Nicholas D. Hastie, Aude Saint-Pierre, Panos Deloukas, Smita R. Kulkarni, Eric Boerwinkle, Wolfram Goessling, Gian Andri Thun, Eric J.G. Sijbrands, Shih-Jen Hwang, Carole Proust, Hirotsugu Ueshima, Kristian Hveem, Pierre Meneton, Joshua C. Denny, Olivier Devuyst, Kerri L. Wiggins, Ming-Huei Chen, Robert W. Lawrence, Robert L. Wilensky, Andre Franke, Nicole Soranzo, Simon Heath, Margot Haun, Karlhans Endlich, David Altshuler, Harald Grallert, Laurence Tiret, Luigi Ferrucci, Caroline Hayward, Sudha Seshadri, Bénédicte Stengel, Lynne E. Wagenknecht, John Attia, Andreas Ziegler, Renate B. Schnabel, Stefan Schreiber, Santosh Dahgam, Kurt Lohman, Christian M. Shaffer, Barbara Ludwig, Katalin Susztak, Chien-Hsiun Chen, Michele K. Evans, Paolo Vineis, Guo Li, Thomas J. Wang, Meena Kumari, Heather M. Stringham, Bruce M. Psaty, Norman Klopp, Halit Ongen, Ben A. Oostra, Stefan Coassin, Petra Bruse, Wei-Min Chen, Unnur Thorsteinsdottir, Charles N. Rotimi, Robert J. Carroll, Muredach P. Reilly, Niek Verweij, Dena G. Hernandez, Amy J. Swift, Barbara Kollerits, Hyung Lae Kim, Cristian Pattaro, Ivana Kolcic, Ronit Katz, John M. C. Connell, Dan E. Arking, Albert W. Dreisbach, Peter Vollenweider, C. S. Janipalli, Jian'an Luan, Erkki Vartiainen, James T. Willerson, John R. Thompson, Daniela Toniolo, Lyle J. Palmer, Alexander Teumer, Serkalem Demissie-Banjaw, Stella Trompet, James E. Hixson, Sue Shaw-Hawkins, Rossella Sorice, Bernhard R. Winkelmann, John Danesh, Anthony J. Balmforth, Toshio Ogihara, Jyotika K. Fernandes, Ulf Gyllensten, Ville Aalto, Åsa Johansson, Andres Metspalu, John F. Peden, Diana Kuh, Medea Imboden, Antonio Lupo, Su Chi Lim, Young-Jin Kim, Giovanni Malerba, Yurii S. Aulchenko, Satoshi Umemura, Ioanna Tzoulaki, Alan B. Weder, Helena Schmidt, Gerjan Navis, Susan R. Heckbert, Hans J. Rupprecht, Edward G. Lakatta, Christian Gieger, Najaf Amin, Paul Muntner, Lenore J. Launer, Ivana Persico, Hugh Watkins, Ian Ford, K. Radha Mani, Sylvia Stracke, Johanna Kuusisto, John Chalmers, Muhammad Islam, Lars Lind, Stefan R. Bornstein, Marjo-Riitta Järvelin, J. H. Young, Reiner Biffar, Santhi K. Ganesh, Kazuhiko Yamamoto, Annette Peters, Linda S. Adair, Tõnu Esko, Rebecca Hardy, Olga Jarinova, Antonietta Robino, Ruth McPherson, Benjamin F. Voight, Anne U. Jackson, Gang Shi, Stefania Bandinelli, Peter J. van der Most, John S. Gottdiener, Ying A. Wang, Mariza de Andrade, Joshua C. Bis, Leslie J. Raffel, Man Li, Jemma C. Hopewell, Bernhard O. Böhm, Aaron R. Folsom, Noël P. Burtt, S. Sidney, Diana Zelenika, Yuri Milaneschi, Pilar Galan, Iris M. Heid, Bernhard K. Krämer, Jean-Michel Gaspoz, Lynda M. Rose, Massimiliano Cocca, Jaap W. Deckers, Martin Farrall, Kent D. Taylor, Albert V. Smith, Candace Guiducci, Alan R. Shuldiner, Shiro Maeda, Liming Qu, Marilyn C. Cornelis, Xiaoling Wang, Daniel Shriner, Jutta Palmen, Yingchang Lu, Heyo K. Kroemer, Pio D'Adamo, Stephan J. L. Bakker, Tamara B. Harris, Myriam Rheinberger, Tetsuro Miki, Audrey Y. Chu, Ramachandran S. Vasan, Fuu Jen Tsai, Jan A. Staessen, Daniel I. Chasman, Jan Stritzke, Jasmin Divers, Meredith C. Foster, Jeanette M. Stafford, Maksim Struchalin, Arne Schillert, Jacques S. Beckmann, Mark E. Cooper, Jean-Charles Lambert, Mario Pirastu, Katja Butterbach, Carl G. P. Platou, Yan V. Sun, Marcus Fischer, Maciej Tomaszewski, Karl Werdan, Peng Chen, Daniel J. Rader, Thomas Münzel, Lowell F. Satler, Tom R. Gaunt, Brenda W.J.H. Penninx, William H. Matthai, John Whitfield, Rita P.S. Middelberg, Margus Viigimaa, Toshihiro Tanaka, Ida Yii Der Chen, Morris J. Brown, Valur Emilsson, J. Viikari, Wolfgang Lieb, Stephen E. Epstein, Harald Dobnig, Aravinda Chakravarti, Patrick Linsel-Nitschke, Stefan Pilz, Angela Doering, Sarah H. Wild, Patricia B. Munroe, Megan E. Rudock, Nicole Probst-Hensch, Danish Saleheen, Diederick E. Grobbee, Anke Tönjes, Narisu Narisu, Annika Rosengren, Masato Isono, Catherine Helmer, M. J.Kranthi Kumar, Alanna C. Morrison, Kay-Tee Khaw, Tanja Zeller, Jeffrey R. O'Connell, Christian Müller, Georg Homuth, Giriraj R. Chandak, Pankaj Sharma, Marcus Dörr, Veikko Salomaa, Paul F. O'Reilly, David Hadley, Hermann Brenner, Paolo Gasparini, Nanette R. Lee, Bamidele O. Tayo, Robert Clarke, Henri Wallaschofski, Marketa Sjögren, Abbas Dehghan, Melanie Waldenberger, Neil Risch, Vasyl Pihur, Jessica D. Faul, François Cambien, Christian Fuchsberger, Nicholas G. Martin, John C. Chambers, Zouhair Aherrahrou, Karl J. Lackner, Leif Groop, Matthias Olden, Wiek H. van Gilst, Mathias Gorski, Yvonne T. van der Schouw, Patrick Diemert, Christoph Bickel, Yik Ying Teo, Giorgio Pistis, Ruth J. F. Loos, Gudrun Veldre, Thorsten Reffelmann, Lude Franke, Karen L. Mohlke, Stefan Blankenberg, Massimo Mangino, Ian N. M. Day, Atsushi Takahashi, Alan B. Zonderman, Hua Tang, Reijo Laaksonen, Holly Kramer, Gary C. Curhan, Adrienne Tin, Talin Haritunians, Loic Yengo, Philip Howard, Arnika Kathleen Wagner, Anna Maria Corsi, Yen Pei C. Chang, Karin Halina Greiser, Jeanette Erdmann, Solveig Gretarsdottir, Sanjay Kinra, Alex Parker, Belen Ponte, Marina Ciullo, Michael Preuss, Tin Aung, Nicholas L. Smith, Michiaki Kubo, Richard N. Bergman, Alan S. Go, Patricia P. Chang, Gudmundur Thorgeirsson, Christa Meisinger, Gonçalo R. Abecasis, Maria Blettner, Jaana Laitinen, Daniel Taliun, Carlos Iribarren, Paavo Zitting, Thomas Lumley, Andreas Meinitzer, Wayne D. Rosamond, Daehee Kang, Johanne Tremblay, Stephan B. Felix, Colin A. McKenzie, Yuan-Tsong Chen, Lyudmyla Kedenko, Mladen Boban, Fadi J. Charchar, Adebowale Adeyemo, Brendan M. Buckley, Jennifer A. Smith, Reinhold Schmidt, Jaspal S. Kooner, Gavin Lucas, Paul Elliott, Dorairajan Prabhakaran, Tune H. Pers, Tunde Salako, Terrence Forrester, Paul Burton, Jeffrey R. Gulcher, Kelly A. Volcik, Richard M. Myers, Andreas Tomaschitz, H.-Erich Wichmann, Jie Yao, Giuseppe Matullo, Carsten A. Böger, Henry Völzke, Daniela Ruggiero, Federico Murgia, Yoshikuni Kita, Augustine Kong, Giovanni Gambaro, Cinzia Sala, Peter P. Pramstaller, James Scott, Maris Laan, Laura J. Scott, Alistair S. Hall, Sanaz Sedaghat, James F. Wilson, Joanne M. Murabito, Yi-An Ko, Honghuang Lin, Mark Seielstad, Leena Peltonen, Sven Bergmann, Thomas Meitinger, Matthias Nauck, María Soler Artigas, Thomas Illig, Nanette I. Steinle, Samer S. Najjar, Christina Loley, Debbie A Lawlor, Steven C. Hunt, Yali Li, Weihua Zhang, Jie Jin Wang, Daniele Cusi, Marco Orrù, Stephen P. Fortmann, Melissa Garcia, Barry I. Freedman, Joseph M. Lindsay, Juan P. Casas, Tomohiro Katsuya, Grant W. Montgomery, Hubert Scharnagl, Khanh-Dung H. Nguyen, Steven M. Schwartz, Afshin Parsa, Elizabeth G. Holliday, Murielle Bochud, Kiran Musunuru, Bruno H. Stricker, Lori L. Bonnycastle, Ilja M. Nolte, Timothy M. Frayling, Stefan Enroth, Michiel L. Bots, Mark J. Caulfield, Laura Portas, Vincent Chouraki, Carl D. Langefeld, Eran Halperin, Shufeng Chen, Philippa J. Talmud, Terho Lehtimäki, Steve E. Humphries, Gudmar Thorleifsson, Anika Grosshennig, Norbert Watzinger, Fumihiko Takeuchi, Pim van der Harst, Takayoshi Ohkubo, Nabila Bouatia-Naji, Erwin P. Bottinger, Roberto Elosua, Andrew Wong, Vladan Mijatovic, Maija K. Garnaas, Robert Zweiker, Joel N. Hirschhorn, Winfried März, Nilesh J. Samani, Inke R. König, Frank B. Hu, Marcus E. Kleber, Francis S. Collins, Elena Rochtchina, Ewa Zukowska-Szczechowska, Yong Li, Ayse Demirkan, Gina Hilton, G. Ehret, Thomas H. Mosley, Markus Perola, Alexandre F.R. Stewart, Josef Coresh, Olli T. Raitakari, Feng Zhang, Mark Lathrop, Michael Marmot, Yanbin Dong, Christopher J. O'Donnell, Kristin D. Marciante, Asif Rasheed, Mary F. Feitosa, Mary Susan Burnett, Rory Collins, J. Wouter Jukema, Nele Friedrich, Aida Karina Dieffenbach, Ying Wu, Yoon Shin Cho, Aaron Isaacs, Haidong Zhu, Marie Metzger, Myriam Alexander, Tanja B. Grammer, Tatiana Kuznetsova, Dabeeru C. Rao, Jayashri Aragam, Augusto D. Pichard, Jaakko Tuomilehto, Louise V. Wain, Elizabeth J. Atkinson, Tim D. Spector, Reedik Mägi, Tiit Nikopensius, Kenneth M. Kent, Guangju Zhai, Andrew D. Johnson, Menno Pruijm, David P. Strachan, Martin D. Tobin, Joban Sehmi, Janja Nahrstedt, E. Shyong Tai, Thor Aspelund, Jürgen Grässler, Hilma Holm, Matthew Denniff, Joshua W. Knowles, Tien Yin Wong, Erika Salvi, James F. Meschia, Dongfeng Gu, Ron Waksman, Stacey Gabriel, Judith A. Hoffman Bolton, Michael Boehnke, Johannes Haerting, Darina Czamara, Heribert Schunkert, Thomas Quertermous, Peter M. Nilsson, Jong-Young Lee, Yasuharu Tabara, Chittaranjan S. Yajnik, Daniel Levy, John Beilby, Fernando Rivadeneira, Claire Perret, Gudny Eiriksdottir, Jingzhong Ding, George A. Wells, Harold Snieder, Ayo P. Doumatey, Dag S. Thelle, Anja Medack, N. Charlotte Onland-Moret, Michael Stumvoll, David Ellinghaus, Ingrid B. Borecki, Tatsuhiko Tsunoda, Ian H. de Boer, M. Arfan Ikram, Andrew M. Taylor, Johannes H. Smit, Gary F. Mitchell, Anna-Liisa Hartikainen, Markku Laakso, Mark McEvoy, Andrew S. Plump, Toby Johnson, Cornelia M. van Duijn, Ozren Polasek, Wilmar Igl, Vincent Mooser, Rodney J. Scott, Mika Kähönen, Peter Schwarz, Psychiatry, EMGO - Mental health, Pattaro, Cristian, Teumer, Alexander, Gorski, Mathia, Chu, Audrey Y., Li, Man, Mijatovic, Vladan, Garnaas, Maija, Tin, Adrienne, Sorice, Rossella, Li, Yong, Taliun, Daniel, Olden, Matthia, Foster, Meredith, Yang, Qiong, Chen, Ming Huei, Pers, Tune H., Johnson, Andrew D., Ko, Yi An, Fuchsberger, Christian, Tayo, Bamidele, Nalls, Michael, Feitosa, Mary F., Isaacs, Aaron, Dehghan, Abba, D'Adamo, ADAMO PIO, Adeyemo, Adebowale, Dieffenbach, Aida Karina, Zonderman, Alan B., Nolte, Ilja M., Van Der Most, Peter J., Wright, Alan F., Shuldiner, Alan R., Morrison, Alanna C., Hofman, Albert, Smith, Albert V., Dreisbach, Albert W., Franke, Andre, Uitterlinden, Andre G., Metspalu, Andre, Tonjes, Anke, Lupo, Antonio, Robino, Antonietta, Johansson, Åsa, Demirkan, Ayse, Kollerits, Barbara, Freedman, Barry I., Ponte, Belen, Oostra, Ben A., Paulweber, Bernhard, Krämer, Bernhard K., Mitchell, Braxton D., Buckley, Brendan M., Peralta, Carmen A., Hayward, Caroline, Helmer, Catherine, Rotimi, Charles N., Shaffer, Christian M., Müller, Christian, Sala, Cinzia, Van Duijn, Cornelia M., Saint Pierre, Aude, Ackermann, Daniel, Shriner, Daniel, Ruggiero, Daniela, Toniolo, Daniela, Lu, Yingchang, Cusi, Daniele, Czamara, Darina, Ellinghaus, David, Siscovick, David S., Ruderfer, Dougla, Gieger, Christian, Grallert, Harald, Rochtchina, Elena, Atkinson, Elizabeth J., Holliday, Elizabeth G., Boerwinkle, Eric, Salvi, Erika, Bottinger, Erwin P., Murgia, Federico, Rivadeneira, Fernando, Ernst, Florian, Kronenberg, Florian, Hu, Frank B., Navis, Gerjan J., Curhan, Gary C., Ehret, George B., Homuth, Georg, Coassin, Stefan, Thun, Gian Andri, Pistis, Giorgio, Gambaro, Giovanni, Malerba, Giovanni, Montgomery, Grant W., Eiriksdottir, Gudny, Jacobs, Gunnar, Li, Guo, Wichmann, H. Erich, Campbell, Harry, Schmidt, Helena, Wallaschofski, Henri, Völzke, Henry, Brenner, Hermann, Kroemer, Heyo K., Kramer, Holly, Lin, Honghuang, Leach, I. Mateo, Ford, Ian, Guessous, Idri, Rudan, Igor, Prokopenko, Inga, Borecki, Ingrid, Heid, Iris M., Kolcic, Ivana, Persico, Ivana, Jukema, J. 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0301 basic medicine ,Nephrology ,Genetics and Molecular Biology (all) ,estimated glomerular filtration rate ,estimated glomerular filtration rate, chronic kidney disease, genetic determinants ,General Physics and Astronomy ,Kidney development ,Genome-wide association study ,Biochemistry ,Settore MED/14 - NEFROLOGIA ,Renal Insufficiency ,Chronic ,Genetics ,AGEN Consortium ,ddc:616 ,education.field_of_study ,Kidney ,Stage renal-disease ,Multidisciplinary ,Genome-wide association ,CHARGe-Heart Failure Group ,Gene Expression Regulation ,Genome-Wide Association Study ,Genotype ,Humans ,Renal Insufficiency, Chronic ,Genetic Predisposition to Disease ,Biochemistry, Genetics and Molecular Biology (all) ,Chemistry (all) ,Physics and Astronomy (all) ,Metaanalysis ,Renal Insufficiency, Chronic/genetics ,Biological sciences ,Serum creatinine ,medicine.anatomical_structure ,Efficient ,Ronyons -- Fisiologia ,Hypertension ,ICBP Consortium ,Transmembrane transporter activity ,genetic association, loci, kidney function ,CARDIOGRAM ,Human ,medicine.medical_specialty ,Science ,Population ,Renal function ,ECHOGen Consortium ,Replication ,Biology ,Environment ,Research Support ,General Biochemistry, Genetics and Molecular Biology ,N.I.H ,genetic determinants ,03 medical and health sciences ,GENOME-WIDE ASSOCIATION ,FALSE DISCOVERY RATES ,STAGE RENAL-DISEASE ,SERUM CREATININE ,METAANALYSIS ,VARIANTS ,INDIVIDUALS ,POPULATION ,RISK ,HYPERTENSION ,Kidney function ,Research Support, N.I.H., Extramural ,Internal medicine ,MD Multidisciplinary ,medicine ,Journal Article ,eGFRcrea ,eGFRcys ,ddc:610 ,Genetik ,Mortality ,education ,ddc:613 ,urogenital system ,Individuals ,Extramural ,General Chemistry ,ta3121 ,medicine.disease ,R1 ,030104 developmental biology ,570 Life sciences ,biology ,Genètica ,chronic kidney disease ,Kidney disease ,Meta-Analysis - Abstract
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.
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- 2016
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21. Associations of large artery structure and function with adiposity: Effects of age, gender, and hypertension. The SardiNIA Study
- Author
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Kirill V. Tarasov, David Schlessinger, Manuela Uda, Edward G. Lakatta, Christopher H. Morrell, Marco Orru, and Angelo Scuteri
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Adult ,Male ,Aging ,medicine.medical_specialty ,Waist ,Adolescent ,Carotid Artery, Common ,Context (language use) ,Femoral artery ,Carotid Intima-Media Thickness ,Risk Assessment ,Article ,Body Mass Index ,Young Adult ,Sex Factors ,Risk Factors ,Internal medicine ,medicine.artery ,medicine ,Humans ,Vascular Diseases ,Common carotid artery ,Pulse wave velocity ,Adiposity ,Aged ,Aged, 80 and over ,business.industry ,Age Factors ,Middle Aged ,medicine.disease ,Femoral Artery ,Endocrinology ,Italy ,Nonlinear Dynamics ,Obesity, Abdominal ,Pulsatile Flow ,Hypertension ,Multivariate Analysis ,Linear Models ,cardiovascular system ,Arterial stiffness ,Cardiology ,Population study ,Female ,Waist Circumference ,Cardiology and Cardiovascular Medicine ,business ,Body mass index - Abstract
In the context of obesity epidemic, no large population study has extensively investigated the relationships between total and abdominal adiposity and large artery structure and function nor have such relationships been examined by gender, by age, by hypertensive status. We investigated these potential relationships in a large cohort of community dwelling volunteers participating the SardiNIA Study. Methods and results Total and visceral adiposity and arterial properties were assessed in 6148 subjects, aged 14–102 in a cluster of 4 towns in Sardinia, Italy. Arterial stiffness was measured as aortic pulse wave velocity (PWV), arterial thickness and lumen as common carotid artery (CCA) intima-media thickness (IMT) and diameter, respectively. We reported a nonlinear relationship between total and visceral adiposity and arterial stiffness, thickness, and diameter. The association between adiposity and arterial properties was steeper in women than in men, in younger than in older subjects. Waist correlated with arterial properties better than BMI. Within each BMI quartile, increasing waist circumference was associated with further significant changes in arterial structure and function. Conclusion The relationship between total or abdominal adiposity and arterial aging (PWV and CCA IMT) is not linear as described in the current study. Therefore, BMI- and/or waist-specific reference values for arterial measurements might need to be defined.
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- 2012
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22. Common genetic variation in the 3'-BCL11B gene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk
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Aaron Isaacs, Fernando Rivadeneira, Louise V. Wain, Gudny Eiriksdottir, Joseph A. Vita, Cornelia M. van Duijn, Jingzhong Ding, Samer S. Najjar, Timothy D. Howard, Kim Sutton-Tyrrell, Anne B. Newman, Daniel Levy, Luc M. Van Bortel, Matthias Olden, Gonçalo R. Abecasis, David M. Herrington, Lenore J. Launer, Sofie Bekaert, Toshiko Tanaka, Vilmundur Gudnason, Naomi M. Hamburg, Guy De Backer, Afshin Parsa, Jeanette S. Andrews, Albert Hofman, Anna F.C. Schut, Quince Gibson, Tamara B. Harris, A. R. Shuldiner, Abbas Dehghan, Emelia J. Benjamin, Angelo Scuteri, Bruce M. Psaty, Christian Fuchsberger, John R. Cockcroft, Kevin M. O'Shaughnessy, Jeanette Erdmann, Kirill V. Tarasov, Yongmei Liu, Nicholas L. Smith, Andrew D. Johnson, Ian B. Wilkinson, Thor Aspelund, Tim De Meyer, Manuela Uda, Germaine C. Verwoert, Ramachandran S. Vasan, Paul Elliott, Marie Josee E. van Rijn, Mark P.S. Sie, Jacqueline C.M. Witteman, Martin G. Larson, Serena Sanna, Dirk De Bacquer, Patrick Segers, Yasmin, André G. Uitterlinden, Ben A. Oostra, Marc De Buyzere, Gary F. Mitchell, Sigurdur Sigurdsson, Eric J.G. Sijbrands, Elizabeth S. Jewell, Albert V. Smith, Stephen Newhouse, Wendy S. Post, Patrick F. McArdle, Carmel M. McEniery, Mohammad Arfan Ikram, Luigi Ferrucci, Ernst Rietzschel, Thierry C. Gillebert, Edward G. Lakatta, Francesco U.S. Mattace-Raso, Janine F. Felix, Epidemiology, Medical Oncology, Internal Medicine, Surgery, Radiology & Nuclear Medicine, Intensive Care, and Clinical Genetics
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Genotype ,Vascular Stiffness/physiology ,Locus (genetics) ,Genome-wide association study ,Biology ,Tumor Suppressor Proteins/genetics ,Article ,Cohort Studies ,Young Adult ,Vascular Stiffness ,SDG 3 - Good Health and Well-being ,Gene Frequency ,Risk Factors ,Internal medicine ,Genetics ,medicine ,80 and over ,Cardiovascular Diseases/genetics ,Humans ,Allele ,Pulse wave velocity ,Allele frequency ,Genetics (clinical) ,Alleles ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,Repressor Proteins/genetics ,Tumor Suppressor Proteins ,Hazard ratio ,Genetic Variation ,Middle Aged ,medicine.disease ,Repressor Proteins ,Minor allele frequency ,Phenotype ,Cardiovascular Diseases ,Genetic Loci ,Arterial stiffness ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,Genome-Wide Association Study - Abstract
Background— Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events. Methods and Results— We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20 634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3′- BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency=0.42, β=−0.075±0.012 SD/allele, P =2.8×10 −10 ; replication β=−0.086±0.020 SD/allele, P =1.4×10 −6 ). Combined results for rs7152623 from 11 cohorts gave β=−0.076±0.010 SD/allele, P =3.1×10 −15 . The association persisted when adjusted for mean arterial pressure (β=−0.060±0.009 SD/allele, P =1.0×10 −11 ). Results were consistent in younger (P =2.3×10 −9 ) and older (9 cohorts, n=12 026, β=−0.061±0.014 SD/allele, P =9.4×10 −6 ) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio=1.05; confidence interval=1.02–1.08; P =0.0013) and heart failure (hazard ratio=1.10, CI=1.03–1.16, P =0.004). Conclusions— Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor 1 or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events.
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- 2012
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23. Neuroticism, Depressive Symptoms, and Serum BDNF
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Alessandra Cannas, Angelina R. Sutin, Maria Grazia Piras, Osorio Meirelles, Monia Lobina, Laura Crisponi, Antonio Terracciano, Alan B. Zonderman, David Schlessinger, Manuela Uda, and Antonella Mulas
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Neurotic Disorders ,Population ,Article ,Revised NEO Personality Inventory ,Young Adult ,Sex Factors ,Internal medicine ,medicine ,Humans ,education ,Applied Psychology ,Depression (differential diagnoses) ,Aged ,Aged, 80 and over ,Brain-derived neurotrophic factor ,education.field_of_study ,Depression ,Brain-Derived Neurotrophic Factor ,Age Factors ,Middle Aged ,Center for Epidemiologic Studies Depression Scale ,Neuroticism ,Psychiatry and Mental health ,Endocrinology ,nervous system ,Acute Disease ,Cohort ,Antidepressant ,Female ,Psychology ,Clinical psychology - Abstract
Animal models and clinical studies suggest that brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of depression. We test whether serum and plasma levels of BDNF are associated with trait neuroticism and its facets and with state measures of depressive symptoms.In a community-based cohort (N = 2099), we measured serum and plasma BDNF concentrations and administered the Revised NEO Personality Inventory and the Center for Epidemiological Studies Depression Scale. Covariates included age, sex, cigarette smoking, obesity, and antidepressant use.Serum BDNF concentrations were inversely related to neuroticism (r = -0.074, p.001), in particular the depression facet (r = -0.08, p.001). Lower BDNF concentrations were also associated with severe depressive symptoms (Center for Epidemiological Studies Depression Scale ≥ 28; odds ratio = 0.906; 95% confidence interval = 0.851-0.965). The association of serum BDNF with neuroticism was independent of depressive symptoms, indicating that serum BDNF might represent a biological correlate of neuroticism and not just of transient depressive states. Plasma BDNF was not associated with measures of depression.Our study suggests that lower serum BDNF is associated with both a dispositional vulnerability to depression and acute depressive states in the general population.
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- 2011
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24. Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels
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Günter Weiss, Dena G. Hernandez, Fabio Busonero, Toshiko Tanaka, Serena Sanna, Irene Pichler, Igor Theurl, Eleonora Porcu, Dan L. Longo, Peter P. Pramstaller, Cosetta Minelli, David Schlessinger, Victor J. Wroblewski, Maria Grazia Piras, Eric E. Schadt, Elmar Aigner, Carsten Gnewuch, Alessandra Zanon, Christine Schwienbacher, Silvia Naitza, Andrea Maschio, Luigi Ferrucci, Manfred Mitterer, Jack M. Guralnik, Stefania Bandinelli, Anthony T. Murphy, Manuela Uda, Cristian Pattaro, Scott A. Melville, Derrick R. Witcher, Fabio Marroni, and Andrew A. Hicks
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Adult ,Male ,Iron ,Population ,genetics/metabolism ,Locus (genetics) ,Transferrin receptor ,Polymorphism, Single Nucleotide ,Young Adult ,blood ,Hepcidin ,Receptors ,Receptors, Transferrin ,80 and over ,Genetics ,medicine ,Humans ,Polymorphism ,education ,Molecular Biology ,Genetics (clinical) ,Aged ,Soluble transferrin receptor ,Aged, 80 and over ,chemistry.chemical_classification ,education.field_of_study ,biology ,medicine.diagnostic_test ,Adult, Aged, Aged ,80 and over, Cross-Sectional Studies, Female, Genetic Variation, Humans, Iron ,blood, Male, Middle Aged, Polymorphism ,Single Nucleotide, Receptors ,Transferrin ,genetics/metabolism, Young Adult ,Association Studies Articles ,Genetic Variation ,Single Nucleotide ,General Medicine ,Middle Aged ,Ferritin ,Cross-Sectional Studies ,chemistry ,biology.protein ,Serum iron ,Female - Abstract
The genetic determinants of variation in iron status are actively sought, but remain incompletely understood. Meta-analysis of two genome-wide association (GWA) studies and replication in three independent cohorts was performed to identify genetic loci associated in the general population with serum levels of iron and markers of iron status, including transferrin, ferritin, soluble transferrin receptor (sTfR) and sTfR-ferritin index. We identified and replicated a novel association of a common variant in the type-2 transferrin receptor (TFR2) gene with iron levels, with effect sizes highly consistent across samples. In addition, we identified and replicated an association between the HFE locus and ferritin and confirmed previously reported associations with the TF, TMPRSS6 and HFE genes. The five replicated variants were tested for association with expression levels of the corresponding genes in a publicly available data set of human liver samples, and nominally statistically significant expression differences by genotype were observed for all genes, although only rs3811647 in the TF gene survived the Bonferroni correction for multiple testing. In addition, we measured for the first time the effects of the common variant in TMPRSS6, rs4820268, on hepcidin mRNA in peripheral blood (n = 83 individuals) and on hepcidin levels in urine (n = 529) and observed an association in the same direction, though only borderline significant. These functional findings require confirmation in further studies with larger sample sizes, but they suggest that common variants in TMPRSS6 could modify the hepcidin-iron feedback loop in clinically unaffected individuals, thus making them more susceptible to imbalances of iron homeostasis.
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- 2010
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25. Trait Antagonism and the Progression of Arterial Thickening
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Antonio Terracciano, Paul T. Costa, Kirill V. Tarasov, Angelina R. Sutin, Manuela Uda, Angelo Scuteri, David Schlessinger, Edward G. Lakatta, and Luigi Ferrucci
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Adult ,Carotid Artery Diseases ,Male ,Agreeableness ,medicine.medical_specialty ,Adolescent ,Disease ,Article ,Young Adult ,chemistry.chemical_compound ,Hostility ,Internal medicine ,Internal Medicine ,medicine ,Humans ,Young adult ,Triglycerides ,Aged ,Aged, 80 and over ,Cholesterol ,Vascular disease ,business.industry ,Middle Aged ,medicine.disease ,Tunica intima ,Compliance (physiology) ,Carotid Arteries ,Logistic Models ,Endocrinology ,medicine.anatomical_structure ,Italy ,chemistry ,Intima-media thickness ,Cardiovascular Diseases ,cardiovascular system ,Disease Progression ,Cardiology ,Female ,Tunica Intima ,business ,Stress, Psychological - Abstract
A large body of evidence links antagonism-related traits with cardiovascular outcomes, but less is known about how psychological traits are associated with intermediate markers of cardiovascular disease. Using a large, community-based sample from Sardinia, Italy (n=5614), this study examined how trait antagonism (low agreeableness) and its facets are associated with carotid artery intima-media thickness, a measure of arterial thickening. Controlling for demographic and cardiovascular risk factors, low agreeableness and, in particular, low straightforwardness and low compliance, were associated with greater carotid thickening, measured concurrently and prospectively, and with increases in intima-media thickness over 3 years. Indeed, those in the bottom 10% of agreeableness had a 40% increase in risk for elevated intima-media thickness. Although men have thicker arterial walls, women with antagonistic traits had similar carotid thickening as antagonistic men. Antagonistic individuals, especially those who are manipulative and aggressive, have greater increases in arterial thickening, independent of traditional cardiovascular risk factors.
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- 2010
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26. Hundreds of variants clustered in genomic loci and biological pathways affect human height
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Vilmundur Gudnason, Robert J. Weyant, Robert C. Kaplan, Jeffrey R. O'Connell, Panos Deloukas, Barbara McKnight, Alessandro De Grandi, Gert-Jan B. van Ommen, Eric Boerwinkle, Liming Liang, Douglas F. Levinson, Richard B. Hayes, Mark I. McCarthy, Andrew P. Morris, Joel N. Hirschhorn, Jaakko Kaprio, Nilesh J. Samani, Inke R. König, Frank B. Hu, Nicholas J. Wareham, Ozren Polasek, Michael C. Turchin, Daniel F. Gudbjartsson, Wilmar Igl, Vincent Mooser, Aki S. Havulinna, Themistocles L. Assimes, Cameron D. Palmer, Lachlan J. M. Coin, Eva Albrecht, Hana Lango Allen, Inês Barroso, Eco J. C. de Geus, H.-Erich Wichmann, Michael A. Province, Sarah H. Wild, Patricia B. Munroe, Jeanette Erdmann, Mattias Lorentzon, Michael Preuss, Nelson B. Freimer, Mika Kähönen, Tushar Bhangale, Nicole L. Glazer, Markku S. Nieminen, Andrew A. Hicks, Jonathan Tyrer, Grant W. Montgomery, Ruth J. F. Loos, Shaun Purcell, Manfred Kayser, Marjo-Riitta Järvelin, Guillaume Paré, Terho Lehtimäki, Irene Pichler, Ida Surakka, Tõnu Esko, Peter Kraft, Talin Haritunians, Juha Sinisalo, Mari Nelis, Veronique Vitart, Alan R. Sanders, Alistair S. Hall, Carlos Iribarren, Mark E. Cooper, André G. Uitterlinden, Peter Kovacs, David Schlessinger, Florian Ernst, Marja-Liisa Lokki, M. Juhani Junttila, Martin Ridderstråle, Jorma Viikari, Inga Prokopenko, Christopher J. O'Donnell, Jennie Hui, Aila Rissanen, Gonçalo R. Abecasis, Jouke-Jan Hottenga, Tomi Pastinen, Kevin B. Jacobs, Jan Smit, Kristin G. Ardlie, Niina Pellikka, Neil R. Robertson, Martina Müller, John F. Peden, Mary F. Feitosa, Thomas W. Winkler, Kari Stefansson, Jianjun Liu, Jaana Laitinen, Shen Haiqing, Martin Farrall, Nilanjan Chatterjee, Eleanor Wheeler, Tamara B. Harris, Åsa Johansson, Anders Hamsten, Elizabeth K. Speliotes, Larry D. Atwood, Valgerdur Steinthorsdottir, Elin Grundberg, Nicole Soranzo, Anna-Liisa Hartikainen, Devin Absher, Cecilia M. Lindgren, Rany M. Salem, Lorena Citterio, Karol Estrada, Sven Bergmann, Tony Kwan, Thomas Meitinger, Alan F. Wright, Richard N. Bergman, Sailaja Vedantam, Kirsi H. Pietiläinen, Lina Zgaga, Anne U. Jackson, Stefan Schreiber, Ju-Hyun Park, Nicola Glorioso, Jianxin Shi, Najaf Amin, Dale R. Nyholt, Lenore J. Launer, Heribert Schunkert, Thomas Quertermous, Mari Liis Tammesoo, Dorret I. Boomsma, Harry Campbell, Albert V. Smith, Andrew R. Wood, Caroline S. Fox, Paavo Zitting, Gabrielle Boucher, Alex N. Parker, Jennifer G. Sambrook, Joyce B. J. van Meurs, Heather M. Stringham, Marjolein J. Peters, Sekar Kathiresan, Elisabeth Widen, Caroline Hayward, Tim D. Spector, Dawn M. Waterworth, Carlo Rivolta, Antti Jula, Albert Hofman, Hugh Watkins, Wendy L. McArdle, Roberto Elosua, Markku Koiranen, Paul M. Ridker, Iris M. Heid, Lee M. Kaplan, Brenda W.J.H. Penninx, Peter M. Visscher, Claes Ohlsson, Per Hall, Benjamin F. Voight, Ben A. Oostra, Anna F. Dominiczak, Martin den Heijer, Andrea Maschio, Quince Gibson, Peter P. Pramstaller, Nigel W. Rayner, Carsten Oliver Schmidt, Toby Johnson, Henrik Grönberg, M. Carola Zillikens, Alan R. Shuldiner, Cornelia M. van Duijn, Samuli Ripatti, Erik Ingelsson, John R. Thompson, Stephen J. Chanock, Johannes Kettunen, David J. Hunter, Lyle J. Palmer, Ulf Gyllensten, Jianfeng Xu, Astrid Petersmann, Johan G. Eriksson, Guillaume Lettre, Teresa Ferreira, Fredrik Wiklund, Andreas Ziegler, Andres Metspalu, Jerome I. Rotter, Suzanne Rafelt, Julius S. Ngwa, Francis S. Collins, Michael N. Weedon, Thomas Illig, Wolfgang Hoffman, Nancy L. Heard-Costa, Anke Tönjes, Daniel I. Chasman, Alice M. Arnold, Olli T. Raitakari, Anna L. Dixon, Lu Qi, Michael E. Goddard, Anneli Pouta, Mark J. Caulfield, Liesbeth Vandenput, Christian Gieger, L. Adrienne Cupples, Veikko Salomaa, Elizabeth L. Altmaier, Nicholas G. Martin, Thomas D. Kocher, Jubao Duan, David S. Siscovick, Heikki V. Huikuri, Willem H. Ouwehand, Kari E. North, Christian Hengstenberg, Jacques S. Beckmann, Constance Chen, John Perry, Ana Marušić, Olle Melander, John D. Rioux, Erika Salvi, Andrew T. Hattersley, Paul Elliott, Leif Groop, Cristen J. Willer, Manuela Uda, Gudmar Thorleifsson, Eric E. Schadt, Charles C. White, Pablo V. Gejman, Serena Sanna, Ulla Sovio, Robert W. Lawrence, Unnur Thorsteinsdottir, Ayellet V. Segrè, Daniele Cusi, G. Bragi Walters, Ken Sin Lo, Ivana Kolcic, Igor Rudan, Sonja I. Berndt, Keri L. Monda, Soumya Raychaudhuri, Jian'an Luan, Joshua C. Randall, Anthony J. Balmforth, Yurii S. Aulchenko, Peter Almgren, Karen L. Mohlke, Timothy M. Frayling, Shamika Ketkar, Thomas H. Mosley, Markus Perola, Henry Völzke, Laura Zagato, Leena Peltonen, Seppo Koskinen, Massimo Mangino, Ke Hao, Tsegaselassie Workalemahu, Lambertus A. Kiemeney, Helene Alavere, Jaakko Tuomilehto, Reedik Mägi, James F. Wilson, Ingrid B. Borecki, Zoltán Kutalik, Michael Stumvoll, Dominique J. Verlaan, Arthur W. Musk, Eero Kajantie, Jian Yang, Joshua W. Knowles, Tuomas O. Kilpeläinen, Michael Boehnke, G. Mark Lathrop, John Beilby, Fernando Rivadeneira, Gudny Eiriksdottir, Gonneke Willemsen, Andrew C. Heath, Antonella Mulas, Katja K.H. Aben, David P. Strachan, Thor Aspelund, Jing Hua Zhao, Psychiatry, NCA - Anxiety & Depression, EMGO - Mental health, Internal Medicine, Epidemiology, Intensive Care, Clinical Genetics, Genetic Identification, Medical Research Council (MRC), Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Genetics of Complex Traits, University of Exeter, Department of Epidemiology, Erasmus Medical Centre, Netherlands Genomics Initiative (NGI), Netherlands Genomics Initiative, Department of Medicine, Montreal, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Department of Biostatistics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, deCODE Genetics, deCODE genetics [Reykjavik], Divisions of Genetics and Endocrinology and Program in Genomics, Boston Children's Hospital, Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Institut de Génomique d'Evry (IG), 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)-Université Paris-Saclay, the Genetic Investigation of ANthropocentric Traits (GIANT) Consortium, Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
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Netherlands Twin Register (NTR) ,Multifactorial Inheritance ,[SDV]Life Sciences [q-bio] ,Genome-wide association study ,Aetiology, screening and detection [ONCOL 5] ,0302 clinical medicine ,POPULATION ,SNPS ,Genetics ,0303 health sciences ,Multidisciplinary ,HERITABILITY ,COMMON VARIANTS ,Phenotype ,DISEASES ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Science & Technology - Other Topics ,GROWTH ,Allelic heterogeneity ,Chromosomes, Human, Pair 3 ,Metabolic Networks and Pathways ,TRAITS ,Common disease-common variant ,General Science & Technology ,Locus (genetics) ,Biology ,Polymorphism, Single Nucleotide ,Article ,Molecular epidemiology [NCEBP 1] ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,ADULT ,STRATIFICATION ,MD Multidisciplinary ,Humans ,Genetic Predisposition to Disease ,Genetic variability ,030304 developmental biology ,Science & Technology ,MULTIDISCIPLINARY SCIENCES ,Genome, Human ,Hormonal regulation [IGMD 6] ,Body Height ,Genetic architecture ,wide association analysis common variants heritability population adult stratification diseases traits growth snps ,WIDE ASSOCIATION ANALYSIS ,Genetic Loci ,Evaluation of complex medical interventions [NCEBP 2] ,Polygene ,Expression quantitative trait loci ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits1, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait2,3. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways ( P=0.016) and that underlie skeletal growth defects ( P
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- 2010
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27. Cholesterol, triglycerides, and the Five-Factor Model of personality
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Antonio Terracciano, Paul T. Costa, Angelina R. Sutin, David Schlessinger, Manuela Uda, Barbara Deiana, and Edward G. Lakatta
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Personality Inventory ,media_common.quotation_subject ,Impulsivity ,Article ,Young Adult ,chemistry.chemical_compound ,Sex Factors ,Residence Characteristics ,Internal medicine ,medicine ,Humans ,Personality ,Big Five personality traits ,Triglycerides ,Aged ,media_common ,Aged, 80 and over ,Triglyceride ,Cholesterol ,General Neuroscience ,Age Factors ,Conscientiousness ,Middle Aged ,medicine.disease ,Neuroticism ,Logistic Models ,Neuropsychology and Physiological Psychology ,Italy ,chemistry ,Female ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Psychology ,Social psychology ,Blood Chemical Analysis ,Dyslipidemia - Abstract
Unhealthy lipid levels are among the leading controllable risk factors for coronary heart disease. To identify the psychological factors associated with dyslipidemia, this study investigates the personality correlates of cholesterol (total, LDL, and HDL) and triglycerides. A community-based sample (N = 5532) from Sardinia, Italy, had their cholesterol and triglyceride levels assessed and completed a comprehensive personality questionnaire, the NEO-PI-R. All analyses controlled for age, sex, BMI, smoking, drinking, hypertension, and diabetes. Low Conscientiousness and traits related to impulsivity were associated with lower HDL cholesterol and higher triglycerides. Compared to the lowest 10%, those who scored in top 10% on Impulsivity had a 2.5 times greater risk of exceeding the clinical threshold for elevated triglycerides (OR = 2.51, CI = 1.56–4.07). In addition, sex moderated the association between trait depression (a component of Neuroticism) and HDL cholesterol, such that trait depression was associated with lower levels of HDL cholesterol in women but not men. When considering the connection between personality and health, unhealthy lipid profiles may be one intermediate biomarker between personality and morbidity and mortality.
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- 2010
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28. Sex-Specific Correlates of Walking Speed in a Wide Age-Ranged Population
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Magdalena I. Tolea, Marco Masala, Barbara Deiana, Angelo Scuteri, Michael Griswold, Manuela Uda, Samer S. Najjar, Antonio Terracciano, Marco Orru, Paul T. Costa, Eleanor M. Simonsick, Luigi Ferrucci, and David Schlessinger
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Gerontology ,Adult ,Male ,Waist ,Social Psychology ,Adolescent ,Cross-sectional study ,media_common.quotation_subject ,Population ,Walking ,Neuropsychological Tests ,Personality Disorders ,Young Adult ,Age Distribution ,medicine ,Personality ,Humans ,Big Five personality traits ,Sex Distribution ,education ,media_common ,Aged ,Aged, 80 and over ,education.field_of_study ,Depressive Disorder ,Extraversion and introversion ,Middle Aged ,medicine.disease ,Personality disorders ,Preferred walking speed ,Clinical Psychology ,Cross-Sectional Studies ,Population Surveillance ,Journal of Gerontology: Psychological Sciences ,Female ,Geriatrics and Gerontology ,Psychology ,Cognition Disorders ,human activities - Abstract
The goals of this cross-sectional study were to explore correlates of walking speed in a large wide age-ranged population and to identify factors affecting lower walking speed at older ages. Participants were 3,872 community-dwelling adults in the first follow-up of the SardiNIA study who completed a 4-m walking test. Sex-specific correlates of walking speed included marital status, height, waist circumference, pulse wave velocity, comorbidity, subjective health, strength, and personality. Effect modifiers of the age–walking speed association included extraversion (
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- 2010
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29. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk
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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
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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.
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- 2010
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30. Biological, clinical and population relevance of 95 loci for blood lipids
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Richard N. Bergman, Markku S. Nieminen, Peter Vollenweider, André G. Uitterlinden, Luigi Ferrucci, Iris M. Heid, Lynda M. Rose, Brenda W.J.H. Penninx, Nicholas G. Martin, Joshua C. Bis, Aaron Isaacs, Jaspal S. Kooner, Gavin Lucas, Caroline Hayward, Masahiro Koseki, Andrew A. Hicks, Maja Barbalić, Marju Orho-Melander, Xueling Sim, James Scott, Manjinder S. Sandhu, Damien C. Croteau-Chonka, Andreas Ziegler, Wilmar Igi, Igor Rudan, Aki S. Havulinna, Leslie A. Lange, Hilma Holm, James G. Wilson, Albert V. Smith, Chiara Sabatti, Candace Guiducci, Paul Elliott, A. Cecile J.W. Janssens, Dorret I. Boomsma, Harry Campbell, Lee M. Kaplan, Ruth J. F. Loos, Robert Luben, Veikko Salomaa, Kyunga Kim, James F. Wilson, Mark Seielstad, Ben A. Oostra, Robert Y.L. Zee, Talin Haritunians, Stacey Gabriel, Michael Boehnke, Ida Surakka, Alex N. Parker, Serena Sanna, Fabio Marroni, Leif Groop, Ingrid B. Borecki, Weihua Zhang, John R. Thompson, Paul M. Ridker, James P. Pirruccello, Nicole Soranzo, Ulf Gyllensten, G. Kees Hovingh, Jian'an Luan, Wendy L. McArdle, Alistair S. Hall, Yurii S. Aulchenko, Thomas Meitinger, John Whitfield, Gonçalo R. Abecasis, Yii-Der Ida Chen, Tien Yin Wong, Deborah A. Nickerson, Jaakko Tuomilehto, Kijoung Song, Reijo Laaksonen, Jeanette Erdmann, Daniel J. Rader, Jing Hua Zhao, Irene Pichler, Robert A. Hegele, Marjo-Riitta Järvelin, Guillaume Paré, Juha Sinisalo, Andrew C. Edmondson, Peter P. Pramstaller, E-Shyong Tai, Vilmundur Gudnason, Linda S. Adair, Min Jin Go, Heather M. Stringham, Nancy L. Pedersen, Bruce M. Psaty, Åsa Johansson, Guillaume Lettre, Tamara B. Harris, Christian Gieger, Toby Johnson, Cornelia M. van Duijn, Samuli Ripatti, Johannes H. Smit, Sigrid W. Fouchier, Gonneke Willemsen, Mark J. Rieder, Nicholas D. Hastie, Leena Peltonen, Jacqueline C. M. Witteman, David Schlessinger, Kiran Musunuru, Eric Boerwinkle, Kay-Tee Khaw, Massimo Mangino, Themistocles L. Assimes, Claudia Langenberg, Yoon Shin Cho, Elena Gonzalez, Eric J.G. Sijbrands, Toshiko Tanaka, Inês Barroso, Vincent Mooser, Eco J. C. de Geus, Karen L. Mohlke, Jaakko Kaprio, Eric E. Schadt, Gudmar Thorleifsson, Nelson B. Freimer, H.-Erich Wichmann, Francis S. Collins, Grant W. Montgomery, John J.P. Kastelein, Inke R. Koenig, Xiuqing Guo, Ruth McPherson, Benjamin F. Voight, Stefania Bandinelli, Sally L. Ricketts, S. Matthijs Boekholdt, Xin Yuan, David Altshuler, Marja-Liisa Lokki, Lori L. Bonnycastle, Aimo Ruokonen, Noël P. Burtt, Unnur Thorsteinsdottir, Markus Perola, Edward G. Lakatta, Serkalem Demissie, Kenechi Ejebe, Muredach P. Reilly, Florian Kronenberg, Panagiotis Deloukas, Gabriel Crawford, Lenore J. Launer, David P. Strachan, Xiaohui Li, Christian Hengstenberg, Olle Melander, Juha Saharinen, Ulf de Faire, Joshua D. Smith, Heribert Schunkert, Thomas Quertermous, Young Jin Kim, Alan R. Tall, Anna F. Dominiczak, Nicholas J. Wareham, Robert Roberts, Mark J. Caulfield, Tanya M. Teslovich, Daniel I. Chasman, Manuela Uda, Jong-Young Lee, Erik Ingelsson, Christopher W. Kuzawa, Jerome I. Rotter, Gina M. Peloso, Christie M. Ballantyne, Mingyao Li, Alan F. Wright, Albert Hofman, Angelo Scuteri, Rick Twee-Hee Ong, L. Adrienne Cupples, Taesung Park, Veronique Vitart, Kaisa Silander, Jouke-Jan Hottenga, Kari Stefansson, Christopher J. O'Donnell, Mary F. Feitosa, Tim D. Spector, Mark I. McCarthy, Nilesh J. Samani, Christopher T. Johansen, David Masson, Cristian Pattaro, Ioannis M. Stylianou, Angela Doering, Patricia B. Munroe, Herman A. Taylor, Patrik K. E. Magnusson, John C. Chambers, Claudia Lamina, Sekar Kathiresan, Dawn M. Waterworth, Jose M. Ordovas, Alan B. Feranil, Cristen J. Willer, Kirsten Ohm Kyvik, Gérard Waeber, Ronald M. Krauss, Medical Research Council (MRC), Psychiatry, EMGO - Mental health, NCA - Anxiety & Depression, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Experimental Vascular Medicine, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Epidemiology, Internal Medicine, and Clinical Genetics
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Male ,Netherlands Twin Register (NTR) ,genetics/metabolism ,Blood lipids ,Genome-wide association study ,KLF14 ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,blood/genetics/therapy ,DISEASE ,chemistry.chemical_compound ,Mice ,African Americans ,genetics, Animals, Asian Continental Ancestry Group ,genetics, Cholesterol ,HDL ,blood, Cholesterol ,LDL ,blood, Coronary Artery Disease ,blood/genetics/therapy, Europe ,ethnology, European Continental Ancestry Group ,genetics, Female, Genetic Loci ,genetics, Genome-Wide Association Study, Genotype, Humans, Lipid Metabolism ,genetics, Lipids ,blood, Liver ,metabolism, Male, Mice, N-Acetylgalactosaminyltransferases ,genetics/metabolism, Phenotype, Polymorphism ,Single Nucleotide ,genetics, Protein Phosphatase 1 ,genetics/metabolism, Reproducibility of Results, Triglycerides ,blood ,0302 clinical medicine ,Protein Phosphatase 1 ,genetics ,Genetics ,RISK ,0303 health sciences ,education.field_of_study ,Multidisciplinary ,CHOLESTEROL ,Genomics ,Lipids ,3. Good health ,Multidisciplinary Sciences ,Europe ,Phenotype ,Liver ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Science & Technology - Other Topics ,N-Acetylgalactosaminyltransferases ,Female ,lipids (amino acids, peptides, and proteins) ,lipids ,gwas ,TRAITS ,Asian Continental Ancestry Group ,Genotype ,General Science & Technology ,Population ,European Continental Ancestry Group ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Article ,White People ,03 medical and health sciences ,Asian People ,SDG 3 - Good Health and Well-being ,Animals ,Humans ,Polymorphism ,GENOME-WIDE ASSOCIATION ,education ,Triglycerides ,030304 developmental biology ,ethnology ,Science & Technology ,Cholesterol ,Cholesterol, HDL ,Reproducibility of Results ,Lipid metabolism ,Cholesterol, LDL ,Lipid Metabolism ,SCARB1 ,Black or African American ,chemistry ,Genetic Loci ,metabolism ,Genome-Wide Association Study - Abstract
Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P-8), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD. © 2010 Macmillan Publishers Limited. All rights reserved.
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- 2010
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31. Meta-analysis and imputation refines the association of 15q25 with smoking quantity
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Mark J. Caulfield, Paul Scheet, Ruth J. F. Loos, Ozren Polasek, Vincent Mooser, Michael Wittig, Stephen E. Epstein, James F. Wilson, Gonçalo R. Abecasis, Jennifer E. Huffman, Augusto D. Pichard, Mary Susan Burnett, Rajesh Rawal, Federica Tozzi, Nilesh J. Samani, Hans J. Grabe, Robert L. Wilensky, Miles Parkes, Jing Hua Zhao, Jaspal S. Kooner, Daniel J. Rader, Wade H. Berrettini, Per Bakke, Robert W. Mahley, Astrid Petersmann, Alan F. Wright, Kenneth M. Kent, Lowell F. Satler, Alistair S. Hall, Xin Yuan, Hakon Hakonarson, Henry Völzke, Peter Vollenweider, Xiangjun Xiao, John B. Vincent, Joseph M. Lindsay, Scott M. Grundy, Christopher G. Mathew, Caroline Hayward, Susan Campbell, John R. Thompson, Alexander Teumer, Ins Barroso, David Schlessinger, Jack Satsangi, Benjamin J. Wright, Carl A. Anderson, Fabio Busonero, James L. Kennedy, Harry Campbell, Dan Rujescu, Anne Barton, H.-Erich Wichmann, Philip J. Barter, Veronique Vitart, Antonio Terracciano, Ruth McPherson, S. Horstmann, Anna F. Dominiczak, Martin Preisig, Susanne Lucae, David St Clair, Lina Zgaga, Jane Worthington, Joseph M. Devaney, Wendy Thomson, Anne Farmer, Antero Kesäniemi, Ulrich John, Tariq Ahmad, William H. Matthai, Jason Z. Liu, Muredach P. Reilly, Ivana Kolcic, Igor Rudan, Norbert Dahmen, Martin Farrall, Anthony J. Balmforth, Nicholas J. Wareham, Steve Eyre, T. Brueckl, Kay-Tee Khaw, Liming Qu, Christopher W. Knouff, Sarah H. Wild, Patricia B. Munroe, Claudia Lamina, Dawn M. Waterworth, John Strauss, John C. Chambers, Marcus Ising, Richard O. Day, Amund Gulsvik, Gérard Waeber, Arne Schäfer, Andre Franke, Clyde Francks, Pierandrea Muglia, Mingyao Li, Peter McGuffin, Keith Matthews, Manuela Uda, Sreekumar G. Pillai, Jonathan Marchini, Lefkos T. Middleton, Ron Waksman, and Wellcome Trust Case Control Consortium
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Genetics ,0303 health sciences ,education.field_of_study ,Population ,Single-nucleotide polymorphism ,Genome-wide association study ,Locus (genetics) ,Biology ,Article ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Genome-Wide Association ,Nicotine Dependence ,Lung-Cancer ,Susceptibility Locus ,Risk-Factors ,Disease ,Genes ,SNPS ,Colaus Study ,SNP ,1000 Genomes Project ,Allele ,education ,030217 neurology & neurosurgery ,Imputation (genetics) ,genome-wide association study ,smoking initiation ,smoking quantity ,030304 developmental biology - Abstract
Smoking is a leading global cause of disease and mortality(1). We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.
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32. Genome-wide association scan for five major dimensions of personality
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Elżbieta Śliwerska, Eline Slagboom, Paul T. Costa, Barbara Deiana, Fabio Busonero, Nicholas S. Patriciu, A. C. J. W. Janssens, Serena Sanna, Matthew Scally, Dorret I. Boomsma, Andrea Maschio, Antonio Terracciano, Gonçalo R. Abecasis, Manuela Uda, Sandra Villafuerte, C M van Duijn, Marijn A. Distel, Margit Burmeister, David Schlessinger, Wei-Min Chen, Najaf Amin, Gianluca Usala, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Epidemiology, and Public Health
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Agreeableness ,Netherlands Twin Register (NTR) ,Adult ,Male ,Adolescent ,Genotype ,media_common.quotation_subject ,Genome-wide association study ,Personality Assessment ,Polymorphism, Single Nucleotide ,Article ,Cellular and Molecular Neuroscience ,Personality ,Humans ,Genetic Predisposition to Disease ,Big Five personality traits ,Molecular Biology ,media_common ,Aged ,Genetics ,Aged, 80 and over ,Extraversion and introversion ,Reproducibility of Results ,Conscientiousness ,Middle Aged ,Neuroticism ,Psychiatry and Mental health ,Italy ,personality genome-wide association founder population psychiatry five-factor model population-based twin deficit hyperactivity disorder national-comorbidity-survey coronary-artery-disease cross-cultural twin neo-pi-r clock gene alzheimer-disease linkage analysis 3111t/c polymorphism ,Female ,Personality Assessment Inventory ,Psychology ,Genome-Wide Association Study - Abstract
Personality traits are summarized by five broad dimensions with pervasive influences on major life outcomes, strong links to psychiatric disorders and clear heritable components. To identify genetic variants associated with each of the five dimensions of personality we performed a genome-wide association (GWA) scan of 3972 individuals from a genetically isolated population within Sardinia, Italy. On the basis of the analyses of 362 129 single-nucleotide polymorphisms we found several strong signals within or near genes previously implicated in psychiatric disorders. They include the association of neuroticism with SNAP25 (rs362584, P= 5 x 10(-5)), extraversion with BDNF and two cadherin genes (CDH13 and CDH23; Ps
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33. High Neuroticism and low Conscientiousness are associated with interleukin-6
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Silvia Naitza, Angelina R. Sutin, Barbara Deiana, Paul T. Costa, David Schlessinger, Luigi Ferrucci, Manuela Uda, and Antonio Terracciano
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Neurotic Disorders ,Health Status ,media_common.quotation_subject ,Health Behavior ,Population ,Disease ,Impulsivity ,Article ,medicine ,Humans ,Personality ,Big Five personality traits ,Overeating ,education ,Psychiatry ,Applied Psychology ,Aged ,media_common ,Aged, 80 and over ,Inflammation ,education.field_of_study ,Interleukin-6 ,Conscientiousness ,Middle Aged ,Neuroticism ,Psychiatry and Mental health ,C-Reactive Protein ,Logistic Models ,Italy ,Impulsive Behavior ,Female ,medicine.symptom ,Psychology ,Biomarkers ,Clinical psychology - Abstract
BackgroundHigh Neuroticism and low Conscientiousness are frequently implicated in health-risk behaviors, such as smoking and overeating, as well as health outcomes, including mortality. Their associations with physiological markers of morbidity and mortality, such as inflammation, are less well documented. The present research examines the association between the five major dimensions of personality and interleukin-6 (IL-6), a pro-inflammatory cytokine often elevated in patients with chronic morbidity and frailty.MethodA population-based sample (n=4923) from four towns in Sardinia, Italy, had their levels of IL-6 measured and completed a comprehensive personality questionnaire, the NEO-PI-R. Analyses controlled for factors known to have an effect on IL-6: age; sex; smoking; weight; aspirin use; disease burden.ResultsHigh Neuroticism and low Conscientiousness were both associated with higher levels of IL-6. The findings remained significant after controlling for the relevant covariates. Similar results were found for C-reactive protein, a related marker of chronic inflammation. Further, smoking and weight partially mediated the association between impulsivity-related traits and higher IL-6 levels. Finally, logistic regressions revealed that participants either in the top 10% of the distribution of Neuroticism or the bottom 10% of conscientiousness had an approximately 40% greater risk of exceeding clinically relevant thresholds of IL-6.ConclusionsConsistent with the literature on personality and self-reported health, individuals high on Neuroticism or low on Conscientiousness show elevated levels of this inflammatory cytokine. Identifying critical medical biomarkers associated with personality may help to elucidate the physiological mechanisms responsible for the observed connections between personality traits and physical health.
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34. Age- and gender-specific awareness, treatment, and control of cardiovascular risk factors and subclinical vascular lesions in a founder population: The SardiNIA Study
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Kirill V. Tarasov, Antonio Cao, Giuseppe Albai, Edward G. Lakatta, Maria Grazia Piras, Manuela Uda, Angelo Scuteri, David Schlessinger, Samer S. Najjar, Marco Orrù, and James B. Strait
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Male ,Health Knowledge, Attitudes, Practice ,Endocrinology, Diabetes and Metabolism ,Prevalence ,Medicine (miscellaneous) ,Risk Factors ,Epidemiology ,Practice Patterns, Physicians' ,Subclinical infection ,Aged, 80 and over ,Metabolic Syndrome ,education.field_of_study ,Nutrition and Dietetics ,Age Factors ,Awareness ,Middle Aged ,Founder Effect ,Italy ,Cardiovascular Diseases ,Hypertension ,Practice Guidelines as Topic ,Female ,Guideline Adherence ,Cardiology and Cardiovascular Medicine ,Adult ,medicine.medical_specialty ,Adolescent ,Population ,Risk Assessment ,Article ,Young Adult ,Sex Factors ,Internal medicine ,Diabetes mellitus ,Diabetes Mellitus ,medicine ,Humans ,Hypoglycemic Agents ,Obesity ,Risk factor ,education ,Antihypertensive Agents ,Aged ,Dyslipidemias ,business.industry ,Atherosclerosis ,medicine.disease ,Drug Utilization ,Endocrinology ,Cardiovascular agent ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,business ,Dyslipidemia - Abstract
We investigated the gender-specific control of cardiovascular (CV) risk factors and subclinical vascular lesions in a founder population in Italy.6148 subjects were enrolled (aged 14-102 years) from four towns. Hypertension (HT), diabetes mellitus (DM) and dyslipidemia (LIP) were defined in accordance with guidelines. A self-reported diagnosis defined awareness of these conditions, and the current use of specific medications as treatment. Prevalence was HT 29.2%, DM 4.8%, LIP 44.1% and was higher in men than in women. Disease prevalence increased with age for every CV risk factor. Men were less likely than women to take anti-HT drugs and to reach BP control (9.9% vs. 16%). Only 17.6% of HT65 years had a BPor =140/90 mmHg, though 48.5% were treated. The use of statins was very low (1/3 of eligible subjects65 years, those with the highest treatment rate). The ratio of control-to-treated HT was lower in subjects with, than in those without, thicker carotid arteries (31.5% vs. 38.8%, p0.05) or stiffer aortas (26.0% vs. 40.0%, p0.05) or carotid plaques (26.3% vs. 41.1%, p0.05).A large number of subjects at high CV risk are not treated and the management of subclinical vascular lesions is far from optimal.
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35. Genome-wide association study identifies eight loci associated with blood pressure
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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)
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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.
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- 2009
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36. Common variants in the SLCO1B3 locus are associated with bilirubin levels and unconjugated hyperbilirubinemia
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Gonçalo R. Abecasis, Antonella Mulas, Gianluca Usala, Mara Marongiu, Maria Grazia Piras, Marco Masala, Manuela Uda, Silvia Naitza, David Schlessinger, Mariano Dei, Laura Crisponi, Serena Sanna, Lucia Perseu, Renzo Galanello, Fabio Busonero, Andrea Maschio, Alan R. Shuldiner, Antonio Cao, Patrick F. McArdle, and Sandra Lai
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Genotype ,Bilirubin ,Genome-wide association study ,Locus (genetics) ,Organic Anion Transporters, Sodium-Independent ,Biology ,Solute Carrier Organic Anion Transporter Family Member 1B3 ,chemistry.chemical_compound ,Internal medicine ,Genetics ,medicine ,Humans ,Molecular Biology ,Genetics (clinical) ,Chromosome 12 ,Aged ,Hyperbilirubinemia ,Unconjugated hyperbilirubinemia ,Aged, 80 and over ,Association Studies Articles ,Genetic Variation ,General Medicine ,Middle Aged ,Glucuronic acid ,Endocrinology ,Italy ,chemistry ,Biochemistry ,Old Order Amish ,Female ,Hemoglobin ,Genome-Wide Association Study - Abstract
Bilirubin, resulting largely from the turnover of hemoglobin, is found in the plasma in two main forms: unconjugated or conjugated with glucuronic acid. Unconjugated bilirubin is transported into hepatocytes. There, it is glucuronidated by UGT1A1 and secreted into the bile canaliculi. We report a genome wide association scan in 4300 Sardinian individuals for total serum bilirubin levels. In addition to the two known loci previously involved in the regulation of bilirubin levels, UGT1A1 (P = 6.2 x 10(-62)) and G6PD (P = 2.5 x 10(-8)), we observed a strong association on chromosome 12 within the SLCO1B3 gene (P = 3.9 x 10(-9)). Our findings were replicated in an independent sample of 1860 Sardinians and in 832 subjects from the Old Order Amish (combined P5 x 10(-14)). We also show that SLC01B3 variants contribute to idiopathic mild unconjugated hyperbilirubinemia. Thus, SLC01B3 appears to be involved in the regulation of serum bilirubin levels in healthy individuals and in some bilirubin-related disorders that are only partially explained by other known gene variants.
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- 2009
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37. Using New Tools to Define the Genetic Underpinnings of Risky Traits Associated With Coronary Artery Disease: The SardiNIA Study
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Manuela Uda, James B. Strait, Edward G. Lakatta, and Samer S. Najjar
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Blood Glucose ,Genetic Markers ,Linkage disequilibrium ,Genotype ,Lipoproteins ,Genetic Carrier Screening ,Genome-wide association study ,Coronary Artery Disease ,Biology ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Article ,Heterozygote Detection ,Coronary artery disease ,Novel gene ,Quantitative Trait, Heritable ,medicine ,Humans ,Obesity ,Risk factor ,Genetics ,medicine.disease ,Uric Acid ,Italy ,Evolutionary biology ,Genomewide association ,Cardiology and Cardiovascular Medicine ,Blood Flow Velocity ,Genome-Wide Association Study - Abstract
Genome-wide association studies are increasingly being applied to search for novel genes that might underlie cardiovascular diseases. In this article, we briefly review the principles that underlie modern genetic analyses, and provide several illustrations from the SardiNIA Study of genome-wide association studies for cardiovascular risk factor traits.
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- 2009
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38. DNA polymorphisms at the BCL11A , HBS1L-MYB , and β- globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease
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Guillaume Lettre, Vijay G. Sankaran, Marcos André Cavalcanti Bezerra, Manuela Uda, Fernando Ferreira Costa, Serena Sanna, Stuart H. Orkin, Antonio Cao, Joel N. Hirschhorn, David Schlessinger, and Aderson S Araujo
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Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,Genotype ,Genes, myb ,Anemia ,Pain ,Single-nucleotide polymorphism ,Anemia, Sickle Cell ,Disease ,Biology ,Polymorphism, Single Nucleotide ,HBG2 ,Cohort Studies ,Polymorphism (computer science) ,hemic and lymphatic diseases ,Fetal hemoglobin ,medicine ,Humans ,SNP ,Fetal Hemoglobin ,Genetics ,Multidisciplinary ,Nuclear Proteins ,medicine.disease ,Globins ,Repressor Proteins ,Commentary ,Female ,Carrier Proteins - Abstract
Sickle cell disease (SCD) is a debilitating monogenic blood disorder with a highly variable phenotype characterized by severe pain crises, acute clinical events, and early mortality. Interindividual variation in fetal hemoglobin (HbF) expression is a known and potentially heritable modifier of SCD severity. High HbF levels are correlated with reduced morbidity and mortality. Common single nucleotide polymorphisms (SNPs) at the BCL11A and HBS1L-MYB loci have been implicated previously in HbF level variation in nonanemic European populations. We recently demonstrated an association between a BCL11A SNP and HbF levels in one SCD cohort [Uda M, et al. (2008) Proc Natl Acad Sci USA 105:1620–1625]. Here, we genotyped additional BCL11A SNPs, HBS1L-MYB SNPs, and an SNP upstream of G γ- globin ( HBG2 ; the Xmn I polymorphism), in two independent SCD cohorts: the African American Cooperative Study of Sickle Cell Disease (CSSCD) and an SCD cohort from Brazil. We studied the effect of these SNPs on HbF levels and on a measure of SCD-related morbidity (pain crisis rate). We strongly replicated the association between these SNPs and HbF level variation (in the CSSCD, P values range from 0.04 to 2 × 10 −42 ). Together, common SNPs at the BCL11A , HBS1L-MYB , and β- globin ( HBB ) loci account for >20% of the variation in HbF levels in SCD patients. We also have shown that HbF-associated SNPs associate with pain crisis rate in SCD patients. These results provide a clear example of inherited common sequence variants modifying the severity of a monogenic disease.
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- 2008
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39. Identification of ten loci associated with height highlights new biological pathways in human growth
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Joel N. Hirschhorn, Frank B. Hu, Serena Sanna, Susana Eyheramendy, Guillaume Lettre, Karen L. Mohlke, Johannah L. Butler, Sonja I. Berndt, Valeriya Lyssenko, Iris M. Heid, Bo Isomaa, Peter Kraft, Michael Boehnke, Stephen J. Chanock, Veikko Salomaa, Anne U. Jackson, H-Erich Wichmann, Leif Groop, Rachel Hackett, Leena Peltonen, Thomas Illig, Gonçalo R. Abecasis, Candace Guiducci, David J. Hunter, Fredrick R. Schumacher, Christian Gieger, Kevin B. Jacobs, Richard B. Hayes, David Schlessinger, Benjamin F. Voight, and Manuela Uda
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Genetics ,0303 health sciences ,Genetic Linkage ,Genome, Human ,Body height ,Locus (genetics) ,Computational biology ,Biology ,Polymorphism, Single Nucleotide ,Article ,Body Height ,Biological pathway ,03 medical and health sciences ,0302 clinical medicine ,Genetic linkage ,Humans ,Human genome ,Human height ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Height is a classic polygenic trait, reflecting the combined influence of multiple as-yet-undiscovered genetic factors. We carried out a meta-analysis of genome-wide association study data of height from 15,821 individuals at 2.2 million SNPs, and followed up the strongest findings in10,000 subjects. Ten newly identified and two previously reported loci were strongly associated with variation in height (P values from 4 x 10(-7) to 8 x 10(-22)). Together, these 12 loci account for approximately 2% of the population variation in height. Individuals withor =8 height-increasing alleles andor =16 height-increasing alleles differ in height by approximately 3.5 cm. The newly identified loci, along with several additional loci with strongly suggestive associations, encompass both strong biological candidates and unexpected genes, and highlight several pathways (let-7 targets, chromatin remodeling proteins and Hedgehog signaling) as important regulators of human stature. These results expand the picture of the biological regulation of human height and of the genetic architecture of this classical complex trait.
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- 2008
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40. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of β-thalassemia
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Renzo Galanello, Fabio Busonero, G. Abecasis, Paolo Moi, Silvia Naitza, Maria Grazia Piras, Natascia Sestu, Mariano Dei, Ramaiah Nagaraja, Sandra Lai, Vijay G. Sankaran, Stuart H. Orkin, Giuseppe Albai, Carla Sollaino, Antonio Cao, Guillaume Lettre, Wei-Min Chen, Manuela Uda, Maria Dolores Cipollina, Serena Sanna, Gianluca Usala, David Schlessinger, Antonella Mulas, Isadora Asunis, Joel N. Hirschhorn, Manila Deiana, Andrea Maschio, Laura Crisponi, Stefania Satta, and Lucia Perseu
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Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,Hereditary persistence of fetal hemoglobin ,Genetic Linkage ,Thalassemia ,Genome-wide association study ,KLF1 ,Biology ,Polymorphism, Single Nucleotide ,HBG2 ,Cohort Studies ,Gene Frequency ,hemic and lymphatic diseases ,Fetal hemoglobin ,medicine ,Humans ,Fetal Hemoglobin ,Aged ,Aged, 80 and over ,Genetics ,Multidisciplinary ,Genome, Human ,Genetic heterogeneity ,beta-Thalassemia ,Nuclear Proteins ,Biological Sciences ,Middle Aged ,medicine.disease ,Sickle cell anemia ,Repressor Proteins ,Phenotype ,Italy ,Immunology ,Female ,Carrier Proteins - Abstract
β-Thalassemia and sickle cell disease both display a great deal of phenotypic heterogeneity, despite being generally thought of as simple Mendelian diseases. The reasons for this are not well understood, although the level of fetal hemoglobin (HbF) is one well characterized ameliorating factor in both of these conditions. To better understand the genetic basis of this heterogeneity, we carried out genome-wide scans with 362,129 common SNPs on 4,305 Sardinians to look for genetic linkage and association with HbF levels, as well as other red blood cell-related traits. Among major variants affecting HbF levels, SNP rs11886868 in the BCL11A gene was strongly associated with this trait ( P < 10 −35 ). The C allele frequency was significantly higher in Sardinian individuals with elevated HbF levels, detected by screening for β-thalassemia, and patients with attenuated forms of β-thalassemia vs. those with thalassemia major. We also show that the same BCL11A variant is strongly associated with HbF levels in a large cohort of sickle cell patients. These results indicate that BCL11A variants, by modulating HbF levels, act as an important ameliorating factor of the β-thalassemia phenotype, and it is likely they could help ameliorate other hemoglobin disorders. We expect our findings will help to characterize the molecular mechanisms of fetal globin regulation and could eventually contribute to the development of new therapeutic approaches for β-thalassemia and sickle cell anemia.
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- 2008
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41. Transcriptional Control of Ovarian Development in Somatic Cells
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Antonino Forabosco, Maria Colombino, Chris Ottolenghi, Laura Crisponi, Manuela Uda, Antonio Cao, and David Schlessinger
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Time Factors ,Transcription, Genetic ,Somatic cell ,Endocrinology, Diabetes and Metabolism ,Granulosa cell ,Morphogenesis ,Cell Communication ,Biology ,Mice ,Oogenesis ,Endocrinology ,Physiology (medical) ,Transcriptional regulation ,Animals ,Humans ,Transcription factor ,Ovum ,Regulation of gene expression ,Genetics ,Gene Expression Profiling ,Egg Proteins ,Ovary ,Gene Expression Regulation, Developmental ,Obstetrics and Gynecology ,Cell Differentiation ,Gene expression profiling ,Reproductive Medicine ,Models, Animal ,Somatic sex determination ,Female - Abstract
Developmental transitions of the bipotential gonad to the embryonic ovary and thence to the follicle-filled mature ovary are expected to be coordinated by sets of transcription factors. We infer candidate lists here, focusing on somatic cell fate and function. For the mouse, developmental stages of ovary differentiation are relatively discretely phased, and provide a unique tool to investigate the intricate mechanisms that lead to the acquisition of female reproductive competence. Cross-platform gene expression profiles supplement functional studies of specific genes and comparative information about human biology. Available data suggest that: (1) peak transcription activity just precedes the two most decisive steps of early ovary differentiation (i.e., entry into meiosis and follicle formation); (2) alternating peak gene activities in oocytes and somatic cells may reflect reciprocal interactions; and (3) in addition to stable states of chromatin modification associated with morphogenesis, some features of differentiation are labile, contingent on the expression state of critical factors. Examples are the maintenance of somatic sex determination by continued Foxl2 action and the reversible maintenance of follicles in a quiescent state by nuclear Foxo3.
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- 2007
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42. FOXL2 modulates cartilage, skeletal development and IGF1-dependent growth in mice
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Alessandro Puddu, Loredana Marcia, Mario Lovicu, Manila Deiana, Mara Marongiu, David Schlessinger, Laura Crisponi, Antonino Forabosco, Emanuele Pelosi, Manuela Uda, Yonqing Zhang, and Angela Loi
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Forkhead Box Protein L2 ,Male ,medicine.medical_specialty ,Gonadal dysgenesis ,Cartilage metabolism ,Biology ,Blepharophimosis ,Mice ,Ptosis ,Internal medicine ,medicine ,Animals ,Humans ,Insulin-Like Growth Factor I ,Bone Development ,Cartilage ,Forkhead Transcription Factors ,medicine.disease ,Premature ovarian failure ,body regions ,Forkhead box L2 ,Endocrinology ,medicine.anatomical_structure ,Urogenital Abnormalities ,Skin Abnormalities ,Female ,medicine.symptom ,Haploinsufficiency ,Developmental Biology ,Research Article ,Signal Transduction - Abstract
Background Haploinsufficiency of the FOXL2 transcription factor in humans causes Blepharophimosis/Ptosis/Epicanthus Inversus syndrome (BPES), characterized by eyelid anomalies and premature ovarian failure. Mice lacking Foxl2 recapitulate human eyelid/forehead defects and undergo female gonadal dysgenesis. We report here that mice lacking Foxl2 also show defects in postnatal growth and embryonic bone and cartilage formation. Methods Foxl2−/− male mice at different stages of development have been characterized and compared to wild type. Body length and weight were measured and growth curves were created. Skeletons were stained with alcian blue and/or alizarin red. Bone and cartilage formation was analyzed by Von Kossa staining and immunofluorescence using anti-FOXL2 and anti-SOX9 antibodies followed by confocal microscopy. Genes differentially expressed in skull vaults were evaluated by microarray analysis. Analysis of the GH/IGF1 pathway was done evaluating the expression of several hypothalamic-pituitary-bone axis markers by RT-qPCR. Results Compared to wild-type, Foxl2 null mice are smaller and show skeletal abnormalities and defects in cartilage and bone mineralization, with down-regulation of the GH/IGF1 axis. Consistent with these effects, we find FOXL2 expressed in embryos at 9.5 dpc in neural tube epithelium, in head mesenchyme near the neural tube, and within the first branchial arch; then, starting at 12.5 dpc, expressed in cartilaginous tissue; and at PO and P7, in hypothalamus. Conclusions Our results support FOXL2 as a master transcription factor in a spectrum of developmental processes, including growth, cartilage and bone formation. Its action overlaps that of SOX9, though they are antagonistic in female vs male gonadal sex determination but conjoint in cartilage and skeletal development. Electronic supplementary material The online version of this article (doi:10.1186/s12861-015-0072-y) contains supplementary material, which is available to authorized users.
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- 2015
43. Personality Traits in Sardinia: Testing Founder Population Effects on Trait Means and Variances
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Edward G. Lakatta, Cinzia Mameli, David Schlessinger, Antonio Terracciano, Alan B. Zonderman, Robert R. McCrae, Paul T. Costa, Giuseppe Pilia, Loredana Vacca, and Manuela Uda
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Male ,media_common.quotation_subject ,Emotions ,Quantitative trait locus ,Personality Assessment ,Revised NEO Personality Inventory ,Genetics ,Humans ,Personality ,Big Five personality traits ,Genetics (clinical) ,Ecology, Evolution, Behavior and Systematics ,media_common ,Analysis of Variance ,Sex Characteristics ,Models, Genetic ,Genetic Variation ,Founder Effect ,Genetic architecture ,Italy ,Trait ,Educational Status ,Female ,Personality Assessment Inventory ,Psychology ,Social psychology ,Demography ,Founder effect - Abstract
Potential founder population effects on personality trait means and variances were examined in a large, genetically homogeneous sample (N = 5,669) from the Ogliastra, an isolated region within Sardinia, Italy. The Italian version of the Revised NEO Personality Inventory showed good psychometric properties: Internal consistency reliabilities ranged from 0.80 to 0.87; the factor structure replicated the American normative structure; and associations with education and gender replicated cross-cultural patterns. The hypothesis that mean trait levels in the Sardinian founder population would differ from mainland Italian values was not supported. Phenotypic variation in this founder population was within the range found in other cultures. However, the hypothesis of restricted phenotypic variation was supported for all five factors and 28 of the 30 facets when a Sardinian subsample matched on age, sex, and education was compared to a mainland Italian sample. The genetic homogeneity effect on the phenotypic expression of complex traits merits further exploration.
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- 2006
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44. Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways
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Sophie H. Van Wingerden, Wei V. Zhuang, Mladen Boban, John R. B. Perry, Joop S.E. Laven, Shah Ebrahim, Andrea D. Coviello, Barbara McKnight, Laura Crisponi, Sharon L.R. Kardia, Daniel I. Chasman, Lorna M. Lopez, George Dedoussis, Stefania Bandinelli, Nora Franceschini, Florian Ernst, A. Cecile J.W. Janssens, Yvonne T. van der Schouw, Henri Wallaschofski, Jari Lahti, Triin Laisk, Elizabeth A. Streeten, Joanne M. Murabito, Liana Ferreli, Harold Snieder, Dale R. Nyholt, Lenore J. Launer, Panagiotis Deloukas, Melissa E. Garcia, Eco J. C. de Geus, H.-Erich Wichmann, John M. Starr, Eva Albrecht, Paul M. Ridker, N. Charlotte Onland-Moret, Petra H.M. Peeters, Massimo Mangino, Jacques S. Beckmann, Stephen J. Chanock, Grant W. Montgomery, Julie E. Buring, Barbara Thorand, Diederick E. Grobbee, Irena Martinović Klarić, Constance Chen, So-Youn Shin, Ozren Polasek, Daniel F. Gudbjartsson, Patrick Sulem, Carla H. van Gils, Eleonora Porcu, Cinzia Sala, Tim D. Spector, Alexander N. Parker, Ellen W. Demerath, Guillaume Paré, Krista Fischer, Simon N. Stacey, Mara Marongiu, Lina Zgaga, Jouke-Jan Hottenga, Unnur Styrkarsdottir, Debbie A Lawlor, Douglas P. Kiel, Guangju Zhai, Kari Stefansson, Lisette Stolk, Igor Rudan, David Schlessinger, Katri R Currency Signikkönen, Z. Kutalik, Ian J. Deary, Frank J.M. Broekmans, Ulf de Faire, Vincent Mooser, Luigi Ferrucci, Maria G. Stathopoulou, Pio D'Adamo, Marek Zygmunt, Linda Broer, James F. Wilson, Lovorka Barać Lauc, Angelo Scuteri, Patrik K. E. Magnusson, Frank B. Hu, Jennifer A. Smith, Toomas Haller, Giorgio Pistis, Colette J M Wijnands-van Gent, Emil Rehnberg, Marlies Voorhuis, Anna Murray, David Melzer, Chunyan He, Tamara B. Harris, Merli Hass, Patrick F. McArdle, Valur Emilsson, Gérard Waeber, Manuela Uda, Nancy L. Pedersen, Jenny A. Visser, Behrooz Z. Alizadeh, Andres Salumets, Andrew D. Johnson, Gonneke Willemsen, Sheila Ulivi, Tmu Esko, Vilmundur Gudnason, Bart C.J.M. Fauser, Maja Barbalić, Henry Völzke, Ronald P. Stolk, Aarno Palotie, Peter Van Nierop, Thor Aspelund, Elisabeth Widen, Caroline Hayward, Johan G. Eriksson, Alan F. Wright, Marilyn C. Cornelis, Tanguy Corre, Eric Boerwinkle, Ben A. Oostra, Alice M. Arnold, Kathleen Stirrups, Yvonne V. Louwers, M. Carola Zillikens, Anne B. Newman, Jerome I. Rotter, Jianjun Liu, Per Hall, Aaron R. Folsom, David Karasik, Yan V. Sun, Albert Hofman, Gudny Eiriksdottir, Andrew B. Singleton, Victor J M Pop, Pau Navarro, Tatijana Zemunik, Andres Metspalu, Andrew S. Plump, Cornelia M. van Duijn, Dorret I. Boomsma, Harry Campbell, Nicole Soranzo, Bruce M. Psaty, Enda M. Byrne, Christian Gieger, Albert Tenesa, Nicholas G. Martin, Unnur Thorsteinsdottir, Kathryn L. Lunetta, Laufey Tryggvadottir, Serena Sanna, Kim Tsui, Ivana Kolcic, Laura M. Yerges-Armstrong, Jacqueline M. Vink, Bruce H. R. Wolffenbuttel, Daniela Toniolo, Peter M. Visscher, Rob M. van Dam, Erik Ingelsson, Sandra Lai, Corrado Masciullo, Albert V. Smith, Paolo Gasparini, Sarah E. Medland, Nicole L. Glazer, Peter Kraft, André G. Uitterlinden, David J. Hunter, Andrea Burri, Jules J. Keyzer, Susan E. Hankinson, Gail Davies, Andrew C. Heath, Biological Psychology, EMGO+ - Mental Health, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Surgery, Hematology, Clinical Genetics, Study T.L., Lisette, Stolk, John R. B., Perry, Daniel I., Chasman, Chunyan, He, Massimo, Mangino, Patrick, Sulem, Maja, Barbalic, Linda, Broer, Enda M., Byrne, Florian, Ernst, Tõnu, Esko, Nora, Franceschini, Daniel F., Gudbjartsson, Jouke Jan, Hottenga, Peter, Kraft, Patrick F., Mcardle, Eleonora, Porcu, So Youn, Shin, Albert V., Smith, Sophie van, Wingerden, Guangju, Zhai, Wei V., Zhuang, Eva, Albrecht, Behrooz Z., Alizadeh, Thor, Aspelund, Stefania, Bandinelli, Lovorka Barac, Lauc, Jacques S., Beckmann, Mladen, Boban, Eric, Boerwinkle, Frank J., Broekman, Andrea, Burri, Harry, Campbell, Stephen J., Chanock, Constance, Chen, Marilyn C., Corneli, Tanguy, Corre, Andrea D., Coviello, D'Adamo, ADAMO PIO, Gail, Davie, Ulf de, Faire, Eco J. C., de Geu, Ian J., Deary, George V. Z., Dedoussi, Panagiotis, Delouka, Shah, Ebrahim, Gudny, Eiriksdottir, Valur, Emilsson, Johan G., Eriksson, Bart C. J. M., Fauser, Liana, Ferreli, Luigi, Ferrucci, Krista, Fischer, Aaron R., Folsom, Melissa E., Garcia, Gasparini, Paolo, Christian, Gieger, Nicole, Glazer, Diederick E., Grobbee, Per, Hall, Toomas, Haller, Susan E., Hankinson, Merli, Ha, Caroline, Hayward, Andrew C., Heath, Albert, Hofman, Erik, Ingelsson, A. Cecile J. W., Janssen, Andrew D., Johnson, David, Karasik, Sharon L. R., Kardia, Jules, Keyzer, Douglas P., Kiel, Ivana, Kolcic, Zoltán, Kutalik, Jari, Lahti, Sandra, Lai, Triin, Laisk, Joop S. E., Laven, Debbie A., Lawlor, Jianjun, Liu, Lorna M., Lopez, Yvonne V., Louwer, Patrik K. E., Magnusson, Mara, Marongiu, Nicholas G., Martin, Irena Martinovic, Klaric, Corrado, Masciullo, Barbara, Mcknight, Sarah E., Medland, David, Melzer, Vincent, Mooser, Pau, Navarro, Anne B., Newman, Dale R., Nyholt, N., Charlotte Onland Moret, Aarno, Palotie, Guillaume, Paré, Alex N., Parker, Nancy L., Pedersen, Petra H. M., Peeter, Giorgio, Pisti, Andrew S., Plump, Ozren, Polasek, Victor J. M., Pop, Bruce M., Psaty, Katri, Räikkönen, Emil, Rehnberg, Jerome I., Rotter, Igor, Rudan, Cinzia, Sala, Andres, Salumet, Angelo, Scuteri, Andrew, Singleton, Jennifer A., Smith, Harold, Snieder, Nicole, Soranzo, Simon N., Stacey, John M., Starr, Maria G., Stathopoulou, Kathleen, Stirrup, Ronald P., Stolk, Unnur, Styrkarsdottir, Yan V., Sun, Albert, Tenesa, Barbara, Thorand, Daniela, Toniolo, Laufey, Tryggvadottir, Kim, Tsui, Sheila, Ulivi, Rob M., van Dam, Yvonne T., van der Schouw, Carla H., van Gil, Peter van, Nierop, Jacqueline M., Vink, Peter M., Visscher, Marlies, Voorhui, Gérard, Waeber, Henri, Wallaschofski, H., Erich Wichmann, Elisabeth, Widen, Colette J. M., Wijnands van Gent, Gonneke, Willemsen, James F., Wilson, Bruce H. R., Wolffenbuttel, Alan F., Wright, Laura M., Yerges Armstrong, Tatijana, Zemunik, Lina, Zgaga, M., Carola Zilliken, Marek, Zygmunt, The LifeLines Cohort, Study, Alice M., Arnold, Dorret I., Boomsma, Julie E., Buring, Laura, Crisponi, Ellen W., Demerath, Vilmundur, Gudnason, Tamara B., Harri, Frank B., Hu, David J., Hunter, Lenore J., Launer, Andres, Metspalu, Grant W., Montgomery, Ben A., Oostra, Paul M., Ridker, Serena, Sanna, David, Schlessinger, Tim D., Spector, Kari, Stefansson, Elizabeth A., Streeten, Unnur, Thorsteinsdottir, Manuela, Uda, André G., Uitterlinden, Cornelia M., van Duijn, Henry, Völzke, Anna, Murray, Joanne M., Murabito, Jenny A., Visser, Kathryn L., Lunetta, Faculteit Medische Wetenschappen/UMCG, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), and Center for Liver, Digestive and Metabolic Diseases (CLDM)
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Netherlands Twin Register (NTR) ,Candidate gene ,Menopause ,dna repair ,DNA Repair ,PROTEIN ,Genome-wide association study ,DNA-Directed DNA Polymerase ,medicine.disease_cause ,Bioinformatics ,DISEASE ,PREMATURE OVARIAN FAILURE ,0302 clinical medicine ,NATURAL MENOPAUSE ,MUTATION ,GENE-EXPRESSION ,Genetics ,0303 health sciences ,Mutation ,030219 obstetrics & reproductive medicine ,Age Factors ,3. Good health ,Premature ovarian failure ,DNA Polymerase gamma ,menopause ,loci ,genetics ,Female ,DNA repair ,DNA Primase ,Biology ,Polymorphism, Single Nucleotide ,White People ,Article ,03 medical and health sciences ,FOLLICLE-STIMULATING-HORMONEPREMATURE OVARIAN FAILUREGENOME-WIDE ASSOCIATIONGENE-EXPRESSIONONSETPOLYMORPHISMSMUTATIONHERITABILITYCHROMOSOMEMENARCHE ,medicine ,Humans ,GENOME-WIDE ASSOCIATION ,Gene ,POLYMORPHISMS ,030304 developmental biology ,Genetic association ,DNA Helicases ,Immunity ,Proteins ,medicine.disease ,FOLLICLE-STIMULATING-HORMONE ,DNA Repair Enzymes ,Exodeoxyribonucleases ,Genetic Loci ,ONSET ,Genome-Wide Association Study - Abstract
To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 - 10 g8). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-I °B signaling and mitochondrial dysfunction as biological processes related to timing of menopause. © 2012 Nature America, Inc. All rights reserved.
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- 2012
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45. Genome-wide association study of susceptibility loci for breast cancer in Sardinian population
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Mario Lovicu, Maria Teresa Ionta, Antonio Cossu, Magdalena Zoledziewska, Gonçalo R. Abecasis, Francesco Tanda, Francesco Atzori, Manuela Uda, Robert N. Hoover, Serena Sanna, Nazario Olla, Grazia Palomba, Sandra Lai, David Schlessinger, Laura Crisponi, Stephen J. Chanock, Mario Budroni, Maristella Pitzalis, Douglas F. Easton, N. Olmeo, Eleonora Porcu, Marina Pisano, Gianmauro Cuccuru, David J. Hunter, Giuseppe Palmieri, Ilenia Zara, Antonella Mulas, Mariano Dei, Angela Loi, and Kyriaki Michailidou
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Cancer Research ,Genome-wide association study ,Population ,Genes, BRCA2 ,Genes, BRCA1 ,Single-nucleotide polymorphism ,Breast Neoplasms ,Penetrance ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Genotype ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Sardinian population ,International HapMap Project ,Receptor, Fibroblast Growth Factor, Type 2 ,BRCA1/2 mutation analysis ,education ,030304 developmental biology ,0303 health sciences ,education.field_of_study ,business.industry ,High Mobility Group Proteins ,medicine.disease ,3. Good health ,Oncology ,TOX3 ,Italy ,Genetic Loci ,030220 oncology & carcinogenesis ,Case-Control Studies ,Trans-Activators ,Female ,business ,Apoptosis Regulatory Proteins ,Receptors, Progesterone ,Breast cancer risk ,Research Article - Abstract
Background Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles. Methods We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs. Results Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p
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- 2014
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46. Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty
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Toos Van Beijsterveldt, Nicholas Schork, Ruth Loos, Eleftheria Zeggini, LAURA CRISPONI, Valur Emilsson, Nicole Soranzo, Ozren Polasek, Elisabeth Thiering, Elina Hypponen, Andrew Hattersley, Craig Pennell, Alexandra Lewin, ANGELO SCUTERI, Adamo Pio D'Adamo, Antje Körner, Peter Kraft, Thor Aspelund, Timo Lakka, Johannes Kettunen, Mara Marongiu, Christel Middeldorp, Mika Kähönen, Lachlan Coin, Alina Rodriguez, Terho Lehtimäki, Kalliope Panoutsopoulou, Carol Wang, Kathryn Lunetta, George Davey Smith, Debbie A Lawlor, Jianjun Liu, Nicholas Timpson, Xavier Estivill, Tuomas Kilpeläinen, Thomas Price, Mariona Bustamante, Evangelia Stergiakouli, Struan Grant, Gerard Waeber, Lyle John Palmer, Paolo Gasparini, Katja Pahkala, André Scherag, John Holloway, Carmen Iñiguez, Paul Elliott, Albert Vernon Smith, MANUELA UDA, Harri Niinikoski, Oliver Davis, Mads Melbye, Ida Surakka, Frank Geller, Rick Jansen, Mark McCarthy, Cecilia Lindgren, Hilleke Evertje Hulshoff Pol, Nicole Warrington, Ellen Demerath, ReproGen Consortium, Early Growth Genetics (EGG) Consortium, Cousminer, Diana L, Stergiakouli, Evangelia, Berry, Diane J, Ang, Wei, Hyppönen, Elina, Widen, Elisabeth, Biological Psychology, EMGO+ - Mental Health, Internal Medicine, Epidemiology, Obstetrics & Gynecology, Hebebrand, Johannes (Beitragende*r), Hinney, Anke (Beitragende*r), Psychiatry, and EMGO - Mental health
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Male ,Netherlands Twin Register (NTR) ,puberty ,Medizin ,Body Mass Index ,0302 clinical medicine ,Sexual maturity ,Breast ,Sexual Maturation ,Child ,Genetics (clinical) ,Adiposity ,2. Zero hunger ,0303 health sciences ,Genome ,Articles ,General Medicine ,Menarche ,Female ,medicine.medical_specialty ,Adolescent ,Genotype ,males ,030209 endocrinology & metabolism ,Genitalia, Male ,Biology ,Polymorphism, Single Nucleotide ,White People ,03 medical and health sciences ,Sex Factors ,SDG 3 - Good Health and Well-being ,Internal medicine ,Genetics ,medicine ,Humans ,Sex organ ,Allele ,Molecular Biology ,Tanner scale ,030304 developmental biology ,Breast development ,maturation ,ta1184 ,Puberty ,ta3121 ,medicine.disease ,Obesity ,body mass ,Endocrinology ,Genetic Loci ,Body mass index ,Chromosomes, Human, Pair 16 ,Genome-Wide Association Study ,Transcription Factors - Abstract
Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11 000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) (P = 8.9 × 10(-9)), a menarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P = 4.6 × 10(-5)) and short adult stature (p = 7.5 × 10(-6)) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes. Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, body mass index (BMI)-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.
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- 2014
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47. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome
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Manila Deiana, Francesca Chiappe, Annie Nivelon, Luigi Bisceglia, Giuseppe Pilia, Lienhardt-Roussie A, Ramaiah Nagaraja, Laura Crisponi, M Nicolino, Antonio Cao, Ristaldi Ms, Paolo Gasparini, Loi A, R. Marzella, Mariano Rocchi, Patrizia Amati, Leopoldo Zelante, David Schlessinger, Alain Verloes, Manuela Uda, S. Porcu, and Dominique Bonneau
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Adult ,Forkhead Box Protein L2 ,Male ,Female sex determination ,Molecular Sequence Data ,Blepharophimosis ,Winged Helix ,Biology ,FOXL2 Gene ,Mice ,Forkhead Transcription Factors ,Ptosis ,Chromosome Segregation ,Gene Duplication ,Nose Diseases ,Genetics ,medicine ,Animals ,Blepharoptosis ,Humans ,Abnormalities, Multiple ,Amino Acid Sequence ,Child ,Base Sequence ,Sequence Homology, Amino Acid ,Ovary ,Eyelids ,Syndrome ,medicine.disease ,Pedigree ,DNA-Binding Proteins ,Proton-Translocating ATPases ,Forkhead box L2 ,Codon, Nonsense ,Mutation ,Eyelid Diseases ,Female ,Chromosomes, Human, Pair 3 ,medicine.symptom ,Transcription Factor Gene ,Transcription Factors - Abstract
In type I blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), eyelid abnormalities are associated with ovarian failure. Type II BPES shows only the eyelid defects, but both types map to chromosome 3q23. We have positionally cloned a novel, putative winged helix/forkhead transcription factor gene, FOXL2, that is mutated to produce truncated proteins in type I families and larger proteins in type II. Consistent with an involvement in those tissues, FOXL2 is selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appears predominantly in the ovary. FOXL2 represents a candidate gene for the polled/intersex syndrome XX sex-reversal goat.
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- 2001
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48. Amelioration of Sardinian 0 thalassemia by genetic modifiers
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Lucia Perseu, Antonio Cao, Maria Carla Sollaino, Gonçalo R. Abecasis, Susanna Barella, Renzo Galanello, Maria Eliana Lai, Serena Sanna, Manuela Uda, Stefania Satta, and Gianluca Usala
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Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,Thalassemia ,Quantitative Trait Loci ,Immunology ,Single-nucleotide polymorphism ,Alpha-thalassemia ,Biology ,Polymorphism, Single Nucleotide ,Biochemistry ,Proto-Oncogene Proteins c-myb ,Red Cells, Iron, and Erythropoiesis ,alpha-Thalassemia ,hemic and lymphatic diseases ,Fetal hemoglobin ,medicine ,Humans ,Allele ,Alleles ,Fetal Hemoglobin ,Genetics ,Homozygote ,beta-Thalassemia ,Nuclear Proteins ,Beta thalassemia ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Null allele ,Repressor Proteins ,Hemoglobinopathy ,Italy ,Female ,Carrier Proteins - Abstract
Sardinian beta-thalassemia patients all are homozygotes for the same null allele in the beta-globin gene, but the clinical manifestations are extremely variable in severity. Previous studies have shown that the coinheritance of alpha-thalassemia or the presence of genetic variants that sustain fetal hemoglobin production has a strong impact on ameliorating the clinical phenotype. Here we evaluate the contribution of variants in the BCL11A, and HBS1L-MYB genes, implicated in the regulation of fetal hemoglobin, and of alpha-thalassemia coinheritance in 50 thalassemia intermedia and 75 thalassemia major patients. We confirm that alpha-thalassemia and allele C of single nucleotide polymorphism rs-11886868 in BCL11A were selectively represented in thalassemia intermedia patients. Moreover, allele G at single nucleotide polymorphism rs9389268 in the HBS1L-MYB locus was significantly more frequent in the thalassemia intermedia patients. This trio of genetic factors can account for 75% of the variation differences in phenotype severity.
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- 2009
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49. Refining genome-wide linkage intervals using a meta-analysis of genome-wide association studies identifies loci influencing personality dimensions
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A. Cecile J.W. Janssens, Anu Realo, Yurii S. Aulchenko, Nicholas G. Martin, Margaret J. Wright, Ben A. Oostra, Marleen H. M. de Moor, Andres Metspalu, Gonneke Willemsen, Andrew C. Heath, Tõnu Esko, Laura J. Bierut, Katri Räikkönen, Eco J. C. de Geus, Gonçalo R. Abecasis, Toshiko Tanaka, Gu Zhu, Narelle K. Hansell, Grant W. Montgomery, Michelle Luciano, Anatoly V. Kirichenko, Cornelia M. van Duijn, Paul T. Costa, Michele L. Pergadia, Jouke-Jan Hottenga, Aaron Isaacs, Irina V. Zorkoltseva, Ian J. Deary, Brenda W.J.H. Penninx, Pamela A. F. Madden, Tatiana I. Axenovich, Gail Davies, Viatcheslav Saviouk, Manuela Uda, Antonio Terracciano, Dorret I. Boomsma, Sarah E. Medland, Najaf Amin, Luigi Ferrucci, Psychiatry, EMGO - Mental health, Epidemiology, Immunology, Clinical Genetics, Biological Psychology, Clinical Child and Family Studies, and EMGO+ - Mental Health
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Netherlands Twin Register (NTR) ,Candidate gene ,Potassium Channels ,Personality Inventory ,A BEHAVIOR PATTERN ,Genome-wide association study ,Chromosomes, Human, Pair 11/genetics ,LARGE PEDIGREES ,0302 clinical medicine ,NEUROTICISM ,Big Five personality traits ,Genetics (clinical) ,POPULATION ,media_common ,Genetics ,0303 health sciences ,education.field_of_study ,Genome ,Human/genetics ,Inwardly Rectifying/genetics ,Chromosome Mapping ,Single Nucleotide ,ALZHEIMERS-DISEASE ,Phenotype ,Genome-Wide Association Study/methods ,linkage ,TRAITS ,Human ,Agreeableness ,media_common.quotation_subject ,Population ,Locus (genetics) ,Biology ,Polymorphism, Single Nucleotide ,Article ,Chromosomes ,Pair 11/genetics ,03 medical and health sciences ,Personality/genetics ,Personality ,Humans ,KCNJ1 ,Potassium Channels, Inwardly Rectifying ,Polymorphism ,education ,030304 developmental biology ,Genetic association ,GENDER-DIFFERENCES ,Genome, Human ,Chromosomes, Human, Pair 11 ,SEARCH METAANALYSIS ,MAJOR DEPRESSION ,NEO ,COGNITIVE IMPAIRMENT ,personality ,Genome, Human/genetics ,Potassium Channels, Inwardly Rectifying/genetics ,GSMA ,Lod Score ,Chromosome Mapping/methods ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Personality traits are complex phenotypes related to psychosomatic health. Individually, various gene finding methods have not achieved much success in finding genetic variants associated with personality traits. We performed a meta-analysis of four genome-wide linkage scans (N=6149 subjects) of five basic personality traits assessed with the NEO Five-Factor Inventory. We compared the significant regions from the meta-analysis of linkage scans with the results of a meta-analysis of genome-wide association studies (GWAS) (N∼17 000). We found significant evidence of linkage of neuroticism to chromosome 3p14 (rs1490265, LOD=4.67) and to chromosome 19q13 (rs628604, LOD=3.55); of extraversion to 14q32 (ATGG002, LOD=3.3); and of agreeableness to 3p25 (rs709160, LOD=3.67) and to two adjacent regions on chromosome 15, including 15q13 (rs970408, LOD=4.07) and 15q14 (rs1055356, LOD=3.52) in the individual scans. In the meta-analysis, we found strong evidence of linkage of extraversion to 4q34, 9q34, 10q24 and 11q22, openness to 2p25, 3q26, 9p21, 11q24, 15q26 and 19q13 and agreeableness to 4q34 and 19p13. Significant evidence of association in the GWAS was detected between openness and rs677035 at 11q24 (P-value=2.6 × 10 -06, KCNJ1). The findings of our linkage meta-analysis and those of the GWAS suggest that 11q24 is a susceptible locus for openness, with KCNJ1 as the possible candidate gene. © 2013 Macmillan Publishers Limited. All rights reserved.
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- 2013
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50. A common biological basis of obesity and nicotine addiction
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Peter Kovacs, Angela Döring, Frank Geller, Lenka Foretova, Dana Mates, Paul M. Ridker, Francesco Mauri, Mark J. Caulfield, Nora Franceschini, Neonilia Szeszenia-Dabrowska, Toshiko Tanaka, Pagona Lagiou, Jennifer E. Huffman, Paul Scheet, Gudmar Thorleifsson, Jacqueline M. Vink, Nicole Vogelzangs, Ida Surakka, Jeffrey R. Gulcher, Ulrich John, Veikko Salomaa, Eco J. C. de Geus, Hakon Hakonarson, Anne Barton, Luigi Barzan, H.-Erich Wichmann, Anneli Pouta, Peter Vollenweider, Kristina Kjærheim, Jed E. Rose, Ruth J. F. Loos, Susanne Lucae, Danielle Posthuma, Henning Tiemeier, Fangyi Gu, Mark I. McCarthy, Unnur Styrkarsdottir, James McKay, Talin Haritunians, Martin Preisig, Olle Melander, Xavier Castellsagué, William H. Matthai, Piera Angelica Merlini, Daniel I. Chasman, Michael Stumvoll, Ozren Polasek, Nilesh J. Samani, Søren Besenbacher, Jane Worthington, Daniel F. Gudbjartsson, Alistair S. Hall, Antonio Agudo, Keith Matthews, Gonçalo R. Abecasis, Jaana Laitinen, Norbert Dahmen, Robert W. Mahley, Mari Nelis, Inga Prokopenko, Anke Tönjes, Iris H Gudjonsdottir, Joshua W. Knowles, Jing Hua Zhao, Jouke-Jan Hottenga, Vincent Mooser, Jack Satsangi, Cristina Canova, Stephen P. Fortmann, Hreinn Stefansson, Manuela Uda, T. Brueckl, Mary Susan Burnett, Michael Boehnke, Veronique Vitart, Philip J. Barter, Ruth McPherson, Benjamin F. Voight, Patrick F. Sullivan, Pier Mannuccio Mannucci, Michael Wittig, Kari Stefansson, Lowell F. Satler, Eric Boerwinkle, Benjamin J. Wright, Ben A. Oostra, John Strauss, Stefania Bandinelli, S. Horstmann, Jonathan Marchini, Simone Benhamou, Stephen E. Epstein, Rajesh Rawal, Vladimir Janout, Miles Parkes, Liming Qu, Yuri Milaneschi, Peter Almgren, Kaisu Keskitalo, Matti Isohanni, Dan Rujescu, John P. A. Ioannidis, Peter Rudnai, Stefan Walter, Diego Ardissino, John B. Vincent, Leif Groop, Kent D. Taylor, Christopher J. O'Donnell, Christopher W. Knouff, David I. Conway, Thomas Quertermous, Joseph M. Lindsay, Stephen M. Schwartz, Tariq Ahmed, Jolanta Lissowska, Evan L. Thacker, Igor Rudan, Sreekumar G. Pillai, Janet Audrain-McGovern, Daniel Levy, S. Kathiresan, Timothy M. Frayling, Brenda W.J.H. Penninx, Shen Huei-Yi, Johannes H. Smit, Gonneke Willemsen, Henry Völzke, John R. B. Perry, Federica Tozzi, Roberto Elosua, Devin Absher, G B Walters, Augusto D. Pichard, Stephen J. Chanock, Katja K.H. Aben, Anna-Liisa Hartikainen, Maria Krestyaninova, Ivana Holcatova, Tim D. Spector, Ming D. Li, Xiangjun Xiao, Barbara McKnight, Hans J. Grabe, Martin den Heijer, Caroline Hayward, Unnur Thorsteinsdottir, Douglas F. Levinson, Claes Ladenvall, Robert L. Wilensky, Danyu Lin, Nicole Soranzo, Lefkos T. Middleton, Jason S. Liu, Wade H. Berrettini, Laura M. Thornton, Muredach P. Reilly, Jack M. Guralnik, Ron Waksman, Per Bakke, Alan F. Wright, Andre Franke, Thorgeir E. Thorgeirsson, Barbara Nitz, Anthony J. Balmforth, Jaspal S. Kooner, Gavin Lucas, Esther H. Lips, Helena Furberg, Albert Hofman, Patrick Sulem, Astrid Petersmann, Ivana Kolcic, Jaakko Tuomilehto, Lorenzo Richiardi, Pablo V. Gejman, Claire J. Steves, Thorarinn Tyrfingsson, Yurii S. Aulchenko, Brendan M. Everett, Ariana Znaor, Maxine Allen, Thorunn Rafnar, Mark Lathrop, Reedik Mägi, Kenneth M. Kent, M. Perola, Nicholas J. Wareham, Daniel J. Rader, John R. Thompson, Sarah R. Preis, Peter Kraft, Caryn Lerman, Hogni Oskarsson, Alan R. Sanders, Alexander Teumer, Xin Yuan, Cornelia M. van Duijn, Samuli Ripatti, André G. Uitterlinden, Carl A. Anderson, Martin Farrall, Kay-Tee Khaw, Joachim Heinrich, Heather M. Stringham, Bruce M. Psaty, Jaakko Kaprio, Valgerdur Steinthorsdottir, Steve Eyre, James F. Wilson, David J. Hunter, Johannes Kettunen, Wendy Thomson, Antero Kesäniemi, Karen L. Mohlke, Christian Gieger, Tatiana V. Macfarlane, Jubao Duan, Anne Farmer, Clyde Francks, Joshua C. Bis, Harry Campbell, Pierandrea Muglia, Andres Metspalu, Dawn M. Waterworth, Ramachandran S. Vasan, Hermine H. Maes, David Zaridze, Luisa Bernardinelli, Vladimir Bencko, Massimo Mangino, Lambertus A. Kiemeney, Solveig Gretarsdottir, Tõnu Esko, Anne U. Jackson, Claire M. Healy, Scott M. Grundy, David St Clair, Curt D. Furberg, Mingyao Li, Peter McGuffin, Christopher G. Mathew, David Altshuler, Dorret I. Boomsma, Susan Campbell, Jianxin Shi, Najaf Amin, James L. Kennedy, Ana M. Valdes, Anna F. Dominiczak, Themistocles L. Assimes, Susan E. Hankinson, Inês Barroso, Marjo-Riitta Järvelin, Guillaume Paré, Joe Devaney, Antonio Terracciano, David Schlessinger, Paul Brennan, Shih-Jen Hwang, Luigi Ferrucci, Ray Lowry, Jennifer Dackor, Eleonora Fabianova, Lina Zgaga, Emelia J. Benjamin, Fabio Busonero, Sarah H. Wild, Patricia B. Munroe, John C. Chambers, Carlos Iribarren, Marcus Ising, Yunjung Kim, Richard O. Day, Amund Gulsvik, Gérard Waeber, Claudia Lamina, Arne Schäfer, Functional Genomics, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Hjelt Institute (-2014), Department of Public Health, Institute for Molecular Medicine Finland, Genetic Epidemiology, Human genetics, and NCA - Neurobiology of mental health
- Subjects
obesity ,FOOD-INTAKE ,TAG Consortium ,medicine.medical_treatment ,Oxford-GSK Consortium ,LOCI ,Iceland ,Aetiology, screening and detection [ONCOL 5] ,VARIANTS ,3124 Neurology and psychiatry ,Nicotine ,0302 clinical medicine ,DEPENDENCE ,030212 general & internal medicine ,Age of Onset ,ENGAGE consortium ,POPULATION ,Addiction ,Body Mass Index ,Nicotine dependence ,Smoking ,media_common ,Psychiatry ,2. Zero hunger ,0303 health sciences ,education.field_of_study ,ASSOCIATION ,Tobacco Use Disorder ,DSM-V ,CANCER ,3142 Public health care science, environmental and occupational health ,3. Good health ,Psychiatry and Mental health ,Meta-analysis ,Original Article ,addiction ,Life Sciences & Biomedicine ,medicine.drug ,medicine.medical_specialty ,media_common.quotation_subject ,Population ,body mass index ,Polymorphism, Single Nucleotide ,smoking ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,SDG 3 - Good Health and Well-being ,Internal medicine ,medicine ,Humans ,SMOKING-BEHAVIOR ,nicotine dependence ,education ,Biological Psychiatry ,Molecular epidemiology Aetiology, screening and detection [NCEBP 1] ,030304 developmental biology ,Science & Technology ,business.industry ,Appetite ,medicine.disease ,Obesity ,BODY-MASS INDEX ,Behavior, Addictive ,Endocrinology ,Smoking cessation ,business ,Body mass index - Abstract
Contains fulltext : 128630.pdf (Publisher’s version ) (Open Access) Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34,216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 x 10(-7)). These findings replicate in a second large data set (N=127,274, thereof 76,242 smokers) for both SI (P=1.2 x 10(-5)) and CPD (P=9.3 x 10(-5)). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.
- Published
- 2013
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