271 results on '"Jaspal S Kooner"'
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2. Associations of autozygosity with a broad range of human phenotypes
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David W Clark, Yukinori Okada, Kristjan H S Moore, Dan Mason, Nicola Pirastu, Ilaria Gandin, Hannele Mattsson, Catriona L K Barnes, Kuang Lin, Jing Hua Zhao, Patrick Deelen, Rebecca Rohde, Claudia Schurmann, Xiuqing Guo, Franco Giulianini, Weihua Zhang, Carolina Medina-Gomez, Robert Karlsson, Yanchun Bao, Traci M Bartz, Clemens Baumbach, Ginevra Biino, Matthew J Bixley, Marco Brumat, Jin-Fang Chai, Tanguy Corre, Diana L Cousminer, Annelot M Dekker, David A Eccles, Kristel R van Eijk, Christian Fuchsberger, He Gao, Marine Germain, Scott D Gordon, Hugoline G de Haan, Sarah E Harris, Edith Hofer, Alicia Huerta-Chagoya, Catherine Igartua, Iris E Jansen, Yucheng Jia, Tim Kacprowski, Torgny Karlsson, Marcus E Kleber, Shengchao Alfred Li, Ruifang Li-Gao, Anubha Mahajan, Koichi Matsuda, Karina Meidtner, Weihua Meng, May E Montasser, Peter J van der Most, Matthias Munz, Teresa Nutile, Teemu Palviainen, Gauri Prasad, Rashmi B Prasad, Tallapragada Divya Sri Priyanka, Federica Rizzi, Erika Salvi, Bishwa R Sapkota, Daniel Shriner, Line Skotte, Melissa C Smart, Albert Vernon Smith, Ashley van der Spek, Cassandra N Spracklen, Rona J Strawbridge, Salman M Tajuddin, Stella Trompet, Constance Turman, Niek Verweij, Clara Viberti, Lihua Wang, Helen R Warren, Robyn E Wootton, Lisa R Yanek, Jie Yao, Noha A Yousri, Wei Zhao, Adebowale A Adeyemo, Saima Afaq, Carlos Alberto Aguilar-Salinas, Masato Akiyama, Matthew L Albert, Matthew A Allison, Maris Alver, Tin Aung, Fereidoun Azizi, Amy R Bentley, Heiner Boeing, Eric Boerwinkle, Judith B Borja, Gert J de Borst, Erwin P Bottinger, Linda Broer, Harry Campbell, Stephen Chanock, Miao-Li Chee, Guanjie Chen, Yii-Der I Chen, Zhengming Chen, Yen-Feng Chiu, Massimiliano Cocca, Francis S Collins, Maria Pina Concas, Janie Corley, Giovanni Cugliari, Rob M van Dam, Anna Damulina, Maryam S Daneshpour, Felix R Day, Graciela E Delgado, Klodian Dhana, Alexander S F Doney, Marcus Dörr, Ayo P Doumatey, Nduna Dzimiri, S Sunna Ebenesersdóttir, Joshua Elliott, Paul Elliott, Ralf Ewert, Janine F Felix, Krista Fischer, Barry I Freedman, Giorgia Girotto, Anuj Goel, Martin Gögele, Mark O Goodarzi, Mariaelisa Graff, Einat Granot-Hershkovitz, Francine Grodstein, Simonetta Guarrera, Daniel F Gudbjartsson, Kamran Guity, Bjarni Gunnarsson, Yu Guo, Saskia P Hagenaars, Christopher A Haiman, Avner Halevy, Tamara B Harris, Mehdi Hedayati, David A van Heel, Makoto Hirata, Imo Höfer, Chao Agnes Hsiung, Jinyan Huang, Yi-Jen Hung, M Arfan Ikram, Anuradha Jagadeesan, Pekka Jousilahti, Yoichiro Kamatani, Masahiro Kanai, Nicola D Kerrison, Thorsten Kessler, Kay-Tee Khaw, Chiea Chuen Khor, Dominique P V de Kleijn, Woon-Puay Koh, Ivana Kolcic, Peter Kraft, Bernhard K Krämer, Zoltán Kutalik, Johanna Kuusisto, Claudia Langenberg, Lenore J Launer, Deborah A Lawlor, I-Te Lee, Wen-Jane Lee, Markus M Lerch, Liming Li, Jianjun Liu, Marie Loh, Stephanie J London, Stephanie Loomis, Yingchang Lu, Jian’an Luan, Reedik Mägi, Ani W Manichaikul, Paolo Manunta, Gísli Másson, Nana Matoba, Xue W Mei, Christa Meisinger, Thomas Meitinger, Massimo Mezzavilla, Lili Milani, Iona Y Millwood, Yukihide Momozawa, Amy Moore, Pierre-Emmanuel Morange, Hortensia Moreno-Macías, Trevor A Mori, Alanna C Morrison, Taulant Muka, Yoshinori Murakami, Alison D Murray, Renée de Mutsert, Josyf C Mychaleckyj, Mike A Nalls, Matthias Nauck, Matt J Neville, Ilja M Nolte, Ken K Ong, Lorena Orozco, Sandosh Padmanabhan, Gunnar Pálsson, James S Pankow, Cristian Pattaro, Alison Pattie, Ozren Polasek, Neil Poulter, Peter P Pramstaller, Lluis Quintana-Murci, Katri Räikkönen, Sarju Ralhan, Dabeeru C Rao, Wouter van Rheenen, Stephen S Rich, Paul M Ridker, Cornelius A Rietveld, Antonietta Robino, Frank J A van Rooij, Daniela Ruggiero, Yasaman Saba, Charumathi Sabanayagam, Maria Sabater-Lleal, Cinzia Felicita Sala, Veikko Salomaa, Kevin Sandow, Helena Schmidt, Laura J Scott, William R Scott, Bahareh Sedaghati-Khayat, Bengt Sennblad, Jessica van Setten, Peter J Sever, Wayne H-H Sheu, Yuan Shi, Smeeta Shrestha, Sharvari Rahul Shukla, Jon K Sigurdsson, Timo Tonis Sikka, Jai Rup Singh, Blair H Smith, Alena Stančáková, Alice Stanton, John M Starr, Lilja Stefansdottir, Leon Straker, Patrick Sulem, Gardar Sveinbjornsson, Morris A Swertz, Adele M Taylor, Kent D Taylor, Natalie Terzikhan, Yih-Chung Tham, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Annika Tillander, Russell P Tracy, Teresa Tusié-Luna, Ioanna Tzoulaki, Simona Vaccargiu, Jagadish Vangipurapu, Jan H Veldink, Veronique Vitart, Uwe Völker, Eero Vuoksimaa, Salma M Wakil, Melanie Waldenberger, Gurpreet S Wander, Ya Xing Wang, Nicholas J Wareham, Sarah Wild, Chittaranjan S Yajnik, Jian-Min Yuan, Lingyao Zeng, Liang Zhang, Jie Zhou, Najaf Amin, Folkert W Asselbergs, Stephan J L Bakker, Diane M Becker, Benjamin Lehne, David A Bennett, Leonard H van den Berg, Sonja I Berndt, Dwaipayan Bharadwaj, Lawrence F Bielak, Murielle Bochud, Mike Boehnke, Claude Bouchard, Jonathan P Bradfield, Jennifer A Brody, Archie Campbell, Shai Carmi, Mark J Caulfield, David Cesarini, John C Chambers, Giriraj Ratan Chandak, Ching-Yu Cheng, Marina Ciullo, Marilyn Cornelis, Daniele Cusi, George Davey Smith, Ian J Deary, Rajkumar Dorajoo, Cornelia M van Duijn, David Ellinghaus, Jeanette Erdmann, Johan G Eriksson, Evangelos Evangelou, Michele K Evans, Jessica D Faul, Bjarke Feenstra, Mary Feitosa, Sylvain Foisy, Andre Franke, Yechiel Friedlander, Paolo Gasparini, Christian Gieger, Clicerio Gonzalez, Philippe Goyette, Struan F A Grant, Lyn R Griffiths, Leif Groop, Vilmundur Gudnason, Ulf Gyllensten, Hakon Hakonarson, Anders Hamsten, Pim van der Harst, Chew-Kiat Heng, Andrew A Hicks, Hagit Hochner, Heikki Huikuri, Steven C Hunt, Vincent W V Jaddoe, Philip L De Jager, Magnus Johannesson, Åsa Johansson, Jost B Jonas, J Wouter Jukema, Juhani Junttila, Jaakko Kaprio, Sharon L. R. Kardia, Fredrik Karpe, Meena Kumari, Markku Laakso, Sander W van der Laan, Jari Lahti, Matthias Laudes, Rodney A Lea, Wolfgang Lieb, Thomas Lumley, Nicholas G Martin, Winfried März, Giuseppe Matullo, Mark I McCarthy, Sarah E Medland, Tony R Merriman, Andres Metspalu, Brian F Meyer, Karen L Mohlke, Grant W Montgomery, Dennis Mook-Kanamori, Patricia B Munroe, Kari E North, Dale R Nyholt, Jeffery R O’connell, Carole Ober, Albertine J Oldehinkel, Walter Palmas, Colin Palmer, Gerard G Pasterkamp, Etienne Patin, Craig E Pennell, Louis Perusse, Patricia A Peyser, Mario Pirastu, Tinca J. C. Polderman, David J Porteous, Danielle Posthuma, Bruce M Psaty, John D Rioux, Fernando Rivadeneira, Charles Rotimi, Jerome I Rotter, Igor Rudan, Hester M Den Ruijter, Dharambir K Sanghera, Naveed Sattar, Reinhold Schmidt, Matthias B Schulze, Heribert Schunkert, Robert A Scott, Alan R Shuldiner, Xueling Sim, Neil Small, Jennifer A Smith, Nona Sotoodehnia, E-Shyong Tai, Alexander Teumer, Nicholas J Timpson, Daniela Toniolo, David-Alexandre Tregouet, Tiinamaija Tuomi, Peter Vollenweider, Carol A Wang, David R Weir, John B Whitfield, Cisca Wijmenga, Tien-Yin Wong, John Wright, Jingyun Yang, Lei Yu, Babette S Zemel, Alan B Zonderman, Markus Perola, Patrik K. E. Magnusson, André G Uitterlinden, Jaspal S Kooner, Daniel I Chasman, Ruth J. F. Loos, Nora Franceschini, Lude Franke, Chris S Haley, Caroline Hayward, Robin G Walters, John R. B. Perry, Tōnu Esko, Agnar Helgason, Kari Stefansson, Peter K Joshi, Michiaki Kubo, and James F Wilson
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Science - Abstract
Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.
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- 2019
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3. Contribution of lower physical activity levels to higher risk of insulin resistance and associated metabolic disturbances in South Asians compared to Europeans.
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Saima Afaq, Angad S Kooner, Marie Loh, Jaspal S Kooner, and John C Chambers
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Medicine ,Science - Abstract
BackgroundInsulin resistance and related metabolic disturbances are major risk factors for the higher T2D risk and associated morbidity and mortality amongst South Asians. The contribution of physical activity to the increased prevalence of insulin resistance and related disturbances amongst South Asians is unknown.MethodsWe recruited 902 South Asian and European men and women, aged 35-85 years from the ongoing LOLIPOP study. Clinical characterisation comprised standardised questionnaire and measurement of height, weight, waist and hip circumference and blood pressure. Fasting bloods were taken for assessment of glucose, insulin, lipids and HbA1c. Physical activity was quantified using a validated accelerometer, Actigraph GT3X+, worn for 7 days. Univariate and multivariate approaches were used to investigate the relationship between ethnicity, physical activity, insulin resistance and related metabolic disturbances.ResultsTotal physical activity was ~31% (P = 0.01) lower amongst South Asians compared to Europeans (Mean MET.minutes [SD]: 1505.2 [52] vs. 2050.9 [86.6], PConclusionLower levels of physical activity may contribute to the increased insulin resistance in South Asians compared to Europeans. Our results suggest that lifestyle modification through increased physical activity may help to improve glucose metabolism and reduce the burden of excess T2D and related complications amongst South Asians.
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- 2019
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4. Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.
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Mary F Feitosa, Aldi T Kraja, Daniel I Chasman, Yun J Sung, Thomas W Winkler, Ioanna Ntalla, Xiuqing Guo, Nora Franceschini, Ching-Yu Cheng, Xueling Sim, Dina Vojinovic, Jonathan Marten, Solomon K Musani, Changwei Li, Amy R Bentley, Michael R Brown, Karen Schwander, Melissa A Richard, Raymond Noordam, Hugues Aschard, Traci M Bartz, Lawrence F Bielak, Rajkumar Dorajoo, Virginia Fisher, Fernando P Hartwig, Andrea R V R Horimoto, Kurt K Lohman, Alisa K Manning, Tuomo Rankinen, Albert V Smith, Salman M Tajuddin, Mary K Wojczynski, Maris Alver, Mathilde Boissel, Qiuyin Cai, Archie Campbell, Jin Fang Chai, Xu Chen, Jasmin Divers, Chuan Gao, Anuj Goel, Yanick Hagemeijer, Sarah E Harris, Meian He, Fang-Chi Hsu, Anne U Jackson, Mika Kähönen, Anuradhani Kasturiratne, Pirjo Komulainen, Brigitte Kühnel, Federica Laguzzi, Jian'an Luan, Nana Matoba, Ilja M Nolte, Sandosh Padmanabhan, Muhammad Riaz, Rico Rueedi, Antonietta Robino, M Abdullah Said, Robert A Scott, Tamar Sofer, Alena Stančáková, Fumihiko Takeuchi, Bamidele O Tayo, Peter J van der Most, Tibor V Varga, Veronique Vitart, Yajuan Wang, Erin B Ware, Helen R Warren, Stefan Weiss, Wanqing Wen, Lisa R Yanek, Weihua Zhang, Jing Hua Zhao, Saima Afaq, Najaf Amin, Marzyeh Amini, Dan E Arking, Tin Aung, Eric Boerwinkle, Ingrid Borecki, Ulrich Broeckel, Morris Brown, Marco Brumat, Gregory L Burke, Mickaël Canouil, Aravinda Chakravarti, Sabanayagam Charumathi, Yii-Der Ida Chen, John M Connell, Adolfo Correa, Lisa de Las Fuentes, Renée de Mutsert, H Janaka de Silva, Xuan Deng, Jingzhong Ding, Qing Duan, Charles B Eaton, Georg Ehret, Ruben N Eppinga, Evangelos Evangelou, Jessica D Faul, Stephan B Felix, Nita G Forouhi, Terrence Forrester, Oscar H Franco, Yechiel Friedlander, Ilaria Gandin, He Gao, Mohsen Ghanbari, Bruna Gigante, C Charles Gu, Dongfeng Gu, Saskia P Hagenaars, Göran Hallmans, Tamara B Harris, Jiang He, Sami Heikkinen, Chew-Kiat Heng, Makoto Hirata, Barbara V Howard, M Arfan Ikram, InterAct Consortium, Ulrich John, Tomohiro Katsuya, Chiea Chuen Khor, Tuomas O Kilpeläinen, Woon-Puay Koh, José E Krieger, Stephen B Kritchevsky, Michiaki Kubo, Johanna Kuusisto, Timo A Lakka, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Benjamin Lehne, Cora E Lewis, Yize Li, Shiow Lin, Jianjun Liu, Jingmin Liu, Marie Loh, Tin Louie, Reedik Mägi, Colin A McKenzie, Thomas Meitinger, Andres Metspalu, Yuri Milaneschi, Lili Milani, Karen L Mohlke, Yukihide Momozawa, Mike A Nalls, Christopher P Nelson, Nona Sotoodehnia, Jill M Norris, Jeff R O'Connell, Nicholette D Palmer, Thomas Perls, Nancy L Pedersen, Annette Peters, Patricia A Peyser, Neil Poulter, Leslie J Raffel, Olli T Raitakari, Kathryn Roll, Lynda M Rose, Frits R Rosendaal, Jerome I Rotter, Carsten O Schmidt, Pamela J Schreiner, Nicole Schupf, William R Scott, Peter S Sever, Yuan Shi, Stephen Sidney, Mario Sims, Colleen M Sitlani, Jennifer A Smith, Harold Snieder, John M Starr, Konstantin Strauch, Heather M Stringham, Nicholas Y Q Tan, Hua Tang, Kent D Taylor, Yik Ying Teo, Yih Chung Tham, Stephen T Turner, André G Uitterlinden, Peter Vollenweider, Melanie Waldenberger, Lihua Wang, Ya Xing Wang, Wen Bin Wei, Christine Williams, Jie Yao, Caizheng Yu, Jian-Min Yuan, Wei Zhao, Alan B Zonderman, Diane M Becker, Michael Boehnke, Donald W Bowden, John C Chambers, Ian J Deary, Tõnu Esko, Martin Farrall, Paul W Franks, Barry I Freedman, Philippe Froguel, Paolo Gasparini, Christian Gieger, Jost Bruno Jonas, Yoichiro Kamatani, Norihiro Kato, Jaspal S Kooner, Zoltán Kutalik, Markku Laakso, Cathy C Laurie, Karin Leander, Terho Lehtimäki, Lifelines Cohort Study, Patrik K E Magnusson, Albertine J Oldehinkel, Brenda W J H Penninx, Ozren Polasek, David J Porteous, Rainer Rauramaa, Nilesh J Samani, James Scott, Xiao-Ou Shu, Pim van der Harst, Lynne E Wagenknecht, Nicholas J Wareham, Hugh Watkins, David R Weir, Ananda R Wickremasinghe, Tangchun Wu, Wei Zheng, Claude Bouchard, Kaare Christensen, Michele K Evans, Vilmundur Gudnason, Bernardo L Horta, Sharon L R Kardia, Yongmei Liu, Alexandre C Pereira, Bruce M Psaty, Paul M Ridker, Rob M van Dam, W James Gauderman, Xiaofeng Zhu, Dennis O Mook-Kanamori, Myriam Fornage, Charles N Rotimi, L Adrienne Cupples, Tanika N Kelly, Ervin R Fox, Caroline Hayward, Cornelia M van Duijn, E Shyong Tai, Tien Yin Wong, Charles Kooperberg, Walter Palmas, Kenneth Rice, Alanna C Morrison, Paul Elliott, Mark J Caulfield, Patricia B Munroe, Dabeeru C Rao, Michael A Province, and Daniel Levy
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Medicine ,Science - Abstract
Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
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- 2018
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5. Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.
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Eleanor Wheeler, Aaron Leong, Ching-Ti Liu, Marie-France Hivert, Rona J Strawbridge, Clara Podmore, Man Li, Jie Yao, Xueling Sim, Jaeyoung Hong, Audrey Y Chu, Weihua Zhang, Xu Wang, Peng Chen, Nisa M Maruthur, Bianca C Porneala, Stephen J Sharp, Yucheng Jia, Edmond K Kabagambe, Li-Ching Chang, Wei-Min Chen, Cathy E Elks, Daniel S Evans, Qiao Fan, Franco Giulianini, Min Jin Go, Jouke-Jan Hottenga, Yao Hu, Anne U Jackson, Stavroula Kanoni, Young Jin Kim, Marcus E Kleber, Claes Ladenvall, Cecile Lecoeur, Sing-Hui Lim, Yingchang Lu, Anubha Mahajan, Carola Marzi, Mike A Nalls, Pau Navarro, Ilja M Nolte, Lynda M Rose, Denis V Rybin, Serena Sanna, Yuan Shi, Daniel O Stram, Fumihiko Takeuchi, Shu Pei Tan, Peter J van der Most, Jana V Van Vliet-Ostaptchouk, Andrew Wong, Loic Yengo, Wanting Zhao, Anuj Goel, Maria Teresa Martinez Larrad, Dörte Radke, Perttu Salo, Toshiko Tanaka, Erik P A van Iperen, Goncalo Abecasis, Saima Afaq, Behrooz Z Alizadeh, Alain G Bertoni, Amelie Bonnefond, Yvonne Böttcher, Erwin P Bottinger, Harry Campbell, Olga D Carlson, Chien-Hsiun Chen, Yoon Shin Cho, W Timothy Garvey, Christian Gieger, Mark O Goodarzi, Harald Grallert, Anders Hamsten, Catharina A Hartman, Christian Herder, Chao Agnes Hsiung, Jie Huang, Michiya Igase, Masato Isono, Tomohiro Katsuya, Chiea-Chuen Khor, Wieland Kiess, Katsuhiko Kohara, Peter Kovacs, Juyoung Lee, Wen-Jane Lee, Benjamin Lehne, Huaixing Li, Jianjun Liu, Stephane Lobbens, Jian'an Luan, Valeriya Lyssenko, Thomas Meitinger, Tetsuro Miki, Iva Miljkovic, Sanghoon Moon, Antonella Mulas, Gabriele Müller, Martina Müller-Nurasyid, Ramaiah Nagaraja, Matthias Nauck, James S Pankow, Ozren Polasek, Inga Prokopenko, Paula S Ramos, Laura Rasmussen-Torvik, Wolfgang Rathmann, Stephen S Rich, Neil R Robertson, Michael Roden, Ronan Roussel, Igor Rudan, Robert A Scott, William R Scott, Bengt Sennblad, David S Siscovick, Konstantin Strauch, Liang Sun, Morris Swertz, Salman M Tajuddin, Kent D Taylor, Yik-Ying Teo, Yih Chung Tham, Anke Tönjes, Nicholas J Wareham, Gonneke Willemsen, Tom Wilsgaard, Aroon D Hingorani, EPIC-CVD Consortium, EPIC-InterAct Consortium, Lifelines Cohort Study, Josephine Egan, Luigi Ferrucci, G Kees Hovingh, Antti Jula, Mika Kivimaki, Meena Kumari, Inger Njølstad, Colin N A Palmer, Manuel Serrano Ríos, Michael Stumvoll, Hugh Watkins, Tin Aung, Matthias Blüher, Michael Boehnke, Dorret I Boomsma, Stefan R Bornstein, John C Chambers, Daniel I Chasman, Yii-Der Ida Chen, Yduan-Tsong Chen, Ching-Yu Cheng, Francesco Cucca, Eco J C de Geus, Panos Deloukas, Michele K Evans, Myriam Fornage, Yechiel Friedlander, Philippe Froguel, Leif Groop, Myron D Gross, Tamara B Harris, Caroline Hayward, Chew-Kiat Heng, Erik Ingelsson, Norihiro Kato, Bong-Jo Kim, Woon-Puay Koh, Jaspal S Kooner, Antje Körner, Diana Kuh, Johanna Kuusisto, Markku Laakso, Xu Lin, Yongmei Liu, Ruth J F Loos, Patrik K E Magnusson, Winfried März, Mark I McCarthy, Albertine J Oldehinkel, Ken K Ong, Nancy L Pedersen, Mark A Pereira, Annette Peters, Paul M Ridker, Charumathi Sabanayagam, Michele Sale, Danish Saleheen, Juha Saltevo, Peter Eh Schwarz, Wayne H H Sheu, Harold Snieder, Timothy D Spector, Yasuharu Tabara, Jaakko Tuomilehto, Rob M van Dam, James G Wilson, James F Wilson, Bruce H R Wolffenbuttel, Tien Yin Wong, Jer-Yuarn Wu, Jian-Min Yuan, Alan B Zonderman, Nicole Soranzo, Xiuqing Guo, David J Roberts, Jose C Florez, Robert Sladek, Josée Dupuis, Andrew P Morris, E-Shyong Tai, Elizabeth Selvin, Jerome I Rotter, Claudia Langenberg, Inês Barroso, and James B Meigs
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Medicine - Abstract
BackgroundGlycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.Methods & findingsUsing genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.ConclusionsAs G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
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- 2017
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6. Correction: Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.
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Mariaelisa Graff, Robert A Scott, Anne E Justice, Kristin L Young, Mary F Feitosa, Llilda Barata, Thomas W Winkler, Audrey Y Chu, Anubha Mahajan, David Hadley, Luting Xue, Tsegaselassie Workalemahu, Nancy L Heard-Costa, Marcel den Hoed, Tarunveer S Ahluwalia, Qibin Qi, Julius S Ngwa, Frida Renström, Lydia Quaye, John D Eicher, James E Hayes, Marilyn Cornelis, Zoltan Kutalik, Elise Lim, Jian'an Luan, Jennifer E Huffman, Weihua Zhang, Wei Zhao, Paula J Griffin, Toomas Haller, Shafqat Ahmad, Pedro M Marques-Vidal, Stephanie Bien, Loic Yengo, Alexander Teumer, Albert Vernon Smith, Meena Kumari, Marie Neergaard Harder, Johanne Marie Justesen, Marcus E Kleber, Mette Hollensted, Kurt Lohman, Natalia V Rivera, John B Whitfield, Jing Hua Zhao, Heather M Stringham, Leo-Pekka Lyytikäinen, Charlotte Huppertz, Gonneke Willemsen, Wouter J Peyrot, Ying Wu, Kati Kristiansson, Ayse Demirkan, Myriam Fornage, Maija Hassinen, Lawrence F Bielak, Gemma Cadby, Toshiko Tanaka, Reedik Mägi, Peter J van der Most, Anne U Jackson, Jennifer L Bragg-Gresham, Veronique Vitart, Jonathan Marten, Pau Navarro, Claire Bellis, Dorota Pasko, Åsa Johansson, Søren Snitker, Yu-Ching Cheng, Joel Eriksson, Unhee Lim, Mette Aadahl, Linda S Adair, Najaf Amin, Beverley Balkau, Juha Auvinen, John Beilby, Richard N Bergman, Sven Bergmann, Alain G Bertoni, John Blangero, Amélie Bonnefond, Lori L Bonnycastle, Judith B Borja, Søren Brage, Fabio Busonero, Steve Buyske, Harry Campbell, Peter S Chines, Francis S Collins, Tanguy Corre, George Davey Smith, Graciela E Delgado, Nicole Dueker, Marcus Dörr, Tapani Ebeling, Gudny Eiriksdottir, Tõnu Esko, Jessica D Faul, Mao Fu, Kristine Færch, Christian Gieger, Sven Gläser, Jian Gong, Penny Gordon-Larsen, Harald Grallert, Tanja B Grammer, Niels Grarup, Gerard van Grootheest, Kennet Harald, Nicholas D Hastie, Aki S Havulinna, Dena Hernandez, Lucia Hindorff, Lynne J Hocking, Oddgeir L Holmens, Christina Holzapfel, Jouke Jan Hottenga, Jie Huang, Tao Huang, Jennie Hui, Cornelia Huth, Nina Hutri-Kähönen, Alan L James, John-Olov Jansson, Min A Jhun, Markus Juonala, Leena Kinnunen, Heikki A Koistinen, Ivana Kolcic, Pirjo Komulainen, Johanna Kuusisto, Kirsti Kvaløy, Mika Kähönen, Timo A Lakka, Lenore J Launer, Benjamin Lehne, Cecilia M Lindgren, Mattias Lorentzon, Robert Luben, Michel Marre, Yuri Milaneschi, Keri L Monda, Grant W Montgomery, Marleen H M De Moor, Antonella Mulas, Martina Müller-Nurasyid, A W Musk, Reija Männikkö, Satu Männistö, Narisu Narisu, Matthias Nauck, Jennifer A Nettleton, Ilja M Nolte, Albertine J Oldehinkel, Matthias Olden, Ken K Ong, Sandosh Padmanabhan, Lavinia Paternoster, Jeremiah Perez, Markus Perola, Annette Peters, Ulrike Peters, Patricia A Peyser, Inga Prokopenko, Hannu Puolijoki, Olli T Raitakari, Tuomo Rankinen, Laura J Rasmussen-Torvik, Rajesh Rawal, Paul M Ridker, Lynda M Rose, Igor Rudan, Cinzia Sarti, Mark A Sarzynski, Kai Savonen, William R Scott, Serena Sanna, Alan R Shuldiner, Steve Sidney, Günther Silbernagel, Blair H Smith, Jennifer A Smith, Harold Snieder, Alena Stančáková, Barbara Sternfeld, Amy J Swift, Tuija Tammelin, Sian-Tsung Tan, Barbara Thorand, Dorothée Thuillier, Liesbeth Vandenput, Henrik Vestergaard, Jana V van Vliet-Ostaptchouk, Marie-Claude Vohl, Uwe Völker, Gérard Waeber, Mark Walker, Sarah Wild, Andrew Wong, Alan F Wright, M Carola Zillikens, Niha Zubair, Christopher A Haiman, Loic Lemarchand, Ulf Gyllensten, Claes Ohlsson, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Louis Pérusse, James F Wilson, Caroline Hayward, Ozren Polasek, Francesco Cucca, Kristian Hveem, Catharina A Hartman, Anke Tönjes, Stefania Bandinelli, Lyle J Palmer, Sharon L R Kardia, Rainer Rauramaa, Thorkild I A Sørensen, Jaakko Tuomilehto, Veikko Salomaa, Brenda W J H Penninx, Eco J C de Geus, Dorret I Boomsma, Terho Lehtimäki, Massimo Mangino, Markku Laakso, Claude Bouchard, Nicholas G Martin, Diana Kuh, Yongmei Liu, Allan Linneberg, Winfried März, Konstantin Strauch, Mika Kivimäki, Tamara B Harris, Vilmundur Gudnason, Henry Völzke, Lu Qi, Marjo-Riitta Järvelin, John C Chambers, Jaspal S Kooner, Philippe Froguel, Charles Kooperberg, Peter Vollenweider, Göran Hallmans, Torben Hansen, Oluf Pedersen, Andres Metspalu, Nicholas J Wareham, Claudia Langenberg, David R Weir, David J Porteous, Eric Boerwinkle, Daniel I Chasman, CHARGE Consortium, EPIC-InterAct Consortium, PAGE Consortium, Gonçalo R Abecasis, Inês Barroso, Mark I McCarthy, Timothy M Frayling, Jeffrey R O'Connell, Cornelia M van Duijn, Michael Boehnke, Iris M Heid, Karen L Mohlke, David P Strachan, Caroline S Fox, Ching-Ti Liu, Joel N Hirschhorn, Robert J Klein, Andrew D Johnson, Ingrid B Borecki, Paul W Franks, Kari E North, L Adrienne Cupples, Ruth J F Loos, and Tuomas O Kilpeläinen
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Genetics ,QH426-470 - Abstract
[This corrects the article DOI: 10.1371/journal.pgen.1006528.].
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- 2017
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7. Genome-wide physical activity interactions in adiposity - A meta-analysis of 200,452 adults.
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Mariaelisa Graff, Robert A Scott, Anne E Justice, Kristin L Young, Mary F Feitosa, Llilda Barata, Thomas W Winkler, Audrey Y Chu, Anubha Mahajan, David Hadley, Luting Xue, Tsegaselassie Workalemahu, Nancy L Heard-Costa, Marcel den Hoed, Tarunveer S Ahluwalia, Qibin Qi, Julius S Ngwa, Frida Renström, Lydia Quaye, John D Eicher, James E Hayes, Marilyn Cornelis, Zoltan Kutalik, Elise Lim, Jian'an Luan, Jennifer E Huffman, Weihua Zhang, Wei Zhao, Paula J Griffin, Toomas Haller, Shafqat Ahmad, Pedro M Marques-Vidal, Stephanie Bien, Loic Yengo, Alexander Teumer, Albert Vernon Smith, Meena Kumari, Marie Neergaard Harder, Johanne Marie Justesen, Marcus E Kleber, Mette Hollensted, Kurt Lohman, Natalia V Rivera, John B Whitfield, Jing Hua Zhao, Heather M Stringham, Leo-Pekka Lyytikäinen, Charlotte Huppertz, Gonneke Willemsen, Wouter J Peyrot, Ying Wu, Kati Kristiansson, Ayse Demirkan, Myriam Fornage, Maija Hassinen, Lawrence F Bielak, Gemma Cadby, Toshiko Tanaka, Reedik Mägi, Peter J van der Most, Anne U Jackson, Jennifer L Bragg-Gresham, Veronique Vitart, Jonathan Marten, Pau Navarro, Claire Bellis, Dorota Pasko, Åsa Johansson, Søren Snitker, Yu-Ching Cheng, Joel Eriksson, Unhee Lim, Mette Aadahl, Linda S Adair, Najaf Amin, Beverley Balkau, Juha Auvinen, John Beilby, Richard N Bergman, Sven Bergmann, Alain G Bertoni, John Blangero, Amélie Bonnefond, Lori L Bonnycastle, Judith B Borja, Søren Brage, Fabio Busonero, Steve Buyske, Harry Campbell, Peter S Chines, Francis S Collins, Tanguy Corre, George Davey Smith, Graciela E Delgado, Nicole Dueker, Marcus Dörr, Tapani Ebeling, Gudny Eiriksdottir, Tõnu Esko, Jessica D Faul, Mao Fu, Kristine Færch, Christian Gieger, Sven Gläser, Jian Gong, Penny Gordon-Larsen, Harald Grallert, Tanja B Grammer, Niels Grarup, Gerard van Grootheest, Kennet Harald, Nicholas D Hastie, Aki S Havulinna, Dena Hernandez, Lucia Hindorff, Lynne J Hocking, Oddgeir L Holmens, Christina Holzapfel, Jouke Jan Hottenga, Jie Huang, Tao Huang, Jennie Hui, Cornelia Huth, Nina Hutri-Kähönen, Alan L James, John-Olov Jansson, Min A Jhun, Markus Juonala, Leena Kinnunen, Heikki A Koistinen, Ivana Kolcic, Pirjo Komulainen, Johanna Kuusisto, Kirsti Kvaløy, Mika Kähönen, Timo A Lakka, Lenore J Launer, Benjamin Lehne, Cecilia M Lindgren, Mattias Lorentzon, Robert Luben, Michel Marre, Yuri Milaneschi, Keri L Monda, Grant W Montgomery, Marleen H M De Moor, Antonella Mulas, Martina Müller-Nurasyid, A W Musk, Reija Männikkö, Satu Männistö, Narisu Narisu, Matthias Nauck, Jennifer A Nettleton, Ilja M Nolte, Albertine J Oldehinkel, Matthias Olden, Ken K Ong, Sandosh Padmanabhan, Lavinia Paternoster, Jeremiah Perez, Markus Perola, Annette Peters, Ulrike Peters, Patricia A Peyser, Inga Prokopenko, Hannu Puolijoki, Olli T Raitakari, Tuomo Rankinen, Laura J Rasmussen-Torvik, Rajesh Rawal, Paul M Ridker, Lynda M Rose, Igor Rudan, Cinzia Sarti, Mark A Sarzynski, Kai Savonen, William R Scott, Serena Sanna, Alan R Shuldiner, Steve Sidney, Günther Silbernagel, Blair H Smith, Jennifer A Smith, Harold Snieder, Alena Stančáková, Barbara Sternfeld, Amy J Swift, Tuija Tammelin, Sian-Tsung Tan, Barbara Thorand, Dorothée Thuillier, Liesbeth Vandenput, Henrik Vestergaard, Jana V van Vliet-Ostaptchouk, Marie-Claude Vohl, Uwe Völker, Gérard Waeber, Mark Walker, Sarah Wild, Andrew Wong, Alan F Wright, M Carola Zillikens, Niha Zubair, Christopher A Haiman, Loic Lemarchand, Ulf Gyllensten, Claes Ohlsson, Albert Hofman, Fernando Rivadeneira, André G Uitterlinden, Louis Pérusse, James F Wilson, Caroline Hayward, Ozren Polasek, Francesco Cucca, Kristian Hveem, Catharina A Hartman, Anke Tönjes, Stefania Bandinelli, Lyle J Palmer, Sharon L R Kardia, Rainer Rauramaa, Thorkild I A Sørensen, Jaakko Tuomilehto, Veikko Salomaa, Brenda W J H Penninx, Eco J C de Geus, Dorret I Boomsma, Terho Lehtimäki, Massimo Mangino, Markku Laakso, Claude Bouchard, Nicholas G Martin, Diana Kuh, Yongmei Liu, Allan Linneberg, Winfried März, Konstantin Strauch, Mika Kivimäki, Tamara B Harris, Vilmundur Gudnason, Henry Völzke, Lu Qi, Marjo-Riitta Järvelin, John C Chambers, Jaspal S Kooner, Philippe Froguel, Charles Kooperberg, Peter Vollenweider, Göran Hallmans, Torben Hansen, Oluf Pedersen, Andres Metspalu, Nicholas J Wareham, Claudia Langenberg, David R Weir, David J Porteous, Eric Boerwinkle, Daniel I Chasman, CHARGE Consortium, EPIC-InterAct Consortium, PAGE Consortium, Gonçalo R Abecasis, Inês Barroso, Mark I McCarthy, Timothy M Frayling, Jeffrey R O'Connell, Cornelia M van Duijn, Michael Boehnke, Iris M Heid, Karen L Mohlke, David P Strachan, Caroline S Fox, Ching-Ti Liu, Joel N Hirschhorn, Robert J Klein, Andrew D Johnson, Ingrid B Borecki, Paul W Franks, Kari E North, L Adrienne Cupples, Ruth J F Loos, and Tuomas O Kilpeläinen
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Genetics ,QH426-470 - Abstract
Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
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- 2017
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8. Correction: The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.
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Thomas W Winkler, Anne E Justice, Mariaelisa Graff, Llilda Barata, Mary F Feitosa, Su Chu, Jacek Czajkowski, Tõnu Esko, Tove Fall, Tuomas O Kilpeläinen, Yingchang Lu, Reedik Mägi, Evelin Mihailov, Tune H Pers, Sina Rüeger, Alexander Teumer, Georg B Ehret, Teresa Ferreira, Nancy L Heard-Costa, Juha Karjalainen, Vasiliki Lagou, Anubha Mahajan, Michael D Neinast, Inga Prokopenko, Jeannette Simino, Tanya M Teslovich, Rick Jansen, Harm-Jan Westra, Charles C White, Devin Absher, Tarunveer S Ahluwalia, Shafqat Ahmad, Eva Albrecht, Alexessander Couto Alves, Jennifer L Bragg-Gresham, Anton J M de Craen, Joshua C Bis, Amélie Bonnefond, Gabrielle Boucher, Gemma Cadby, Yu-Ching Cheng, Charleston W K Chiang, Graciela Delgado, Ayse Demirkan, Nicole Dueker, Niina Eklund, Gudny Eiriksdottir, Joel Eriksson, Bjarke Feenstra, Krista Fischer, Francesca Frau, Tessel E Galesloot, Frank Geller, Anuj Goel, Mathias Gorski, Tanja B Grammer, Stefan Gustafsson, Saskia Haitjema, Jouke-Jan Hottenga, Jennifer E Huffman, Anne U Jackson, Kevin B Jacobs, Åsa Johansson, Marika Kaakinen, Marcus E Kleber, Jari Lahti, Irene Mateo Leach, Benjamin Lehne, Youfang Liu, Ken Sin Lo, Mattias Lorentzon, Jian'an Luan, Pamela A F Madden, Massimo Mangino, Barbara McKnight, Carolina Medina-Gomez, Keri L Monda, May E Montasser, Gabriele Müller, Martina Müller-Nurasyid, Ilja M Nolte, Kalliope Panoutsopoulou, Laura Pascoe, Lavinia Paternoster, Nigel W Rayner, Frida Renström, Federica Rizzi, Lynda M Rose, Kathy A Ryan, Perttu Salo, Serena Sanna, Hubert Scharnagl, Jianxin Shi, Albert Vernon Smith, Lorraine Southam, Alena Stančáková, Valgerdur Steinthorsdottir, Rona J Strawbridge, Yun Ju Sung, Ioanna Tachmazidou, Toshiko Tanaka, Gudmar Thorleifsson, Stella Trompet, Natalia Pervjakova, Jonathan P Tyrer, Liesbeth Vandenput, Sander W van der Laan, Nathalie van der Velde, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Niek Verweij, Efthymia Vlachopoulou, Lindsay L Waite, Sophie R Wang, Zhaoming Wang, Sarah H Wild, Christina Willenborg, James F Wilson, Andrew Wong, Jian Yang, Loïc Yengo, Laura M Yerges-Armstrong, Lei Yu, Weihua Zhang, Jing Hua Zhao, Ehm A Andersson, Stephan J L Bakker, Damiano Baldassarre, Karina Banasik, Matteo Barcella, Cristina Barlassina, Claire Bellis, Paola Benaglio, John Blangero, Matthias Blüher, Fabrice Bonnet, Lori L Bonnycastle, Heather A Boyd, Marcel Bruinenberg, Aron S Buchman, Harry Campbell, Yii-Der Ida Chen, Peter S Chines, Simone Claudi-Boehm, John Cole, Francis S Collins, Eco J C de Geus, Lisette C P G M de Groot, Maria Dimitriou, Jubao Duan, Stefan Enroth, Elodie Eury, Aliki-Eleni Farmaki, Nita G Forouhi, Nele Friedrich, Pablo V Gejman, Bruna Gigante, Nicola Glorioso, Alan S Go, Omri Gottesman, Jürgen Gräßler, Harald Grallert, Niels Grarup, Yu-Mei Gu, Linda Broer, Annelies C Ham, Torben Hansen, Tamara B Harris, Catharina A Hartman, Maija Hassinen, Nicholas Hastie, Andrew T Hattersley, Andrew C Heath, Anjali K Henders, Dena Hernandez, Hans Hillege, Oddgeir Holmen, Kees G Hovingh, Jennie Hui, Lise L Husemoen, Nina Hutri-Kähönen, Pirro G Hysi, Thomas Illig, Philip L De Jager, Shapour Jalilzadeh, Torben Jørgensen, J Wouter Jukema, Markus Juonala, Stavroula Kanoni, Maria Karaleftheri, Kay Tee Khaw, Leena Kinnunen, Steven J Kittner, Wolfgang Koenig, Ivana Kolcic, Peter Kovacs, Nikolaj T Krarup, Wolfgang Kratzer, Janine Krüger, Diana Kuh, Meena Kumari, Theodosios Kyriakou, Claudia Langenberg, Lars Lannfelt, Chiara Lanzani, Vaneet Lotay, Lenore J Launer, Karin Leander, Jaana Lindström, Allan Linneberg, Yan-Ping Liu, Stéphane Lobbens, Robert Luben, Valeriya Lyssenko, Satu Männistö, Patrik K Magnusson, Wendy L McArdle, Cristina Menni, Sigrun Merger, Lili Milani, Grant W Montgomery, Andrew P Morris, Narisu Narisu, Mari Nelis, Ken K Ong, Aarno Palotie, Louis Pérusse, Irene Pichler, Maria G Pilia, Anneli Pouta, Myriam Rheinberger, Rasmus Ribel-Madsen, Marcus Richards, Kenneth M Rice, Treva K Rice, Carlo Rivolta, Veikko Salomaa, Alan R Sanders, Mark A Sarzynski, Salome Scholtens, Robert A Scott, William R Scott, Sylvain Sebert, Sebanti Sengupta, Bengt Sennblad, Thomas Seufferlein, Angela Silveira, P Eline Slagboom, Jan H Smit, Thomas H Sparsø, Kathleen Stirrups, Ronald P Stolk, Heather M Stringham, Morris A Swertz, Amy J Swift, Ann-Christine Syvänen, Sian-Tsung Tan, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Emmanouil Tsafantakis, Peter J van der Most, Uwe Völker, Marie-Claude Vohl, Judith M Vonk, Melanie Waldenberger, Ryan W Walker, Roman Wennauer, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Alan F Wright, M Carola Zillikens, Suzanne C van Dijk, Natasja M van Schoor, Folkert W Asselbergs, Paul I W de Bakker, Jacques S Beckmann, John Beilby, David A Bennett, Richard N Bergman, Sven Bergmann, Carsten A Böger, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Stefan R Bornstein, Erwin P Bottinger, Claude Bouchard, John C Chambers, Stephen J Chanock, Daniel I Chasman, Francesco Cucca, Daniele Cusi, George Dedoussis, Jeanette Erdmann, Johan G Eriksson, Denis A Evans, Ulf de Faire, Martin Farrall, Luigi Ferrucci, Ian Ford, Lude Franke, Paul W Franks, Philippe Froguel, Ron T Gansevoort, Christian Gieger, Henrik Grönberg, Vilmundur Gudnason, Ulf Gyllensten, Per Hall, Anders Hamsten, Pim van der Harst, Caroline Hayward, Markku Heliövaara, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Albert Hofman, Frank Hu, Heikki V Huikuri, Kristian Hveem, Alan L James, Joanne M Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Sekar Kathiresan, Lambertus A L M Kiemeney, Mika Kivimaki, Paul B Knekt, Heikki A Koistinen, Jaspal S Kooner, Seppo Koskinen, Johanna Kuusisto, Winfried Maerz, Nicholas G Martin, Markku Laakso, Timo A Lakka, Terho Lehtimäki, Guillaume Lettre, Douglas F Levinson, Lars Lind, Marja-Liisa Lokki, Pekka Mäntyselkä, Mads Melbye, Andres Metspalu, Braxton D Mitchell, Frans L Moll, Jeffrey C Murray, Arthur W Musk, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Ben A Oostra, Lyle J Palmer, James S Pankow, Gerard Pasterkamp, Nancy L Pedersen, Oluf Pedersen, Brenda W Penninx, Markus Perola, Annette Peters, Ozren Polašek, Peter P Pramstaller, Bruce M Psaty, Lu Qi, Thomas Quertermous, Olli T Raitakari, Tuomo Rankinen, Rainer Rauramaa, Paul M Ridker, John D Rioux, Fernando Rivadeneira, Jerome I Rotter, Igor Rudan, Hester M den Ruijter, Juha Saltevo, Naveed Sattar, Heribert Schunkert, Peter E H Schwarz, Alan R Shuldiner, Juha Sinisalo, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Jan A Staessen, Bandinelli Stefania, Unnur Thorsteinsdottir, Michael Stumvoll, Jean-Claude Tardif, Elena Tremoli, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, André L M Verbeek, Sita H Vermeulen, Jorma S Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Gérard Waeber, Mark Walker, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, Eleftheria Zeggini, arcOGEN Consortium, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Aravinda Chakravarti, Deborah J Clegg, L Adrienne Cupples, Penny Gordon-Larsen, Cashell E Jaquish, D C Rao, Goncalo R Abecasis, Themistocles L Assimes, Inês Barroso, Sonja I Berndt, Michael Boehnke, Panos Deloukas, Caroline S Fox, Leif C Groop, David J Hunter, Erik Ingelsson, Robert C Kaplan, Mark I McCarthy, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Joel N Hirschhorn, Cecilia M Lindgren, Iris M Heid, Kari E North, Ingrid B Borecki, Zoltán Kutalik, and Ruth J F Loos
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Genetics ,QH426-470 - Abstract
[This corrects the article DOI: 10.1371/journal.pgen.1005378.].
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- 2016
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9. Investigation of Genetic Variation Underlying Central Obesity amongst South Asians.
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William R Scott, Weihua Zhang, Marie Loh, Sian-Tsung Tan, Benjamin Lehne, Uzma Afzal, Juan Peralta, Richa Saxena, Sarju Ralhan, Gurpreet S Wander, Kiymet Bozaoglu, Dharambir K Sanghera, Paul Elliott, James Scott, John C Chambers, and Jaspal S Kooner
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Medicine ,Science - Abstract
South Asians are 1/4 of the world's population and have increased susceptibility to central obesity and related cardiometabolic disease. Knowledge of genetic variants affecting risk of central obesity is largely based on genome-wide association studies of common SNPs in Europeans. To evaluate the contribution of DNA sequence variation to the higher levels of central obesity (defined as waist hip ratio adjusted for body mass index, WHR) among South Asians compared to Europeans we carried out: i) a genome-wide association analysis of >6M genetic variants in 10,318 South Asians with focused analysis of population-specific SNPs; ii) an exome-wide association analysis of ~250K SNPs in protein-coding regions in 2,637 South Asians; iii) a comparison of risk allele frequencies and effect sizes of 48 known WHR SNPs in 12,240 South Asians compared to Europeans. In genome-wide analyses, we found no novel associations between common genetic variants and WHR in South Asians at P
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- 2016
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10. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.
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Thomas W Winkler, Anne E Justice, Mariaelisa Graff, Llilda Barata, Mary F Feitosa, Su Chu, Jacek Czajkowski, Tõnu Esko, Tove Fall, Tuomas O Kilpeläinen, Yingchang Lu, Reedik Mägi, Evelin Mihailov, Tune H Pers, Sina Rüeger, Alexander Teumer, Georg B Ehret, Teresa Ferreira, Nancy L Heard-Costa, Juha Karjalainen, Vasiliki Lagou, Anubha Mahajan, Michael D Neinast, Inga Prokopenko, Jeannette Simino, Tanya M Teslovich, Rick Jansen, Harm-Jan Westra, Charles C White, Devin Absher, Tarunveer S Ahluwalia, Shafqat Ahmad, Eva Albrecht, Alexessander Couto Alves, Jennifer L Bragg-Gresham, Anton J M de Craen, Joshua C Bis, Amélie Bonnefond, Gabrielle Boucher, Gemma Cadby, Yu-Ching Cheng, Charleston W K Chiang, Graciela Delgado, Ayse Demirkan, Nicole Dueker, Niina Eklund, Gudny Eiriksdottir, Joel Eriksson, Bjarke Feenstra, Krista Fischer, Francesca Frau, Tessel E Galesloot, Frank Geller, Anuj Goel, Mathias Gorski, Tanja B Grammer, Stefan Gustafsson, Saskia Haitjema, Jouke-Jan Hottenga, Jennifer E Huffman, Anne U Jackson, Kevin B Jacobs, Åsa Johansson, Marika Kaakinen, Marcus E Kleber, Jari Lahti, Irene Mateo Leach, Benjamin Lehne, Youfang Liu, Ken Sin Lo, Mattias Lorentzon, Jian'an Luan, Pamela A F Madden, Massimo Mangino, Barbara McKnight, Carolina Medina-Gomez, Keri L Monda, May E Montasser, Gabriele Müller, Martina Müller-Nurasyid, Ilja M Nolte, Kalliope Panoutsopoulou, Laura Pascoe, Lavinia Paternoster, Nigel W Rayner, Frida Renström, Federica Rizzi, Lynda M Rose, Kathy A Ryan, Perttu Salo, Serena Sanna, Hubert Scharnagl, Jianxin Shi, Albert Vernon Smith, Lorraine Southam, Alena Stančáková, Valgerdur Steinthorsdottir, Rona J Strawbridge, Yun Ju Sung, Ioanna Tachmazidou, Toshiko Tanaka, Gudmar Thorleifsson, Stella Trompet, Natalia Pervjakova, Jonathan P Tyrer, Liesbeth Vandenput, Sander W van der Laan, Nathalie van der Velde, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Niek Verweij, Efthymia Vlachopoulou, Lindsay L Waite, Sophie R Wang, Zhaoming Wang, Sarah H Wild, Christina Willenborg, James F Wilson, Andrew Wong, Jian Yang, Loïc Yengo, Laura M Yerges-Armstrong, Lei Yu, Weihua Zhang, Jing Hua Zhao, Ehm A Andersson, Stephan J L Bakker, Damiano Baldassarre, Karina Banasik, Matteo Barcella, Cristina Barlassina, Claire Bellis, Paola Benaglio, John Blangero, Matthias Blüher, Fabrice Bonnet, Lori L Bonnycastle, Heather A Boyd, Marcel Bruinenberg, Aron S Buchman, Harry Campbell, Yii-Der Ida Chen, Peter S Chines, Simone Claudi-Boehm, John Cole, Francis S Collins, Eco J C de Geus, Lisette C P G M de Groot, Maria Dimitriou, Jubao Duan, Stefan Enroth, Elodie Eury, Aliki-Eleni Farmaki, Nita G Forouhi, Nele Friedrich, Pablo V Gejman, Bruna Gigante, Nicola Glorioso, Alan S Go, Omri Gottesman, Jürgen Gräßler, Harald Grallert, Niels Grarup, Yu-Mei Gu, Linda Broer, Annelies C Ham, Torben Hansen, Tamara B Harris, Catharina A Hartman, Maija Hassinen, Nicholas Hastie, Andrew T Hattersley, Andrew C Heath, Anjali K Henders, Dena Hernandez, Hans Hillege, Oddgeir Holmen, Kees G Hovingh, Jennie Hui, Lise L Husemoen, Nina Hutri-Kähönen, Pirro G Hysi, Thomas Illig, Philip L De Jager, Shapour Jalilzadeh, Torben Jørgensen, J Wouter Jukema, Markus Juonala, Stavroula Kanoni, Maria Karaleftheri, Kay Tee Khaw, Leena Kinnunen, Steven J Kittner, Wolfgang Koenig, Ivana Kolcic, Peter Kovacs, Nikolaj T Krarup, Wolfgang Kratzer, Janine Krüger, Diana Kuh, Meena Kumari, Theodosios Kyriakou, Claudia Langenberg, Lars Lannfelt, Chiara Lanzani, Vaneet Lotay, Lenore J Launer, Karin Leander, Jaana Lindström, Allan Linneberg, Yan-Ping Liu, Stéphane Lobbens, Robert Luben, Valeriya Lyssenko, Satu Männistö, Patrik K Magnusson, Wendy L McArdle, Cristina Menni, Sigrun Merger, Lili Milani, Grant W Montgomery, Andrew P Morris, Narisu Narisu, Mari Nelis, Ken K Ong, Aarno Palotie, Louis Pérusse, Irene Pichler, Maria G Pilia, Anneli Pouta, Myriam Rheinberger, Rasmus Ribel-Madsen, Marcus Richards, Kenneth M Rice, Treva K Rice, Carlo Rivolta, Veikko Salomaa, Alan R Sanders, Mark A Sarzynski, Salome Scholtens, Robert A Scott, William R Scott, Sylvain Sebert, Sebanti Sengupta, Bengt Sennblad, Thomas Seufferlein, Angela Silveira, P Eline Slagboom, Jan H Smit, Thomas H Sparsø, Kathleen Stirrups, Ronald P Stolk, Heather M Stringham, Morris A Swertz, Amy J Swift, Ann-Christine Syvänen, Sian-Tsung Tan, Barbara Thorand, Anke Tönjes, Angelo Tremblay, Emmanouil Tsafantakis, Peter J van der Most, Uwe Völker, Marie-Claude Vohl, Judith M Vonk, Melanie Waldenberger, Ryan W Walker, Roman Wennauer, Elisabeth Widén, Gonneke Willemsen, Tom Wilsgaard, Alan F Wright, M Carola Zillikens, Suzanne C van Dijk, Natasja M van Schoor, Folkert W Asselbergs, Paul I W de Bakker, Jacques S Beckmann, John Beilby, David A Bennett, Richard N Bergman, Sven Bergmann, Carsten A Böger, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Stefan R Bornstein, Erwin P Bottinger, Claude Bouchard, John C Chambers, Stephen J Chanock, Daniel I Chasman, Francesco Cucca, Daniele Cusi, George Dedoussis, Jeanette Erdmann, Johan G Eriksson, Denis A Evans, Ulf de Faire, Martin Farrall, Luigi Ferrucci, Ian Ford, Lude Franke, Paul W Franks, Philippe Froguel, Ron T Gansevoort, Christian Gieger, Henrik Grönberg, Vilmundur Gudnason, Ulf Gyllensten, Per Hall, Anders Hamsten, Pim van der Harst, Caroline Hayward, Markku Heliövaara, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Albert Hofman, Frank Hu, Heikki V Huikuri, Kristian Hveem, Alan L James, Joanne M Jordan, Antti Jula, Mika Kähönen, Eero Kajantie, Sekar Kathiresan, Lambertus A L M Kiemeney, Mika Kivimaki, Paul B Knekt, Heikki A Koistinen, Jaspal S Kooner, Seppo Koskinen, Johanna Kuusisto, Winfried Maerz, Nicholas G Martin, Markku Laakso, Timo A Lakka, Terho Lehtimäki, Guillaume Lettre, Douglas F Levinson, Lars Lind, Marja-Liisa Lokki, Pekka Mäntyselkä, Mads Melbye, Andres Metspalu, Braxton D Mitchell, Frans L Moll, Jeffrey C Murray, Arthur W Musk, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Ben A Oostra, Lyle J Palmer, James S Pankow, Gerard Pasterkamp, Nancy L Pedersen, Oluf Pedersen, Brenda W Penninx, Markus Perola, Annette Peters, Ozren Polašek, Peter P Pramstaller, Bruce M Psaty, Lu Qi, Thomas Quertermous, Olli T Raitakari, Tuomo Rankinen, Rainer Rauramaa, Paul M Ridker, John D Rioux, Fernando Rivadeneira, Jerome I Rotter, Igor Rudan, Hester M den Ruijter, Juha Saltevo, Naveed Sattar, Heribert Schunkert, Peter E H Schwarz, Alan R Shuldiner, Juha Sinisalo, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, Jan A Staessen, Bandinelli Stefania, Unnur Thorsteinsdottir, Michael Stumvoll, Jean-Claude Tardif, Elena Tremoli, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, André L M Verbeek, Sita H Vermeulen, Jorma S Viikari, Veronique Vitart, Henry Völzke, Peter Vollenweider, Gérard Waeber, Mark Walker, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, Eleftheria Zeggini, CHARGE Consortium, DIAGRAM Consortium, GLGC Consortium, Global-BPGen Consortium, ICBP Consortium, MAGIC Consortium, Aravinda Chakravarti, Deborah J Clegg, L Adrienne Cupples, Penny Gordon-Larsen, Cashell E Jaquish, D C Rao, Goncalo R Abecasis, Themistocles L Assimes, Inês Barroso, Sonja I Berndt, Michael Boehnke, Panos Deloukas, Caroline S Fox, Leif C Groop, David J Hunter, Erik Ingelsson, Robert C Kaplan, Mark I McCarthy, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Joel N Hirschhorn, Cecilia M Lindgren, Iris M Heid, Kari E North, Ingrid B Borecki, Zoltán Kutalik, and Ruth J F Loos
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Genetics ,QH426-470 - Abstract
Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR
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- 2015
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11. Novel approach identifies SNPs in SLC2A10 and KCNK9 with evidence for parent-of-origin effect on body mass index.
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Clive J Hoggart, Giulia Venturini, Massimo Mangino, Felicia Gomez, Giulia Ascari, Jing Hua Zhao, Alexander Teumer, Thomas W Winkler, Natalia Tšernikova, Jian'an Luan, Evelin Mihailov, Georg B Ehret, Weihua Zhang, David Lamparter, Tõnu Esko, Aurelien Macé, Sina Rüeger, Pierre-Yves Bochud, Matteo Barcella, Yves Dauvilliers, Beben Benyamin, David M Evans, Caroline Hayward, Mary F Lopez, Lude Franke, Alessia Russo, Iris M Heid, Erika Salvi, Sailaja Vendantam, Dan E Arking, Eric Boerwinkle, John C Chambers, Giovanni Fiorito, Harald Grallert, Simonetta Guarrera, Georg Homuth, Jennifer E Huffman, David Porteous, Generation Scotland Consortium, LifeLines Cohort study, GIANT Consortium, Darius Moradpour, Alex Iranzo, Johannes Hebebrand, John P Kemp, Gert J Lammers, Vincent Aubert, Markus H Heim, Nicholas G Martin, Grant W Montgomery, Rosa Peraita-Adrados, Joan Santamaria, Francesco Negro, Carsten O Schmidt, Robert A Scott, Tim D Spector, Konstantin Strauch, Henry Völzke, Nicholas J Wareham, Wei Yuan, Jordana T Bell, Aravinda Chakravarti, Jaspal S Kooner, Annette Peters, Giuseppe Matullo, Henri Wallaschofski, John B Whitfield, Fred Paccaud, Peter Vollenweider, Sven Bergmann, Jacques S Beckmann, Mehdi Tafti, Nicholas D Hastie, Daniele Cusi, Murielle Bochud, Timothy M Frayling, Andres Metspalu, Marjo-Riitta Jarvelin, André Scherag, George Davey Smith, Ingrid B Borecki, Valentin Rousson, Joel N Hirschhorn, Carlo Rivolta, Ruth J F Loos, and Zoltán Kutalik
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Genetics ,QH426-470 - Abstract
The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ∼4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P
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- 2014
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12. The South Asian genome.
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John C Chambers, James Abbott, Weihua Zhang, Ernest Turro, William R Scott, Sian-Tsung Tan, Uzma Afzal, Saima Afaq, Marie Loh, Benjamin Lehne, Paul O'Reilly, Kyle J Gaulton, Richard D Pearson, Xinzhong Li, Anita Lavery, Jana Vandrovcova, Mark N Wass, Kathryn Miller, Joban Sehmi, Laticia Oozageer, Ishminder K Kooner, Abtehale Al-Hussaini, Rebecca Mills, Jagvir Grewal, Vasileios Panoulas, Alexandra M Lewin, Korrinne Northwood, Gurpreet S Wander, Frank Geoghegan, Yingrui Li, Jun Wang, Timothy J Aitman, Mark I McCarthy, James Scott, Sarah Butcher, Paul Elliott, and Jaspal S Kooner
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Medicine ,Science - Abstract
The genetic sequence variation of people from the Indian subcontinent who comprise one-quarter of the world's population, is not well described. We carried out whole genome sequencing of 168 South Asians, along with whole-exome sequencing of 147 South Asians to provide deeper characterisation of coding regions. We identify 12,962,155 autosomal sequence variants, including 2,946,861 new SNPs and 312,738 novel indels. This catalogue of SNPs and indels amongst South Asians provides the first comprehensive map of genetic variation in this major human population, and reveals evidence for selective pressures on genes involved in skin biology, metabolism, infection and immunity. Our results will accelerate the search for the genetic variants underlying susceptibility to disorders such as type-2 diabetes and cardiovascular disease which are highly prevalent amongst South Asians.
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- 2014
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13. Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.
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Conall M O'Seaghdha, Hongsheng Wu, Qiong Yang, Karen Kapur, Idris Guessous, Annie Mercier Zuber, Anna Köttgen, Candice Stoudmann, Alexander Teumer, Zoltán Kutalik, Massimo Mangino, Abbas Dehghan, Weihua Zhang, Gudny Eiriksdottir, Guo Li, Toshiko Tanaka, Laura Portas, Lorna M Lopez, Caroline Hayward, Kurt Lohman, Koichi Matsuda, Sandosh Padmanabhan, Dmitri Firsov, Rossella Sorice, Sheila Ulivi, A Catharina Brockhaus, Marcus E Kleber, Anubha Mahajan, Florian D Ernst, Vilmundur Gudnason, Lenore J Launer, Aurelien Mace, Eric Boerwinckle, Dan E Arking, Chizu Tanikawa, Yusuke Nakamura, Morris J Brown, Jean-Michel Gaspoz, Jean-Marc Theler, David S Siscovick, Bruce M Psaty, Sven Bergmann, Peter Vollenweider, Veronique Vitart, Alan F Wright, Tatijana Zemunik, Mladen Boban, Ivana Kolcic, Pau Navarro, Edward M Brown, Karol Estrada, Jingzhong Ding, Tamara B Harris, Stefania Bandinelli, Dena Hernandez, Andrew B Singleton, Giorgia Girotto, Daniela Ruggiero, Adamo Pio d'Adamo, Antonietta Robino, Thomas Meitinger, Christa Meisinger, Gail Davies, John M Starr, John C Chambers, Bernhard O Boehm, Bernhard R Winkelmann, Jie Huang, Federico Murgia, Sarah H Wild, Harry Campbell, Andrew P Morris, Oscar H Franco, Albert Hofman, Andre G Uitterlinden, Fernando Rivadeneira, Uwe Völker, Anke Hannemann, Reiner Biffar, Wolfgang Hoffmann, So-Youn Shin, Pierre Lescuyer, Hughes Henry, Claudia Schurmann, SUNLIGHT Consortium, GEFOS Consortium, Patricia B Munroe, Paolo Gasparini, Nicola Pirastu, Marina Ciullo, Christian Gieger, Winfried März, Lars Lind, Tim D Spector, Albert V Smith, Igor Rudan, James F Wilson, Ozren Polasek, Ian J Deary, Mario Pirastu, Luigi Ferrucci, Yongmei Liu, Bryan Kestenbaum, Jaspal S Kooner, Jacqueline C M Witteman, Matthias Nauck, W H Linda Kao, Henri Wallaschofski, Olivier Bonny, Caroline S Fox, and Murielle Bochud
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Genetics ,QH426-470 - Abstract
Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
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- 2013
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14. 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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15. A replication study of GWAS-derived lipid genes in Asian Indians: the chromosomal region 11q23.3 harbors loci contributing to triglycerides.
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Timothy R Braun, Latonya F Been, Akhil Singhal, Jacob Worsham, Sarju Ralhan, Gurpreet S Wander, John C Chambers, Jaspal S Kooner, Christopher E Aston, and Dharambir K Sanghera
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Medicine ,Science - Abstract
Recent genome-wide association scans (GWAS) and meta-analysis studies on European populations have identified many genes previously implicated in lipid regulation. Validation of these loci on different global populations is important in determining their clinical relevance, particularly for development of novel drug targets for treating and preventing diabetic dyslipidemia and coronary artery disease (CAD). In an attempt to replicate GWAS findings on a non-European sample, we examined the role of six of these loci (CELSR2-PSRC1-SORT1 rs599839; CDKN2A-2B rs1333049; BUD13-ZNF259 rs964184; ZNF259 rs12286037; CETP rs3764261; APOE-C1-C4-C2 rs4420638) in our Asian Indian cohort from the Sikh Diabetes Study (SDS) comprising 3,781 individuals (2,902 from Punjab and 879 from the US). Two of the six SNPs examined showed convincing replication in these populations of Asian Indian origin. Our study confirmed a strong association of CETP rs3764261 with high-density lipoprotein cholesterol (HDL-C) (p = 2.03×10(-26)). Our results also showed significant associations of two GWAS SNPs (rs964184 and rs12286037) from BUD13-ZNF259 near the APOA5-A4-C3-A1 genes with triglyceride (TG) levels in this Asian Indian cohort (rs964184: p = 1.74×10(-17); rs12286037: p = 1.58×10(-2)). We further explored 45 SNPs in a ∼195 kb region within the chromosomal region 11q23.3 (encompassing the BUD13-ZNF259, APOA5-A4-C3-A1, and SIK3 genes) in 8,530 Asian Indians from the London Life Sciences Population (LOLIPOP) (UK) and SDS cohorts. Five more SNPs revealed significant associations with TG in both cohorts individually as well as in a joint meta-analysis. However, the strongest signal for TG remained with BUD13-ZNF259 (rs964184: p = 1.06×10(-39)). Future targeted deep sequencing and functional studies should enhance our understanding of the clinical relevance of these genes in dyslipidemia and hypertriglyceridemia (HTG) and, consequently, diabetes and CAD.
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- 2012
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16. Genome-wide meta-analysis for serum calcium identifies significantly associated SNPs near the calcium-sensing receptor (CASR) gene.
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Karen Kapur, Toby Johnson, Noam D Beckmann, Joban Sehmi, Toshiko Tanaka, Zoltán Kutalik, Unnur Styrkarsdottir, Weihua Zhang, Diana Marek, Daniel F Gudbjartsson, Yuri Milaneschi, Hilma Holm, Angelo Diiorio, Dawn Waterworth, Yun Li, Andrew B Singleton, Unnur S Bjornsdottir, Gunnar Sigurdsson, Dena G Hernandez, Ranil Desilva, Paul Elliott, Gudmundur I Eyjolfsson, Jack M Guralnik, James Scott, Unnur Thorsteinsdottir, Stefania Bandinelli, John Chambers, Kari Stefansson, Gérard Waeber, Luigi Ferrucci, Jaspal S Kooner, Vincent Mooser, Peter Vollenweider, Jacques S Beckmann, Murielle Bochud, and Sven Bergmann
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Genetics ,QH426-470 - Abstract
Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disorders of bone and mineral metabolism, as well as with cardiovascular mortality. Here we report results from a genome-wide association study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individuals of European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR) gene on 3q13. The top hit with a p-value of 6.3 x 10(-37) is rs1801725, a missense variant, explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of European descent, while for individuals of Indian Asian descent the top hit was rs17251221 (p = 1.1 x 10(-21)), a SNP in strong linkage disequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of 4,126 individuals (p = 1.02 x 10(-4)). This genome-wide meta-analysis shows that common CASR variants modulate serum calcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASR locus. This study highlights the key role of CASR in calcium regulation.
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- 2010
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17. 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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18. Large-scale exome array summary statistics resources for glycemic traits to aid effector gene prioritization [version 1; peer review: 2 approved]
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Natasha H. J. Ng, Sara M. Willems, Jian'an Luan, Rebecca S. Fine, Juan Fernandez, Jennifer Wessel, Eleanor Wheeler, Gaelle Marenne, Hidetoshi Kitajima, Hanieh Yaghootkar, Xueling Sim, Ian J. Deary, Sai Chen, Shuai Wang, Yii-Der Ida Chen, Caroline Hayward, Yuning Chen, Jennifer L. Asimit, Claudia Langenberg, Tibor V. Varga, Archie Campbell, Rona J. Strawbridge, Shuang Feng, Tarunveer S. Ahluwalia, Erica L. Kleinbrink, Emil V. Appel, Ping An, Lawrence F. Bielak, Dan E. Arking, Jennifer A. Brody, Nathan A. Bihlmeyer, David Porteous, Ayse Demirkan, Audrey Y. Chu, Franco Giulianini, James S. Floyd, Stefan Gustafsson, Xiuqing Guo, Johanna Jakobsdottir, Anne U. Jackson, Stavroula Kanoni, Richard A. Jensen, Igor Rudan, Man Li, Sirkka Keinanen-Kiukaanniemi, Alisa K. Manning, Yingchang Lu, Karina Meidtner, Jonathan Marten, Giorgio Pistis, Taulant Muka, Kenneth M. Rice, Bram Prins, Albert Vernon Smith, Serena Sanna, Lorraine Southam, Jennifer A. Smith, Vinicius Tragante, Heather M. Stringham, Helen R. Warren, Sander W. van der Laan, Andrianos M. Yiorkas, Jie Yao, Wei Zhao, Weihua Zhang, Heather M. Highland, Mariaelisa Graff, Eirini Marouli, Anne E. Justice, Wesam A. Alhejily, Saima Afaq, Folkert W. Asselbergs, Najaf Amin, Michiel L. Bots, Lori L. Bonnycastle, Ji Chen, Ivan Brandslund, Abbas Dehghan, John Danesh, Tapani Ebeling, Jessica D. Faul, Aliki-Eleni Farmaki, Steve Franks, Paul W. Franks, Anette P. Gjesing, Andreas Fritsche, Göran Hallmans, Mark O. Goodarzi, Karl-Heinz Herzig, Tamara B. Harris, Min A Jhun, Marie-France Hivert, Marit E. Jørgensen, Torben Jørgensen, Eero Kajantie, Pekka Jousilahti, Sharon L.R. Kardia, Maria Karaleftheri, Heikki A. Koistinen, Leena Kinnunen, Peter Kovacs, Pirjo Komulainen, Markku Laakso, Johanna Kuusisto, Aaron Leong, Lenore J. Launer, Jocelyn E. Manning Fox, Jaana Lindström, Nisa M. Maruthur, Satu Männistö, Antonella Mulas, Leena Moilanen, Matthew Neville, Mike A. Nalls, Alison Pattie, James S. Pankow, Hannu Puolijoki, Eva R.B. Petersen, Paul Redmond, Asif Rasheed, Michael Roden, Frida Renström, Juha Saltevo, Danish Saleheen, Sylvain Sebert, Kai Savonen, Alena Stančáková, Kerrin S. Small, Konstantin Strauch, Jakob Stokholm, Betina H. Thuesen, Juha Auvinen, E-Shyong Tai, Emmanouil Tsafantakis, Anke Tönjes, Jaakko Tuomilehto, Tiinamaija Tuomi, Marja Vääräsmäki, Matti Uusitupa, Magdalena Zoledziewska, Ilonca Vaartjes, Beverley Balkau, Goncalo Abecasis, Alexandra I. Blakemore, Hans Bisgaard, Heiner Boeing, Ruth J.F. Loos, Matthias Blüher, Klaus Bønnelykke, Eric Boerwinkle, Mark J. Caulfield, Erwin P. Bottinger, Daniel I. Chasman, John C. Chambers, Francis S. Collins, Ching-Yu Cheng, Francesco Cucca, Josef Coresh, George Dedoussis, Gert J. de Borst, Hester M. den Ruijter, Panos Deloukas, Ele Ferrannini, Michele K. Evans, Harald Grallert, Oscar H. Franco, Arfan Ikram, Joel N. Hirschhorn, Fredrik Karpe, Erik Ingelsson, Wieland Kiess, Carolina Medina-Gomez, Kay-Tee Kaw, Antje Körner, Jaspal S. Kooner, Cecilia M. Lindgren, Timo Lakka, Ching-Ti Liu, Leonard Lipovich, Patrick E. MacDonald, Jun Liu, Andrew D. Morris, Karen L. Mohlke, Alison Murray, Patricia B. Munroe, Gerard Pasterkamp, Colin N. A . Palmer, Patricia A. Peyser, Oluf Pedersen, Paul M. Ridker, Rainer Rauramaa, Patrik Rorsman, Olov Rolandsson, Veikko Salomaa, Frits R. Rosendaal, Robert Sladek, Matthias B. Schulze, Michael Stumvoll, Timothy D. Spector, Mark Walker, Cornelia M. van Duijn, David R. Weir, Nick J. Wareham, Tien Yin Wong, James G. Wilson, Alan B. Zonderman, Eleftheria Zeggini, Andrew P. Morris, Jerome I. Rotter, Jose C. Florez, Michael Boehnke, James B. Meigs, Mark I. McCarthy, Robert A. Scott, Anubha Mahajan, Inês Barroso, Anna L. Gloyn, Michael A. Province, Niels Grarup, Ruifang Li-Gao, Jette Bork-Jensen, Yongmei Liu, Allan Linneberg, Leslie A. Lange, Sandosh Padmanabhan, Gail Davies, Lars Lind, Bruce M. Psaty, Tea Skaaby, Torben Hansen, Ozren Polasek, John M. Starr, Dennis O. Mook-Kanamori, Vilmundur Gudnason, Kent D. Taylor, Marjo-Riitta Järvelin, Renée de Mutsert, Paul Elliott, Josée Dupuis, Blair H. Smith, and Andrew T. Hattersley
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exome chip ,glycaemic traits ,genetic discovery ,effector genes ,summary statistics resources ,eng ,Medicine ,Science - Abstract
Background Genome-wide association studies for glycemic traits have identified hundreds of loci associated with these biomarkers of glucose homeostasis. Despite this success, the challenge remains to link variant associations to genes, and underlying biological pathways. Methods To identify coding variant associations which may pinpoint effector genes at both novel and previously established genome-wide association loci, we performed meta-analyses of exome-array studies for four glycemic traits: glycated hemoglobin (HbA1c, up to 144,060 participants), fasting glucose (FG, up to 129,665 participants), fasting insulin (FI, up to 104,140) and 2hr glucose post-oral glucose challenge (2hGlu, up to 57,878). In addition, we performed network and pathway analyses. Results Single-variant and gene-based association analyses identified coding variant associations at more than 60 genes, which when combined with other datasets may be useful to nominate effector genes. Network and pathway analyses identified pathways related to insulin secretion, zinc transport and fatty acid metabolism. HbA1c associations were strongly enriched in pathways related to blood cell biology. Conclusions Our results provided novel glycemic trait associations and highlighted pathways implicated in glycemic regulation. Exome-array summary statistic results are being made available to the scientific community to enable further discoveries.
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- 2023
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19. Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity
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Mark K. Bakker, Jos P. Kanning, Gad Abraham, Amy E. Martinsen, Bendik S. Winsvold, John-Anker Zwart, Romain Bourcier, Tomonobu Sawada, Masaru Koido, Yoichiro Kamatani, Sandrine Morel, Philippe Amouyel, Stéphanie Debette, Philippe Bijlenga, Takiy Berrandou, Santhi K. Ganesh, Nabila Bouatia-Naji, Gregory Jones, Matthew Bown, Gabriel J.E. Rinkel, Jan H. Veldink, Ynte M. Ruigrok, Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian’an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex SF Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David CM Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth JF Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O’Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda WJH Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna MM Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin NA Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M. Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Lynn Cherkas, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Christian Kubisch, Michel D Ferrari, Andrea C Belin, Maija Wessman, Arn M J M van den Maagdenberg, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Dale R Nyholt, Masato Akiyama, Varinder S. Alg, Joseph P. Broderick, Ben M. Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M. Friedrich, Emília I. Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C. Hostettler, Henry Houlden, Juha E. Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y. Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A. Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W. M. Monique Verschuren, Robin G. Walters, David J. Werring, Cristen J. Willer, Daniel Woo, Bradford B. Worrall, Sirui Zhou, Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, AMS - Sports, AMS - Ageing & Vitality, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Systems Ecology, Sociology and Social Gerontology, Bakker, Mark K., Kanning, Jos P., Abraham, Gad, Martinsen, Amy E., Winsvold, Bendik S., Zwart, John-Anker, Bourcier, Romain, Sawada, Tomonobu, Koido, Masaru, Kamatani, Yoichiro, Morel, Sandrine, Amouyel, Philippe, Debette, Stéphanie, Bijlenga, Philippe, Berrandou, Takiy, Ganesh, Santhi K., Bouatia-Naji, Nabila, Jones, Gregory, Bown, Matthew, Rinkel, Gabriel J. E., Veldink, Jan H., Ruigrok, Ynte M., Girotto, G., All-In Stroke, Hunt, Group, Cadisp, Consortium for Blood Pressure, International, Headache Genetics Consortium, International, Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group, International, Utrecht University [Utrecht], Baker Heart and Diabetes Institute (AUSTRALIA), University of Melbourne, University of Oslo (UiO), Norwegian University of Science and Technology (NTNU), Oslo University Hospital [Oslo], Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), The University of Tokyo (UTokyo), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Hôpital Universitaire de Genève = University Hospitals of Geneva (HUG), Université de Genève = University of Geneva (UNIGE), Excellence Laboratory LabEx DISTALZ, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Otago [Dunedin, Nouvelle-Zélande], University of Leicester, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHU Amiens-Picardie, HUNT All-In Stroke, CADISP group, International Consortium for Blood Pressure, International Headache Genetics Consortium, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group: Anne Hege Aamodt, Anne Heidi Skogholt, Ben M Brumpton, Cristen J Willer, Else C Sandset, Espen S Kristoffersen, Hanne Ellekjær, Ingrid Heuch, Jonas B Nielsen, Knut Hagen, Kristian Hveem, Lars G Fritsche, Laurent F Thomas, Linda M Pedersen, Maiken E Gabrielsen, Oddgeir L Holmen, Sigrid Børte, Wei Zhou, Shérine Abboud, Massimo Pandolfo, Vincent Thijs, Didier Leys, Marie Bodenant, Fabien Louillet, Emmanuel Touzé, Jean-Louis Mas, Yves Samson, Sara Leder, Anne Léger, Sandrine Deltour, Sophie Crozier, Isabelle Méresse, Sandrine Canaple, Olivier Godefroy, Maurice Giroud, Yannick Béjot, Pierre Decavel, Elizabeth Medeiros, Paola Montiel, Thierry Moulin, Fabrice Vuillier, Jean Dallongeville, Antti J Metso, Tiina Metso, Turgut Tatlisumak, Caspar Grond-Ginsbach, Christoph Lichy, Manja Kloss, Inge Werner, Marie-Luise Arnold, Michael Dos Santos, Armin Grau, Martin Dichgans, Constanze Thomas-Feles, Ralf Weber, Tobias Brandt, Alessandro Pezzini, Valeria De Giuli, Filomena Caria, Loris Poli, Alessandro Padovani, Anna Bersano, Silvia Lanfranconi, Simone Beretta, Carlo Ferrarese, Giacomo Giacolone, Stefano Paolucci, Philippe Lyrer, Stefan Engelter, Felix Fluri, Florian Hatz, Dominique Gisler, Leo Bonati, Henrik Gensicke, Margareth Amort, Hugh Markus, Jennifer Majersik, Bradford Worrall, Andrew Southerland, John Cole, Steven Kittner, Evangelos Evangelou, Helen R Warren, He Gao, Georgios Ntritsos, Niki Dimou, Tonu Esko, Reedik Mägi, Lili Milani, Peter Almgren, Thibaud Boutin, Jun Ding, Franco Giulianini, Elizabeth G Holliday, Anne U Jackson, Ruifang Li-Gao, Wei-Yu Lin, Jian'an Luan, Massimo Mangino, Christopher Oldmeadow, Bram Peter Prins, Yong Qian, Muralidharan Sargurupremraj, Nabi Shah, Praveen Surendran, Sébastien Thériault, Niek Verweij, Sara M Willems, Jing-Hua Zhao, John Connell, Renée de Mutsert, Alex Sf Doney, Martin Farrall, Cristina Menni, Andrew D Morris, Raymond Noordam, Guillaume Paré, Neil R Poulter, Denis C Shields, Alice Stanton, Simon Thom, Gonçalo Abecasis, Najaf Amin, Dan E Arking, Kristin L Ayers, Caterina M Barbieri, Chiara Batini, Joshua C Bis, Tineka Blake, Murielle Bochud, Michael Boehnke, Eric Boerwinkle, Dorret I Boomsma, Erwin P Bottinger, Peter S Braund, Marco Brumat, Archie Campbell, Harry Campbell, Aravinda Chakravarti, John C Chambers, Ganesh Chauhan, Marina Ciullo, Massimiliano Cocca, Francis Collins, Heather J Cordell, Gail Davies, Martin H de Borst, Eco J de Geus, Ian J Deary, Joris Deelen, Fabiola Del Greco M, Cumhur Yusuf Demirkale, Marcus Dörr, Georg B Ehret, Roberto Elosua, Stefan Enroth, A Mesut Erzurumluoglu, Teresa Ferreira, Mattias Frånberg, Oscar H Franco, Ilaria Gandin, Paolo Gasparini, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Anuj Goel, Alan J Gow, Vilmundur Gudnason, Xiuqing Guo, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Sarah E Harris, Catharina A Hartman, Aki S Havulinna, Andrew A Hicks, Edith Hofer, Albert Hofman, Jouke-Jan Hottenga, Jennifer E Huffman, Shih-Jen Hwang, Erik Ingelsson, Alan James, Rick Jansen, Marjo-Riitta Jarvelin, Roby Joehanes, Åsa Johansson, Andrew D Johnson, Peter K Joshi, Pekka Jousilahti, J Wouter Jukema, Antti Jula, Mika Kähönen, Sekar Kathiresan, Bernard D Keavney, Kay-Tee Khaw, Paul Knekt, Joanne Knight, Ivana Kolcic, Jaspal S Kooner, Seppo Koskinen, Kati Kristiansson, Zoltan Kutalik, Maris Laan, Marty Larson, Lenore J Launer, Benjamin Lehne, Terho Lehtimäki, David Cm Liewald, Li Lin, Lars Lind, Cecilia M Lindgren, YongMei Liu, Ruth Jf Loos, Lorna M Lopez, Yingchang Lu, Leo-Pekka Lyytikäinen, Anubha Mahajan, Chrysovalanto Mamasoula, Jaume Marrugat, Jonathan Marten, Yuri Milaneschi, Anna Morgan, Andrew P Morris, Alanna C Morrison, Peter J Munson, Mike A Nalls, Priyanka Nandakumar, Christopher P Nelson, Teemu Niiranen, Ilja M Nolte, Teresa Nutile, Albertine J Oldehinkel, Ben A Oostra, Paul F O'Reilly, Elin Org, Sandosh Padmanabhan, Walter Palmas, Aarno Palotie, Alison Pattie, Brenda Wjh Penninx, Markus Perola, Annette Peters, Ozren Polasek, Peter P Pramstaller, Quang Tri Nguyen, Olli T Raitakari, Rainer Rettig, Kenneth Rice, Paul M Ridker, Janina S Ried, Harriëtte Riese, Samuli Ripatti, Antonietta Robino, Lynda M Rose, Jerome I Rotter, Igor Rudan, Daniela Ruggiero, Yasaman Saba, Cinzia F Sala, Veikko Salomaa, Nilesh J Samani, Antti-Pekka Sarin, Reinhold Schmidt, Helena Schmidt, Nick Shrine, David Siscovick, Albert V Smith, Harold Snieder, Siim Sõber, Rossella Sorice, John M Starr, David J Stott, David P Strachan, Rona J Strawbridge, Johan Sundström, Morris A Swertz, Kent D Taylor, Alexander Teumer, Martin D Tobin, Maciej Tomaszewski, Daniela Toniolo, Michela Traglia, Stella Trompet, Jaakko Tuomilehto, Christophe Tzourio, André G Uitterlinden, Ahmad Vaez, Peter J van der Most, Cornelia M van Duijn, Germaine C Verwoert, Veronique Vitart, Uwe Völker, Peter Vollenweider, Dragana Vuckovic, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, James F Wilson, Alan F Wright, Jie Yao, Tatijana Zemunik, Weihua Zhang, John R Attia, Adam S Butterworth, Daniel I Chasman, David Conen, Francesco Cucca, John Danesh, Caroline Hayward, Joanna Mm Howson, Markku Laakso, Edward G Lakatta, Claudia Langenberg, Olle Melander, Dennis O Mook-Kanamori, Colin Na Palmer, Lorenz Risch, Robert A Scott, Rodney J Scott, Peter Sever, Tim D Spector, Pim van der Harst, Nicholas J Wareham, Eleftheria Zeggini, Daniel Levy, Patricia B Munroe, Christopher Newton-Cheh, Morris J Brown, Andres Metspalu, Bruce M Psaty, Louise V Wain, Paul Elliott, Mark J Caulfield, Padhraig Gormley, Verneri Anttila, Priit Palta, Tonu Esko, Tune H Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M Terwindt, Mikko Kallela, Tobias M Freilinger, Caroline Ran, Scott G Gordon, Anine H Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H H Adams, Terho Lehtimäki, Antti-Pekka Sarin, Juho Wedenoja, David A Hinds, Julie E Buring, Markus Schürks, Paul M Ridker, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M Ring, Jouke-Jan Hottenga, Brenda W J H Penninx, Markus Färkkilä, Ville Artto, Mari Kaunisto, Salli Vepsäläinen, Rainer Malik, Andrew C Heath, Pamela A F Madden, Nicholas G Martin, Grant W Montgomery, Mitja I Kurki, Mart Kals, Reedik Mägi, Kalle Pärn, Eija Hämäläinen, Hailiang Huang, Andrea E Byrnes, Lude Franke, Jie Huang, Evie Stergiakouli, Phil H Lee, Cynthia Sandor, Caleb Webber, Zameel Cader, Bertram Muller-Myhsok, Stefan Schreiber, Thomas Meitinger, Johan G Eriksson, Veikko Salomaa, Kauko Heikkilä, Elizabeth Loehrer, Andre G Uitterlinden, Albert Hofman, Cornelia M van Duijn, Lynn Cherkas, Linda M Pedersen, Audun Stubhaug, Christopher S Nielsen, Minna Männikkö, Evelin Mihailov, Lili Milani, Hartmut Göbel, Ann-Louise Esserlind, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jaakko Kaprio, Arpo J Aromaa, Olli Raitakari, M Arfan Ikram, Tim Spector, Marjo-Riitta Järvelin, Andres Metspalu, Christian Kubisch, David P Strachan, Michel D Ferrari, Andrea C Belin, Martin Dichgans, Maija Wessman, Arn M J M van den Maagdenberg, Dorret I Boomsma, George Davey Smith, Kari Stefansson, Nicholas Eriksson, Mark J Daly, Benjamin M Neale, Jes Olesen, Daniel I Chasman, Dale R Nyholt, Aarno Palotie, Masato Akiyama, Varinder S Alg, Sigrid Børte, Joseph P Broderick, Ben M Brumpton, Jérôme Dauvillier, Hubert Desal, Christian Dina, Christoph M Friedrich, Emília I Gaál-Paavola, Jean-Christophe Gentric, Sven Hirsch, Isabel C Hostettler, Henry Houlden, Kristian Hveem, Juha E Jääskeläinen, Marianne Bakke Johnsen, Liming Li, Kuang Lin, Antti Lindgren, Olivier Martin, Koichi Matsuda, Iona Y Millwood, Olivier Naggara, Mika Niemelä, Joanna Pera, Richard Redon, Guy A Rouleau, Marie Søfteland Sandvei, Sabine Schilling, Eimad Shotar, Agnieszka Slowik, Chikashi Terao, W M Monique Verschuren, Robin G Walters, David J Werring, Cristen J Willer, Daniel Woo, Bradford B Worrall, Sirui Zhou, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and Admin, Oskar
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Advanced and Specialized Nursing ,Incidence ,risk assessment ,Smoking/epidemiology ,intracranial aneurysm ,genetic heterogeneity ,[SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie ,Risk Factors ,Intracranial Aneurysm/epidemiology ,Humans ,Subarachnoid Hemorrhage/epidemiology ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,genetics ,Neurology (clinical) ,aneurysmal subarachnoid hemorrhage ,genetic ,Cardiology and Cardiovascular Medicine - Abstract
Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.
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- 2023
20. Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes
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Liam McAllan, Damir Baranasic, Sergio Villicaña, Scarlett Brown, Weihua Zhang, Benjamin Lehne, Marco Adamo, Andrew Jenkinson, Mohamed Elkalaawy, Borzoueh Mohammadi, Majid Hashemi, Nadia Fernandes, Nathalie Lambie, Richard Williams, Colette Christiansen, Youwen Yang, Liudmila Zudina, Vasiliki Lagou, Sili Tan, Juan Castillo-Fernandez, James W. D. King, Richie Soong, Paul Elliott, James Scott, Inga Prokopenko, Inês Cebola, Marie Loh, Boris Lenhard, Rachel L. Batterham, Jordana T. Bell, John C. Chambers, Jaspal S. Kooner, and William R. Scott
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Multidisciplinary ,General Physics and Astronomy ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology - Abstract
DNA methylation variations are prevalent in human obesity but evidence of a causative role in disease pathogenesis is limited. Here, we combine epigenome-wide association and integrative genomics to investigate the impact of adipocyte DNA methylation variations in human obesity. We discover extensive DNA methylation changes that are robustly associated with obesity (N = 190 samples, 691 loci in subcutaneous and 173 loci in visceral adipocytes, P 500 target genes, and identify putative methylation-transcription factor interactions. Through Mendelian Randomisation, we infer causal effects of methylation on obesity and obesity-induced metabolic disturbances at 59 independent loci. Targeted methylation sequencing, CRISPR-activation and gene silencing in adipocytes, further identifies regional methylation variations, underlying regulatory elements and novel cellular metabolic effects. Our results indicate DNA methylation is an important determinant of human obesity and its metabolic complications, and reveal mechanisms through which altered methylation may impact adipocyte functions.
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- 2023
21. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
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Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, Gina M. Peloso, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, Samuli Olli Ripatti / Principal Investigator, HUSLAB, Epigenetics of Complex Diseases and Traits, Department of Medicine, Helsinki University Hospital Area, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Faculty Common Matters (Faculty of Social Sciences), Elisabeth Ingrid Maria Widen / Principal Investigator, Genomic Discoveries and Clinical Translation, Tampere University, Primary Health Care, Clinical Medicine, Department of Clinical Chemistry, TAYS Heart Centre, Department of Clinical Physiology and Nuclear Medicine, Epidemiology and Data Science, APH - Aging & Later Life, ACS - Diabetes & metabolism, ACS - Heart failure & arrhythmias, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, General practice, APH - Digital Health, Lee Kong Chian School of Medicine (LKCMedicine), Peloso, Gina M [0000-0002-5355-8636], Apollo - University of Cambridge Repository, Epidemiology, Department of Marketing Management, Erasmus MC other, Radiology & Nuclear Medicine, Kanoni, Stavroula, Graham, Sarah E, Wang, Yuxuan, Surakka, Ida, Ramdas, Shweta, Zhu, Xiang, Clarke, Shoa L, Bhatti, Konain Fatima, Vedantam, Sailaja, Winkler, Thomas W, Locke, Adam E, Marouli, Eirini, Zajac, Greg J M, Wu, Kuan-Han H, Ntalla, Ioanna, Hui, Qin, Klarin, Derek, Hilliard, Austin T, Wang, Zeyuan, Xue, Chao, Thorleifsson, Gudmar, Helgadottir, Anna, Gudbjartsson, Daniel F, Holm, Hilma, Olafsson, Isleifur, Hwang, Mi Yeong, Han, Sohee, Akiyama, Masato, Sakaue, Saori, Terao, Chikashi, Kanai, Masahiro, Zhou, Wei, Brumpton, Ben M, Rasheed, Humaira, Havulinna, Aki S, Veturi, Yogasudha, Pacheco, Jennifer Allen, Rosenthal, Elisabeth A, Lingren, Todd, Feng, Qiping, Kullo, Iftikhar J, Narita, Akira, Takayama, Jun, Martin, Hilary C, Hunt, Karen A, Trivedi, Bhavi, Haessler, Jeffrey, Giulianini, Franco, Bradford, Yuki, Miller, Jason E, Campbell, Archie, Lin, Kuang, Millwood, Iona Y, Rasheed, Asif, Hindy, George, Faul, Jessica D, Zhao, Wei, Weir, David R, Turman, Constance, Huang, Hongyan, Graff, Mariaelisa, Choudhury, Ananyo, Sengupta, Dhriti, Mahajan, Anubha, Brown, Michael R, Zhang, Weihua, Yu, Ketian, Schmidt, Ellen M, Pandit, Anita, Gustafsson, Stefan, Yin, Xianyong, Luan, Jian'An, Zhao, Jing-Hua, Matsuda, Fumihiko, Jang, Hye-Mi, Yoon, Kyungheon, Medina-Gomez, Carolina, Pitsillides, Achillea, Hottenga, Jouke Jan, Wood, Andrew R, Ji, Yingji, Gao, Zishan, Haworth, Simon, Yousri, Noha A, Mitchell, Ruth E, Chai, Jin Fang, Aadahl, Mette, Bjerregaard, Anne A, Yao, Jie, Manichaikul, Ani, Hwu, Chii-Min, Hung, Yi-Jen, Warren, Helen R, Ramirez, Julia, Bork-Jensen, Jette, Kårhus, Line L, Goel, Anuj, Sabater-Lleal, Maria, Noordam, Raymond, Mauro, Pala, Matteo, Flori, Mcdaid, Aaron F, Marques-Vidal, Pedro, Wielscher, Matthia, Trompet, Stella, Sattar, Naveed, Møllehave, Line T, Munz, Matthia, Zeng, Lingyao, Huang, Jianfeng, Yang, Bin, Poveda, Alaitz, Kurbasic, Azra, Lamina, Claudia, Forer, Luka, Scholz, Marku, Galesloot, Tessel E, Bradfield, Jonathan P, Ruotsalainen, Sanni E, Daw, Ewarwick, Zmuda, Joseph M, Mitchell, Jonathan S, Fuchsberger, Christian, Christensen, Henry, Brody, Jennifer A, Vazquez-Moreno, Miguel, Feitosa, Mary F, Wojczynski, Mary K, Wang, Zhe, Preuss, Michael H, Mangino, Massimo, Christofidou, Paraskevi, Verweij, Niek, Benjamins, Jan W, Engmann, Jorgen, Tsao, Noah L, Verma, Anurag, Slieker, Roderick C, Lo, Ken Sin, Zilhao, Nuno R, Le, Phuong, Kleber, Marcus E, Delgado, Graciela E, Huo, Shaofeng, Ikeda, Daisuke D, Iha, Hiroyuki, Yang, Jian, Liu, Jun, Demirkan, Ayşe, Leonard, Hampton L, Marten, Jonathan, Frank, Mirjam, Schmidt, Börge, Smyth, Laura J, Cañadas-Garre, Marisa, Wang, Chaolong, Nakatochi, Masahiro, Wong, Andrew, Hutri-Kähönen, Nina, Sim, Xueling, Xia, Rui, Huerta-Chagoya, Alicia, Fernandez-Lopez, Juan Carlo, Lyssenko, Valeriya, Nongmaithem, Suraj S, Bayyana, Swati, Stringham, Heather M, Irvin, Marguerite R, Oldmeadow, Christopher, Kim, Han-Na, Ryu, Seungho, Timmers, Paul R H J, Arbeeva, Liubov, Dorajoo, Rajkumar, Lange, Leslie A, Prasad, Gauri, Lorés-Motta, Laura, Pauper, Marc, Long, Jirong, Li, Xiaohui, Theusch, Elizabeth, Takeuchi, Fumihiko, Spracklen, Cassandra N, Loukola, Anu, Bollepalli, Sailalitha, Warner, Sophie C, Wang, Ya Xing, Wei, Wen B, Nutile, Teresa, Ruggiero, Daniela, Sung, Yun Ju, Chen, Shufeng, Liu, Fangchao, Yang, Jingyun, Kentistou, Katherine A, Banas, Bernhard, Nardone, Giuseppe Giovanni, Meidtner, Karina, Bielak, Lawrence F, Smith, Jennifer A, Hebbar, Prashantha, Farmaki, Aliki-Eleni, Hofer, Edith, Lin, Maoxuan, Concas, Maria Pina, Vaccargiu, Simona, van der Most, Peter J, Pitkänen, Niina, Cade, Brian E, van der Laan, Sander W, Chitrala, Kumaraswamy Naidu, Weiss, Stefan, Bentley, Amy R, Doumatey, Ayo P, Adeyemo, Adebowale A, Lee, Jong Young, Petersen, Eva R B, Nielsen, Aneta A, Choi, Hyeok Sun, Nethander, Maria, Freitag-Wolf, Sandra, Southam, Lorraine, Rayner, Nigel W, Wang, Carol A, Lin, Shih-Yi, Wang, Jun-Sing, Couture, Christian, Lyytikäinen, Leo-Pekka, Nikus, Kjell, Cuellar-Partida, Gabriel, Vestergaard, Henrik, Hidalgo, Bertha, Giannakopoulou, Olga, Cai, Qiuyin, Obura, Morgan O, van Setten, Jessica, Li, Xiaoyin, Liang, Jingjing, Tang, Hua, Terzikhan, Natalie, Shin, Jae Hun, Jackson, Rebecca D, Reiner, Alexander P, Martin, Lisa Warsinger, Chen, Zhengming, Li, Liming, Kawaguchi, Takahisa, Thiery, Joachim, Bis, Joshua C, Launer, Lenore J, Li, Huaixing, Nalls, Mike A, Raitakari, Olli T, Ichihara, Sahoko, Wild, Sarah H, Nelson, Christopher P, Campbell, Harry, Jäger, Susanne, Nabika, Toru, Al-Mulla, Fahd, Niinikoski, Harri, Braund, Peter S, Kolcic, Ivana, Kovacs, Peter, Giardoglou, Tota, Katsuya, Tomohiro, de Kleijn, Dominique, de Borst, Gert J, Kim, Eung Kweon, Adams, Hieab H H, Ikram, M Arfan, Zhu, Xiaofeng, Asselbergs, Folkert W, Kraaijeveld, Adriaan O, Beulens, Joline W J, Shu, Xiao-Ou, Rallidis, Loukianos S, Pedersen, Oluf, Hansen, Torben, Mitchell, Paul, Hewitt, Alex W, Kähönen, Mika, Pérusse, Loui, Bouchard, Claude, Tönjes, Anke, Chen, Yii-Der Ida, Pennell, Craig E, Mori, Trevor A, Lieb, Wolfgang, Franke, Andre, Ohlsson, Clae, Mellström, Dan, Cho, Yoon Shin, Lee, Hyejin, Yuan, Jian-Min, Koh, Woon-Puay, Rhee, Sang Youl, Woo, Jeong-Taek, Heid, Iris M, Stark, Klaus J, Zimmermann, Martina E, Völzke, Henry, Homuth, Georg, Evans, Michele K, Zonderman, Alan B, Polasek, Ozren, Pasterkamp, Gerard, Hoefer, Imo E, Redline, Susan, Pahkala, Katja, Oldehinkel, Albertine J, Snieder, Harold, Biino, Ginevra, Schmidt, Reinhold, Schmidt, Helena, Bandinelli, Stefania, Dedoussis, George, Thanaraj, Thangavel Alphonse, Kardia, Sharon L R, Peyser, Patricia A, Kato, Norihiro, Schulze, Matthias B, Girotto, Giorgia, Böger, Carsten A, Jung, Bettina, Joshi, Peter K, Bennett, David A, De Jager, Philip L, Lu, Xiangfeng, Mamakou, Vasiliki, Brown, Morri, Caulfield, Mark J, Munroe, Patricia B, Guo, Xiuqing, Ciullo, Marina, Jonas, Jost B, Samani, Nilesh J, Kaprio, Jaakko, Pajukanta, Päivi, Tusié-Luna, Teresa, Aguilar-Salinas, Carlos A, Adair, Linda S, Bechayda, Sonny Augustin, de Silva, H Janaka, Wickremasinghe, Ananda R, Krauss, Ronald M, Wu, Jer-Yuarn, Zheng, Wei, Hollander, Anneke Iden, Bharadwaj, Dwaipayan, Correa, Adolfo, Wilson, James G, Lind, Lar, Heng, Chew-Kiat, Nelson, Amanda E, Golightly, Yvonne M, Wilson, James F, Penninx, Brenda, Kim, Hyung-Lae, Attia, John, Scott, Rodney J, Rao, D C, Arnett, Donna K, Hunt, Steven C, Walker, Mark, Koistinen, Heikki A, Chandak, Giriraj R, Mercader, Josep M, Costanzo, Maria C, Jang, Dongkeun, Burtt, Noël P, Villalpando, Clicerio Gonzalez, Orozco, Lorena, Fornage, Myriam, Tai, Eshyong, van Dam, Rob M, Lehtimäki, Terho, Chaturvedi, Nish, Yokota, Mitsuhiro, Liu, Jianjun, Reilly, Dermot F, Mcknight, Amy Jayne, Kee, Frank, Jöckel, Karl-Heinz, Mccarthy, Mark I, Palmer, Colin N A, Vitart, Veronique, Hayward, Caroline, Simonsick, Eleanor, van Duijn, Cornelia M, Jin, Zi-Bing, Qu, Jia, Hishigaki, Haretsugu, Lin, Xu, März, Winfried, Gudnason, Vilmundur, Tardif, Jean-Claude, Lettre, Guillaume, Hart, Leen M 't, Elders, Petra J M, Damrauer, Scott M, Kumari, Meena, Kivimaki, Mika, van der Harst, Pim, Spector, Tim D, Loos, Ruth J F, Province, Michael A, Parra, Esteban J, Cruz, Miguel, Psaty, Bruce M, Brandslund, Ivan, Pramstaller, Peter P, Rotimi, Charles N, Christensen, Kaare, Ripatti, Samuli, Widén, Elisabeth, Hakonarson, Hakon, Grant, Struan F A, Kiemeney, Lambertus A L M, de Graaf, Jacqueline, Loeffler, Marku, Kronenberg, Florian, Gu, Dongfeng, Erdmann, Jeanette, Schunkert, Heribert, Franks, Paul W, Linneberg, Allan, Jukema, J Wouter, Khera, Amit V, Männikkö, Minna, Jarvelin, Marjo-Riitta, Kutalik, Zoltan, Francesco, Cucca, Mook-Kanamori, Dennis O, van Dijk, Ko Willem, Watkins, Hugh, Strachan, David P, Grarup, Niel, Sever, Peter, Poulter, Neil, Chuang, Lee-Ming, Rotter, Jerome I, Dantoft, Thomas M, Karpe, Fredrik, Neville, Matt J, Timpson, Nicholas J, Cheng, Ching-Yu, Wong, Tien-Yin, Khor, Chiea Chuen, Li, Hengtong, Sabanayagam, Charumathi, Peters, Annette, Gieger, Christian, Hattersley, Andrew T, Pedersen, Nancy L, Magnusson, Patrik K E, Boomsma, Dorret I, Willemsen, Allegonda H M, Cupples, Ladrienne, van Meurs, Joyce B J, Ghanbari, Mohsen, Gordon-Larsen, Penny, Huang, Wei, Kim, Young Jin, Tabara, Yasuharu, Wareham, Nicholas J, Langenberg, Claudia, Zeggini, Eleftheria, Kuusisto, Johanna, Laakso, Markku, Ingelsson, Erik, Abecasis, Goncalo, Chambers, John C, Kooner, Jaspal S, de Vries, Paul S, Morrison, Alanna C, Hazelhurst, Scott, Ramsay, Michèle, North, Kari E, Daviglus, Martha, Kraft, Peter, Martin, Nicholas G, Whitfield, John B, Abbas, Shahid, Saleheen, Danish, Walters, Robin G, Holmes, Michael V, Black, Corri, Smith, Blair H, Baras, Ari, Justice, Anne E, Buring, Julie E, Ridker, Paul M, Chasman, Daniel I, Kooperberg, Charle, Tamiya, Gen, Yamamoto, Masayuki, van Heel, David A, Trembath, Richard C, Wei, Wei-Qi, Jarvik, Gail P, Namjou, Bahram, Hayes, M Geoffrey, Ritchie, Marylyn D, Jousilahti, Pekka, Salomaa, Veikko, Hveem, Kristian, Åsvold, Bjørn Olav, Kubo, Michiaki, Kamatani, Yoichiro, Okada, Yukinori, Murakami, Yoshinori, Kim, Bong-Jo, Thorsteinsdottir, Unnur, Stefansson, Kari, Zhang, Jifeng, Chen, Yeugene, Ho, Yuk-Lam, Lynch, Julie A, Rader, Daniel J, Tsao, Philip S, Chang, Kyong-Mi, Cho, Kelly, O'Donnell, Christopher J, Gaziano, John M, Wilson, Peter W F, Frayling, Timothy M, Hirschhorn, Joel N, Kathiresan, Sekar, Mohlke, Karen L, Sun, Yan V, Morris, Andrew P, Boehnke, Michael, Brown, Christopher D, Natarajan, Pradeep, Deloukas, Pano, Willer, Cristen J, Assimes, Themistocles L, and Peloso, Gina M
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Genome-wide association study ,Medizin ,Polymorphism, Single Nucleotide ,Humans ,Genome-Wide Association Study ,Genetic Predisposition to Disease ,Sex Characteristics ,Phenotype ,Lipids/genetics ,Genetic Pleiotropy ,Cholesterol ,GWAS ,Genetics ,Lipids ,Genetic ,SDG 3 - Good Health and Well-being ,Medicine [Science] ,112 Statistics and probability ,Medicinsk genetik ,Genome-wide Association Study ,Gwas ,1184 Genetics, developmental biology, physiology ,3126 Surgery, anesthesiology, intensive care, radiology ,3142 Public health care science, environmental and occupational health ,3141 Health care science ,FOS: Biological sciences ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,3111 Biomedicine ,Medical Genetics - Abstract
Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry metaanalysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk., United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) R01HL127564 R01HL142711, Wellcome Trust 201543/B/16/Z 202802/Z/16/Z, European Commission HEALTH-F2-2013-601456 608765 786833, TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation NNF15CC0018486, American Diabetes Association 1-19-ICTS-068, Academy of Finland 312062 Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation, Finnish innovation fund Sitra (EW) Finska Lakaresallskapet, American Heart Association 15POST24470131 17POST33650016, University of Bristol NIHR Biomedical Research Centre BRC-1215-2001, MRC & WT 217065/Z/19/Z, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MC_UU_00011, CRUK Integrative Cancer Epidemiology Programme C18281/A19169, Medical Research Council UK (MRC) MC_UU_00011/1, UK National Institute for Health Research Academic Clinical Fellowship, American Heart Association 18CDA34110116, Miguel Servet contract from the ISCIII Spanish Health Institute CP17/00142, European Social Fund (ESF), Westlake Education Foundation, British Heart Foundation FS/14/66/3129 Z01HG200362 R01HL142302 R01HL105756
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22. Accelerated ageing is associated with increased COVID-19 severity and differences across ethnic groups may exist
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Joshua, Reeves, Jaspal S, Kooner, and Weihua, Zhang
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Aging ,Risk Factors ,Ethnicity ,Public Health, Environmental and Occupational Health ,Humans ,COVID-19 ,Black People - Abstract
BackgroundWhile increased age is an established risk factor for COVID-19, there is great heterogeneity in outcomes within age groups. This is because chronological age does not reflect health, unlike biological age. We intend to investigate the association between accelerated ageing and COVID-19 outcomes through the lens of three measures, namely phenotypic age acceleration (PhenoAgeAccel), telomere length (Adjusted T/S Ratio) and facial ageing, and to examine whether there are differences across ethnic groups.MethodsTaking participants from the UK Biobank, we associated accelerated ageing with severe COVID-19 outcomes, defined as COVID-related hospitalisation or death. Separate logistic regressions models were created for age and the three accelerated ageing-related variables, adjusting for a variety of covariates in each model. Multivariable logistic regression models were also created within White, Black, Asian and Other ethnic groups to assess for potential differing associations. Forward likelihood ratio logistic regression models were created to evaluate importance of the variables and to assess for patterns of association across the total population and ethnic groups.ResultsAfter adjusting for all covariates, the odds ratio (OR) and 95% confidence interval (95% CI) of COVID-19 severe outcomes for age was 1.080 (1.074–1.086). After further adjusting age for the accelerated ageing variables, the ORs were 1.029 (1.020–1.039) for PhenoAgeAccel and 0.847 (0.772–0.929) for Facial Ageing's “Younger Than You Are” while Adjusted T/S ratio and “Older Than You Are” were statistically insignificant. The OR for age remained similar across ethnic groups. Both PhenoAgeAccel and younger facial ages in the White population and PhenoAgeAccel in the Black population had ORs of 1.031 (1.021–1.042), 0.853 (0.774–0.939), and 1.049 (1.001–1.100), respectively. Both Adjusted T/S Ratio and older facial ages showed statistical insignificance in all ethnicities. In forward logistic regression, age and PhenoAgeAccel were the age-related variables selected most frequently in all models.InterpretationAccelerated ageing is associated with increased COVID-19 severity. The mechanisms at work here are likely immunosenescence and inflamaging. This association indicates that anti-ageing treatment may improve COVID-19 outcome. The results within ethnic groups and that of telomere length were inconclusive, but point to a need for future, more focused research on the topic.
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23. The iHealth-T2D study
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Mirthe Muilwijk, Marie Loh, Sara Mahmood, Saranya Palaniswamy, Samreen Siddiqui, Wnurinham Silva, Gary S. Frost, Heather M. Gage, Marjo-Riitta Jarvelin, Ravindra P. Rannan-Eliya, Sajjad Ahmad, Sujeet Jha, Anuradhani Kasturiratne, Prasad Katulanda, Khadija I. Khawaja, Jaspal S. Kooner, Ananda R. Wickremasinghe, Irene G. M. van Valkengoed, John C. Chambers, Epidemiology and Data Science, ACS - Diabetes & metabolism, and APH - Health Behaviors & Chronic Diseases
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Adult ,Male ,Medicine (miscellaneous) ,Middle Aged ,Prediabetic State ,Asian People ,Diabetes Mellitus, Type 2 ,Obesity, Abdominal ,Humans ,Female ,Pharmacology (medical) ,Obesity ,Aged ,Sri Lanka - Abstract
Background South Asians are at high risk of type 2 diabetes (T2D). Lifestyle modification is effective at preventing T2D amongst South Asians, but the approaches to screening and intervention are limited by high costs, poor scalability and thus low impact on T2D burden. An intensive family-based lifestyle modification programme for the prevention of T2D was developed. The aim of the iHealth-T2D trial is to compare the effectiveness of this programme with usual care. Methods The iHealth-T2D trial is designed as a cluster randomised controlled trial (RCT) conducted at 120 sites across India, Pakistan, Sri Lanka and the UK. A total of 3682 South Asian men and women with age between 40 and 70 years without T2D but at elevated risk for T2D [defined by central obesity (waist circumference ≥ 95 cm in Sri Lanka or ≥ 100 cm in India, Pakistan and the UK) and/or prediabetes (HbA1c ≥ 6.0%)] were included in the trial. Here, we describe in detail the statistical analysis plan (SAP), which was finalised before outcomes were available to the investigators. The primary outcome will be evaluated after 3 years of follow-up after enrolment to the study and is defined as T2D incidence in the intervention arm compared to usual care. Secondary outcomes are evaluated both after 1 and 3 years of follow-up and include biochemical measurements, anthropometric measurements, behavioural components and treatment compliance. Discussion The iHealth-T2D trial will provide evidence of whether an intensive family-based lifestyle modification programme for South Asians who are at high risk for T2D is effective in the prevention of T2D. The data from the trial will be analysed according to this pre-specified SAP. Ethics and dissemination The trial was approved by the international review board of each participating study site. Study findings will be disseminated through peer-reviewed publications and in conference presentations. Trial registration EudraCT 2016–001,350-18. Registered on 14 April 2016. ClinicalTrials.gov NCT02949739. Registered on 31 October 2016.
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24. Author Correction: Identification of genetic effects underlying type 2 diabetes in South Asian and European populations
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Marie Loh, Weihua Zhang, Hong Kiat Ng, Katharina Schmid, Amel Lamri, Lin Tong, Meraj Ahmad, Jung-Jin Lee, Maggie C. Y. Ng, Lauren E. Petty, Cassandra N. Spracklen, Fumihiko Takeuchi, Md. Tariqul Islam, Farzana Jasmine, Anuradhani Kasturiratne, Muhammad Kibriya, Karen L. Mohlke, Guillaume Paré, Gauri Prasad, Mohammad Shahriar, Miao Ling Chee, H. Janaka de Silva, James C. Engert, Hertzel C. Gerstein, K. Radha Mani, Charumathi Sabanayagam, Marijana Vujkovic, Ananda R. Wickremasinghe, Tien Yin Wong, Chittaranjan S. Yajnik, Salim Yusuf, Habibul Ahsan, Dwaipayan Bharadwaj, Sonia S. Anand, Jennifer E. Below, Michael Boehnke, Donald W. Bowden, Giriraj R. Chandak, Ching-Yu Cheng, Norihiro Kato, Anubha Mahajan, Xueling Sim, Mark I. McCarthy, Andrew P. Morris, Jaspal S. Kooner, Danish Saleheen, and John C. Chambers
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Medicine (miscellaneous) ,General Agricultural and Biological Sciences ,General Biochemistry, Genetics and Molecular Biology - Published
- 2022
25. Identification of genetic effects underlying type 2 diabetes in South Asian and European populations
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Marie Loh, Weihua Zhang, Hong Kiat Ng, Katharina Schmid, Amel Lamri, Lin Tong, Meraj Ahmad, Jung-Jin Lee, Maggie C. Y. Ng, Lauren E. Petty, Cassandra N. Spracklen, Fumihiko Takeuchi, Md. Tariqul Islam, Farzana Jasmine, Anuradhani Kasturiratne, Muhammad Kibriya, Karen L. Mohlke, Guillaume Paré, Gauri Prasad, Mohammad Shahriar, Miao Ling Chee, H. Janaka de Silva, James C. Engert, Hertzel C. Gerstein, K. Radha Mani, Charumathi Sabanayagam, Marijana Vujkovic, Ananda R. Wickremasinghe, Tien Yin Wong, Chittaranjan S. Yajnik, Salim Yusuf, Habibul Ahsan, Dwaipayan Bharadwaj, Sonia S. Anand, Jennifer E. Below, Michael Boehnke, Donald W. Bowden, Giriraj R. Chandak, Ching-Yu Cheng, Norihiro Kato, Anubha Mahajan, Xueling Sim, Mark I. McCarthy, Andrew P. Morris, Jaspal S. Kooner, Danish Saleheen, John C. Chambers, Lee Kong Chian School of Medicine (LKCMedicine), Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, and Commission of the European Communities
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endocrine system diseases ,Diabetes ,Medicine (miscellaneous) ,Genetic Variation ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Asians ,Asian People ,Diabetes Mellitus, Type 2 ,Case-Control Studies ,Humans ,Genetic Predisposition to Disease ,Medicine [Science] ,General Agricultural and Biological Sciences ,Genome-Wide Association Study - Abstract
South Asians are at high risk of developing type 2 diabetes (T2D). We carried out a genome-wide association meta-analysis with South Asian T2D cases (n = 16,677) and controls (n = 33,856), followed by combined analyses with Europeans (neff = 231,420). We identify 21 novel genetic loci for significant association with T2D (P = 4.7 × 10-8 to 5.2 × 10-12), to the best of our knowledge at the point of analysis. The loci are enriched for regulatory features, including DNA methylation and gene expression in relevant tissues, and highlight CHMP4B, PDHB, LRIG1 and other genes linked to adiposity and glucose metabolism. A polygenic risk score based on South Asian-derived summary statistics shows ~4-fold higher risk for T2D between the top and bottom quartile. Our results provide further insights into the genetic mechanisms underlying T2D, and highlight the opportunities for discovery from joint analysis of data from across ancestral populations. Ministry of Health (MOH) National Medical Research Council (NMRC) Published version J.C.C. is supported by the Singapore Ministry of Health’s National Medical Research Council under its Singapore. The SINDI study is supported by the National Medical Research Council (NMRC), Singapore (grants 0796/2003, 1176/2008, 1149/2008, STaR/0003/2008, 1249/2010, CG/ SERI/2010, CIRG/1371/2013, and CIRG/1417/2015), and Biomedical Research Council (BMRC), Singapore (08/1/35/19/550 and 09/1/35/19/616).
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- 2022
26. Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function
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Johann S, Hawe, Rory, Wilson, Katharina T, Schmid, Li, Zhou, Lakshmi Narayanan, Lakshmanan, Benjamin C, Lehne, Brigitte, Kühnel, William R, Scott, Matthias, Wielscher, Yik Weng, Yew, Clemens, Baumbach, Dominic P, Lee, Eirini, Marouli, Manon, Bernard, Liliane, Pfeiffer, Pamela R, Matías-García, Matias I, Autio, Stephane, Bourgeois, Christian, Herder, Ville, Karhunen, Thomas, Meitinger, Holger, Prokisch, Wolfgang, Rathmann, Michael, Roden, Sylvain, Sebert, Jean, Shin, Konstantin, Strauch, Weihua, Zhang, Wilson L W, Tan, Stefanie M, Hauck, Juliane, Merl-Pham, Harald, Grallert, Eudes G V, Barbosa, Thomas, Illig, Annette, Peters, Tomas, Paus, Zdenka, Pausova, Panos, Deloukas, Roger S Y, Foo, Marjo-Riitta, Jarvelin, Jaspal S, Kooner, Marie, Loh, Matthias, Heinig, Christian, Gieger, Melanie, Waldenberger, and Krina T, Zondervan
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DNA Replication ,Asia ,Quantitative Trait Loci ,Genetic Variation ,Blood Pressure ,CD8-Positive T-Lymphocytes ,DNA Methylation ,Polymorphism, Single Nucleotide ,Body Mass Index ,Arthritis, Rheumatoid ,Europe ,Leukocytes ,Genetics ,Humans ,CpG Islands ,Genome-Wide Association Study - Abstract
We determined the relationships between DNA sequence variation and DNA methylation using blood samples from 3,799 Europeans and 3,195 South Asians. We identify 11,165,559 SNP-CpG associations (methylation quantitative trait loci (meQTL), P
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- 2022
27. The iHealth-T2D study, prevention of type 2 diabetes amongst South Asians with central obesity and prediabetes: study protocol for a randomised controlled trial
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Anuradhani Kasturiratne, Khadija I. Khawaja, Sajjad Ahmad, Samreen Siddiqui, Khurram Shahzad, Lathika K. Athauda, Ranil Jayawardena, Sara Mahmood, Mirthe Muilwijk, Tayyaba Batool, Saira Burney, Matthew Glover, Saranya Palaniswamy, Vodathi Bamunuarachchi, Manju Panda, Suren Madawanarachchi, Baldeesh Rai, Iqra Sattar, Wnurinham Silva, Swati Waghdhare, Marjo-Riitta Jarvelin, Ravindra P. Rannan-Eliya, Heather M. Gage, Irene G. M. van Valkengoed, Jonathan Valabhji, Gary S. Frost, Marie Loh, Ananda R. Wickremasinghe, Jaspal S. Kooner, Prasad Katulanda, Sujeet Jha, John C. Chambers, Lee Kong Chian School of Medicine (LKCMedicine), Epidemiology and Data Science, Graduate School, ACS - Diabetes & metabolism, APH - Health Behaviors & Chronic Diseases, Public and occupational health, and APH - Methodology
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Adult ,Male ,Medicine (General) ,Medicine (miscellaneous) ,030209 endocrinology & metabolism ,Prediabetic State ,Study Protocol ,03 medical and health sciences ,R5-920 ,0302 clinical medicine ,Asian People ,Cholesterol Blood Level ,Humans ,Pharmacology (medical) ,Medicine [Science] ,030212 general & internal medicine ,Life Style ,Aged ,Randomized Controlled Trials as Topic ,2. Zero hunger ,Dietary Intake ,Middle Aged ,3. Good health ,Diabetes Mellitus, Type 2 ,Obesity, Abdominal ,Female - Abstract
Background People from South Asia are at increased risk of type 2 diabetes (T2D). There is an urgent need to develop approaches for the prevention of T2D in South Asians that are cost-effective, generalisable and scalable across settings. Hypothesis Compared to usual care, the risk of T2D can be reduced amongst South Asians with central obesity or raised HbA1c, through a 12-month lifestyle modification programme delivered by community health workers. Design Cluster randomised clinical trial (1:1 allocation to intervention or usual care), carried out in India, Pakistan, Sri Lanka and the UK, with 30 sites per country (120 sites total). Target recruitment 3600 (30 participants per site) with annual follow-up for 3 years. Entry criteria South Asian, men or women, age 40–70 years with (i) central obesity (waist circumference ≥ 100 cm in India and Pakistan; ≥90 cm in Sri Lanka) and/or (ii) prediabetes (HbA1c 6.0–6.4% inclusive). Exclusion criteria: known type 1 or 2 diabetes, normal or underweight (body mass index 2); pregnant or planning pregnancy; unstable residence or planning to leave the area; and serious illness. Endpoints The primary endpoint is new-onset T2D at 3 years, defined as (i) HbA1c ≥ 6.5% or (ii) physician diagnosis and on treatment for T2D. Secondary endpoints at 1 and 3 years are the following: (i) physical measures: waist circumference, weight and blood pressure; (ii) lifestyle measures: smoking status, alcohol intake, physical activity and dietary intake; (iii) biochemical measures: fasting glucose, insulin and lipids (total and HDL cholesterol, triglycerides); and (iv) treatment compliance. Intervention Lifestyle intervention (60 sites) or usual care (60 sites). Lifestyle intervention was delivered by a trained community health worker over 12 months (5 one-one sessions, 4 group sessions, 13 telephone sessions) with the goal of the participants achieving a 7% reduction in body mass index and a 10-cm reduction in waist circumference through (i) improved diet and (ii) increased physical activity. Usual care comprised a single 30-min session of lifestyle modification advice from the community health worker. Results We screened 33,212 people for inclusion into the study. We identified 10,930 people who met study entry criteria, amongst whom 3682 agreed to take part in the intervention. Study participants are 49.2% female and aged 52.8 (SD 8.2) years. Clinical characteristics are well balanced between intervention and usual care sites. More than 90% of follow-up visits are scheduled to be complete in December 2020. Based on the follow-up to end 2019, the observed incidence of T2D in the study population is in line with expectations (6.1% per annum). Conclusion The iHealth-T2D study will advance understanding of strategies for the prevention of diabetes amongst South Asians, use approaches for screening and intervention that are adapted for low-resource settings. Our study will thus inform the implementation of strategies for improving the health and well-being of this major global ethnic group. IRB approval 16/WM/0171 Trial registration EudraCT 2016-001350-18. Registered on 14 April 2016. ClinicalTrials.govNCT02949739. Registered on 31 October 2016, First posted on 31/10/2016.
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- 2021
28. Reference equations for evaluation of spirometry function tests in South Asia, and among South Asians living in other countries
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Wei Yee Leong, Ananya Gupta, Mehedi Hasan, Sara Mahmood, Samreen Siddiqui, Sajjad Ahmed, Ian Y. Goon, Marie Loh, Theresia H. Mina, Benjamin Lam, Yik Weng Yew, Joanne Ngeow, Jimmy Lee, Eng Sing Lee, Elio Riboli, Paul Elliott, Geak Poh Tan, Sanjay H. Chotirmall, Ananda R. Wickremasinghe, Jaspal S. Kooner, Khadija I. Khawaja, Prasad Katulanda, Malay K. Mridha, Sujeet Jha, Anjana Ranjit Mohan, Guha Pradeepa, Anuradhani Kasturiratne, and John C. Chambers
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Pulmonary and Respiratory Medicine ,Male ,Adult ,Adolescent ,Vital Capacity ,India ,respiratory system ,Nutrition Surveys ,respiratory tract diseases ,Asian People ,Reference Values ,Spirometry ,Forced Expiratory Volume ,Humans ,Female ,Lung ,circulatory and respiratory physiology - Abstract
BackgroundThere are few data to support accurate interpretation of spirometry data in South Asia, a major global region with a high reported burden of chronic respiratory disease.MethodWe measured lung function in 7453 healthy men and women aged ≥18 years, from Bangladesh, North India, South India, Pakistan and Sri Lanka, as part of the South Asia Biobank study. First, we assessed the accuracy of existing equations for predicting normal forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and FEV1/FVC ratio. Then, we used our data to derive (n=5589) and internally validate (n=1864) new prediction equations among South Asians, with further external validation among 339 healthy South Asians living in Singapore.ResultsThe Global Lung Initiative (GLI) and National Health and Nutrition Examination Survey consistently overestimated expiratory volumes (best fit GLI-African American, mean±sdz-score: FEV1−0.94±1.05, FVC −0.91±1.10; n=7453). Age, height and weight were strong predictors of lung function in our participants (p10.03±0.99, FVC 0.04±0.97, FEV1/FVC −0.03±0.99) and external validation (z-scores: FEV10.31±0.99, FVC 0.24±0.97, FEV1/FVC 0.16±0.91). Further adjustment for study regions improves the model fit, with highest accuracy for estimation of region-specific lung function in South Asia.ConclusionWe present improved equations for predicting lung function in South Asians. These offer the opportunity to enhance diagnosis and management of acute and chronic lung diseases in this major global population.
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- 2021
29. Effects of a lifestyle intervention programme after 1 year of follow-up among South Asians at high risk of type 2 diabetes
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Gary Frost, Swati Waghdhare, Matthew Glover, Sajjad Ahmad, Sujeet Jha, Mirthe Muilwijk, Anuradhani Kasturiratne, Manju Panda, Jaspal S. Kooner, Irene G. M. van Valkengoed, Saira Burney, Nilmini Wijemunige, R.P. Rannan-Eliya, Madawa Madawanarachchi, Baldeesh Rai, Khadija Irfan Khawaja, Vodathi Bamunuarachchi, Jonathan Valabhji, Saranya Palaniswamy, Samreen Siddiqui, Sara Mahmood, John C. Chambers, Heather Gage, Iqra Sattar, Ranil Jayawardena, L.K. Athauda, Prasad Katulanda, Marjo-Riitta Järvelin, Wnurinham Silva, Tayyaba Batool, Khurram Shahzad, Rajitha Wickremasinghe, Marie Loh, Epidemiology and Data Science, APH - Health Behaviors & Chronic Diseases, ACS - Diabetes & metabolism, Graduate School, Public and occupational health, and APH - Methodology
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Adult ,Male ,medicine.medical_specialty ,Medicine (General) ,Waist ,prevention strategies ,030209 endocrinology & metabolism ,Type 2 diabetes ,Infectious and parasitic diseases ,RC109-216 ,03 medical and health sciences ,0302 clinical medicine ,R5-920 ,Asian People ,Weight loss ,Diabetes mellitus ,Weight Loss ,Epidemiology ,Humans ,Medicine ,030212 general & internal medicine ,Cluster randomised controlled trial ,Life Style ,Original Research ,diabetes ,business.industry ,Health Policy ,public health ,Public Health, Environmental and Occupational Health ,nutritional and metabolic diseases ,medicine.disease ,Circumference ,3. Good health ,Blood pressure ,Diabetes Mellitus, Type 2 ,Physical therapy ,cluster randomized trial ,Female ,epidemiology ,medicine.symptom ,business ,Follow-Up Studies - Abstract
IntroductionSouth Asians are at high risk of type 2 diabetes (T2D). We assessed whether intensive family-based lifestyle intervention leads to significant weight loss, improved glycaemia and blood pressure in adults at elevated risk for T2D.MethodsThis cluster randomised controlled trial (iHealth-T2D) was conducted at 120 locations across India, Pakistan, Sri Lanka and the UK. We included 3684 South Asian men and women, aged 40–70 years, without T2D but with raised haemoglobin A1c (HbA1c) and/or waist circumference. Participants were randomly allocated either to the family-based lifestyle intervention or control group by location clusters. Participants in the intervention received 9 visits and 13 telephone contacts by community health workers over 1-year period, and the control group received usual care. Reductions in weight (aim >7% reduction), waist circumference (aim ≥5 cm reduction), blood pressure and HbA1C at 12 months of follow-up were assessed. Our linear mixed-effects regression analysis was based on intention-to-treat principle and adjusted for age, sex and baseline values.ResultsThere were 1846 participants in the control and 1838 in the intervention group. Between baseline and 12 months, mean weight of participants in the intervention group reduced by 1.8 kg compared with 0.4 kg in the control group (adjusted mean difference −1.10 kg (95% CI −1.70 to −1.06), pConclusionAn intensive family-based lifestyle intervention adopting low-resource strategies led to effective reduction in weight and waist circumference at 12 months, which has potential long-term benefits for preventing T2D. A higher number of attended sessions increased the effect on waist circumference, blood pressure and HbA1c.Trial registration numberEudraCT: 2016-001350-18; ClinicalTrials.gov: NCT02949739.
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- 2021
30. Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection
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David Adlam, Timothy M. Olson, Nicolas Combaret, Jason C. Kovacic, Siiri E. Iismaa, Abtehale Al-Hussaini, Megan M. O'Byrne, Sara Bouajila, Adrien Georges, Ketan Mishra, Peter S. Braund, Valentina d’Escamard, Siying Huang, Marios Margaritis, Christopher P. Nelson, Mariza de Andrade, Daniella Kadian-Dodov, Catherine A. Welch, Stephani Mazurkiewicz, Xavier Jeunemaitre, Claire Mei Yi Wong, Eleni Giannoulatou, Michael Sweeting, David Muller, Alice Wood, Lucy McGrath-Cadell, Diane Fatkin, Sally L. Dunwoodie, Richard Harvey, Cameron Holloway, Jean-Philippe Empana, Xavier Jouven, Jeffrey W. Olin, Rajiv Gulati, Marysia S. Tweet, Sharonne N. Hayes, Nilesh J. Samani, Robert M. Graham, Pascal Motreff, Nabila Bouatia-Naji, Loïc Belle, Patrick Dupouy, Pierre Barnay, Nicolas Meneveau, Martine Gilard, Gilles Rioufol, Grégoire Range, Philippe Brunel, Nicolas Delarche, Emmanuelle Filippi, Louis Le Bivic, Brahim Harbaoui, Hakim Benamer, Guillaume Cayla, Olivier Varenne, Stephane Peggy Manzo-Silberman, Johanne Silvain, Christian Spaulding, Christophe Caussin, Edouard Gerbaud, Yann Valy, René Koning, Thibault Lhermusier, Stanislas Champin, Emmanuel Salengro, Arnaud Fluttaz, Amer Zabalawi, Yves Cottin, Emmanuel Teiger, Christophe Saint-Etienne, Grégory Ducrocq, Stéphanie Marliere, Emmanuel Boiffard, Pierre Aubry, Jean Louis Georges, Didier Bresson, Fabien De Poli, Gaëtan Karrillon, Vincent Roule, Laurent Bali, Mathieu Valla, Antoine Gerbay, David Houpe, Olivier Dubreuil, Arsène Monnier, Norbert Mayaud, Aurélie Manchuelle, Philippe Commeau, Marc Bedossa, Majid Nikpay, Anuj Goel, Hong-Hee Won, Leanne M. Hall, Christina Willenborg, Stavroula Kanoni, Danish Saleheen, Theodosios Kyriakou, Jemma C. Hopewell, Thomas R. Webb, Lingyao Zeng, Abbas Dehghan, Maris Alver, Sebastian M. Armasu, Kirsi Auro, Andrew Bjonnes, Daniel I. Chasman, Shufeng Chen, Ian Ford, Nora Franceschini, Christian Gieger, Christopher Grace, Stefan Gustafsson, Jie Huang, Shih-Jen Hwang, Yun Kyoung Kim, Marcus E. Kleber, King Wai Lau, Xiangfeng Lu, Yingchang Lu, Leo P. Lyytikäinen, Evelin Mihailov, Alanna Morrison, Natalia Pervjakova, Liming Qu, Lynda M. Rose, Elias Salfati, Richa Saxena, Markus Scholz, Albert V. Smith, Emmi Tikkanen, Andre Uitterlinden, Xueli Yang, Weihua Zhang, Wei Zhao, Paul S. de Vries, Natalie R. van Zuydam, Sonia S. Anand, Lars Bertram, Frank Beutner, George Dedoussis, Philippe Frossard, Dominique Gauguier, Alison H. Goodall, Omri Gottesman, Marc Haber, Bok-Ghee Han, Jianfeng Huang, Shapour Jalilzadeh, Thorsten Kessler, Inke R. König, Lars Lannfelt, Wolfgang Lieb, Lars Lind, Cecilia M. Lindgren, Maisa Lokki, Patrik K. Magnusson, Nadeem H. Mallick, Narinder Mehra, Thomas Meitinger, Fazal-ur-Rehman Memon, Andrew P. Morris, Markku S. Nieminen, Nancy L. Pedersen, Annette Peters, Loukianos S. Rallidis, Asif Rasheed, Maria Samuel, Svati H. Shah, Juha Sinisalo, Kathleen E. Stirrups, Stella Trompet, Laiyuan Wang, Khan S. Zaman, Diego Ardissino, Eric Boerwinkle, Ingrid B. Borecki, Erwin P. Bottinger, Julie E. Buring, John C. Chambers, Rory Collins, L Adrienne Cupples, John Danesh, Ilja Demuth, Roberto Elosua, Stephen E. Epstein, Tõnu Esko, Mary F. Feitosa, Oscar H. Franco, Maria Grazia Franzosi, Christopher B. Granger, Dongfeng Gu, Vilmundur Gudnason, Alistair S. Hall, Anders Hamsten, Tamara B. Harris, Stanley L. Hazen, Christian Hengstenberg, Albert Hofman, Erik Ingelsson, Carlos Iribarren, J Wouter Jukema, Pekka J. Karhunen, Bong-Jo Kim, Jaspal S. Kooner, Iftikhar J. Kullo, Terho Lehtimäki, Ruth J. Loos, Olle Melander, Andres Metspalu, Winfried März, Colin N. Palmer, Markus Perola, Thomas Quertermous, Daniel J. Rader, Paul M. Ridker, Samuli Ripatti, Robert Roberts, Veikko Salomaa, Dharambir K. Sanghera, Stephen M. Schwartz, Udo Seedorf, Alexandre F. Stewart, David J. Stott, Joachim Thiery, Pierre A. Zalloua, Christopher J. O'Donnell, Muredach P. Reilly, Themistocles L. Assimes, John R. Thompson, Jeanette Erdmann, Robert Clarke, Hugh Watkins, Sekar Kathiresan, Ruth McPherson, Panos Deloukas, Heribert Schunkert, Martin Farrall, Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, Mayo Clinic [Rochester], Service de Cardiologie Maladies Vasculaires [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Victor Chang Cardiac Research Institute, University of New South Wales [Sydney] (UNSW), St. Vincent’s Clinical School [Sydney, Australia], UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW)-University of New South Wales [Sydney] (UNSW), Department of Health Sciences Research [Mayo Clinic] (HSR), Mayo Clinic, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Service de génétique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Department of Cardiovascular Medicine, Mayo Clinic, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), and Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)
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Adult ,Male ,medicine.medical_specialty ,Myocardial infarction ,Coronary Vessel Anomalies ,Fibromuscular dysplasia ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Internal medicine ,medicine ,Prevalence ,Fibromuscular Dysplasia ,Humans ,030212 general & internal medicine ,Vascular Diseases ,Artery dissection ,MESH: Australia ,United Kingdom ,USA ,Coronary Vessel Anomalies / epidemiology ,Endothelin-1 / genetics ,Microfilament proteins / genetics ,Genetic association ,Aged ,Endothelin-1 ,business.industry ,Microfilament Proteins ,Australia ,Cardiovascular disease in women ,Middle Aged ,medicine.disease ,R1 ,United States ,3. Good health ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Genetic Loci ,Case-Control Studies ,Cardiology ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Female ,France ,Cardiology and Cardiovascular Medicine ,Scad ,business - Abstract
Background: \ud Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene.\ud \ud Objectives: \ud This study sought to test the association between the rs9349379 genotype and SCAD.\ud \ud Methods: \ud Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD.\ud \ud Results: \ud The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence.\ud \ud Conclusions: \ud The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.
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- 2019
31. Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
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Alexandre C. Pereira, Jie Yao, Makoto Hirata, Ozren Polasek, Dragana Vuckovic, Mariaelisa Graff, Jing Hua Zhao, Michael R. Brown, Xuan Deng, Barbara V. Howard, Vilmundur Gudnason, Tuomo Rankinen, Yuan Shi, Timo A. Lakka, Ulrich Broeckel, Anuradhani Kasturiratne, Eric Boerwinkle, Charles Kooperberg, Hugues Aschard, Stephen S. Rich, Pamela J. Schreiner, Dan E. Arking, Hans J. Grabe, Ilaria Gandin, Mario Sims, Carl D. Langefeld, Yii-Der Ida Chen, Meian He, W. James Gauderman, Bruce M. Psaty, Kent D. Taylor, Tõnu Esko, Olli T. Raitakari, Saima Afaq, Maik Pietzner, Federica Laguzzi, Dennis O. Mook-Kanamori, Gregory P. Wilson, Xiuqing Guo, Jaspal S. Kooner, David R. Jacobs, Yajuan Wang, Raha Pazoki, Wei Zhao, Andres Metspalu, Mary F. Feitosa, Jost B. Jonas, Tin Aung, Tamara B. Harris, Karin Leander, Nancy L. Pedersen, Charles B. Eaton, Sharon L.R. Kardia, Bernardo L. Horta, Candace M. Kammerer, Terrence Forrester, Alexander P. Reiner, Paul W. Franks, Tanika N. Kelly, Igor Rudan, Ruben N. Eppinga, Melissa A. Richard, Colin A. McKenzie, Christine Williams, Christian Gieger, Joseph H. Lee, Brigitte Kühnel, Christopher P. Nelson, Wen Bin Wei, Antonietta Robino, Anne U. Jackson, E. Shyong Tai, Alisa K. Manning, Lisa R. Yanek, Paul Elliott, Lynne E. Wagenknecht, Ananda R. Wickremasinghe, José Eduardo Krieger, Peter S. Sever, Nora Franceschini, André G. Uitterlinden, Paul M. Ridker, Yun J. Sung, Karen L. Mohlke, Thomas H. Mosley, Nilesh J. Samani, Patricia B. Munroe, Jennifer A. Smith, John M. C. Connell, H. Janaka de Silva, Nicholas Y. Q. Tan, Jian'an Luan, Jennifer E. Huffman, Anna F. Dominiczak, Carsten Oliver Schmidt, Christie M. Ballantyne, Peter J. van der Most, Anuj Goel, Jerome I. Rotter, Amy R. Bentley, Lihua Wang, Rajkumar Dorajoo, Lenore J. Launer, Yechiel Friedlander, Mickaël Canouil, Traci M. Bartz, Thomas Meitinger, Robert A. Scott, Mike A. Nalls, Xueling Sim, Sarah E. Harris, Michael A. Province, Chew-Kiat Heng, Zhe Wang, Norihiro Kato, Evangelos Evangelou, Philippe Froguel, Virginia Fisher, Leslie J. Raffel, Renée de Mutsert, Michele K. Evans, Brenda W.J.H. Penninx, Yih Chung Tham, Tin Louie, Nana Matoba, Lawrence F. Bielak, Andrea R. V. R. Horimoto, Jingmin Liu, Lynda M. Rose, Nona Sotoodehnia, Daniel I. Chasman, Jasmin Divers, John M. Starr, Patricia A. Peyser, Ervin R. Fox, Barry I. Freedman, Megan L. Grove, Jeffrey R. O'Connell, Rob M. van Dam, Michiaki Kubo, Jessica D. Faul, Fang-Chi Hsu, Yize Li, Ilja M. Nolte, Caroline Hayward, Paolo Gasparini, Chiea Chuen Khor, Changwei Li, Xu Chen, James E. Hixson, Patrik K. E. Magnusson, John C. Chambers, Yoichiro Kamatani, Sami Heikkinen, M. Abdullah Said, Martin Farrall, Alena Stančáková, Konstantin Strauch, Albert V. Smith, Yik Ying Teo, Bamidele O. Tayo, Tamar Sofer, Caizheng Yu, Maris Alver, Oscar H. Franco, Yongmei Liu, Ioanna Ntalla, Myriam Fornage, W. Craig Johnson, Dina Vojinovic, William R. Scott, David R. Weir, Yanick Hagemeijer, Raymond Noordam, Mathilde Boissel, Cornelia M. van Duijn, Karen Schwander, Jingzhong Ding, James Scott, Diana van Heemst, Ching-Yu Cheng, Woon-Puay Koh, Jianjun Liu, Kenneth J. Mukamal, Blair H. Smith, Claude Bouchard, Claudia Langenberg, Jingjing Liang, Wei Zheng, Najaf Amin, Ulf de Faire, Bing Yu, Archie Campbell, Kari E. North, Salman M. Tajuddin, Fernando Pires Hartwig, Steve B. Kritchevsky, Tibor V. Varga, Pirjo Komulainen, Hugh Watkins, Johanna Kuusisto, Kurt Lohman, Rozenn N. Lemaitre, Ani Manichaikul, Dabeeru C. Rao, Kenneth Rice, Weihua Zhang, Franco Giulianini, Reedik Mägi, Solomon K. Musani, Wanqing Wen, Nicholas J. Wareham, Charles N. Rotimi, Marzyeh Amini, Rainer Rauramaa, Nicholette D. Palmer, Annette Peters, Neil R Poulter, Benjamin Lehne, Matthias Nauck, Harold Snieder, Donald W. Bowden, M. Arfan Ikram, Lisa de las Fuentes, C. Charles Gu, Xiaofeng Zhu, Markku Laakso, Tuomas O. Kilpeläinen, Ching-Ti Liu, Michael Boehnke, Jin-Fang Chai, Lili Milani, L. Adrienne Cupples, Yuri Milaneschi, Kiang Liu, Stephen Sidney, Alan B. Zonderman, Thomas W. Winkler, Ian J. Deary, Fumihiko Takeuchi, Mary K. Wojczynski, Pim van der Harst, Leo-Pekka Lyytikäinen, Jennifer G. Robinson, Chuan Gao, Xiao-Ou Shu, Diane M. Becker, Mohsen Ghanbari, Alanna C. Morrison, Jian-Min Yuan, Tomohiro Katsuya, Ivana Kolcic, Melanie Waldenberger, Terho Lehtimäki, Heikki A. Koistinen, Erin B. Ware, Ya Xing Wang, Marie Loh, Treva Rice, Qing Duan, Aldi T. Kraja, Sabanayagam Charumathi, Tien Yin Wong, Paul S. de Vries, Yujie Wang, Muhammad Riaz, Home Office, Action on Hearing Loss, Imperial College Healthcare NHS Trust- BRC Funding, British Heart Foundation, Medical Research Council (MRC), Wellcome Trust, National Institute for Health Research, Luan, Jian'an [0000-0003-3137-6337], Pietzner, Maik [0000-0003-3437-9963], Zhao, Jing Hua [0000-0003-4930-3582], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, APH - Mental Health, Psychiatry, APH - Digital Health, The University of Texas Health Science Center at Houston (UTHealth), National Institutes of Health [Bethesda] (NIH), Washington University in Saint Louis (WUSTL), University of Regensburg, Queen Mary University of London (QMUL), Washington University School of Medicine in St. Louis, Harbor UCLA Medical Center [Torrance, Ca.], University of North Carolina at Chapel Hill (UNC), Singapore National Eye Centre and Duke-NUS [Singapore], Singapore Eye Research Institute [Singapore] (SERI), National University of Singapore (NUS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University Management, Department of Medicine, University of Helsinki, Endokrinologian yksikkö, HUS Abdominal Center, Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study), Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), de Vries, Paul S, Brown, Michael R, Bentley, Amy R, Sung, Yun J, Winkler, Thomas W, Ntalla, Ioanna, Schwander, Karen, Kraja, Aldi T, Guo, Xiuqing, Franceschini, Nora, Cheng, Ching-Yu, Sim, Xueling, Vojinovic, Dina, Huffman, Jennifer E, Musani, Solomon K, Li, Changwei, Feitosa, Mary F, Richard, Melissa A, Noordam, Raymond, Aschard, Hugue, Bartz, Traci M, Bielak, Lawrence F, Deng, Xuan, Dorajoo, Rajkumar, Lohman, Kurt K, Manning, Alisa K, Rankinen, Tuomo, Smith, Albert V, Tajuddin, Salman M, Evangelou, Evangelo, Graff, Mariaelisa, Alver, Mari, Boissel, Mathilde, Chai, Jin Fang, Chen, Xu, Divers, Jasmin, Gandin, Ilaria, Gao, Chuan, Goel, Anuj, Hagemeijer, Yanick, Harris, Sarah E, Hartwig, Fernando P, He, Meian, Horimoto, Andrea R V R, Hsu, Fang-Chi, Jackson, Anne U, Kasturiratne, Anuradhani, Komulainen, Pirjo, Kühnel, Brigitte, Laguzzi, Federica, Lee, Joseph H, Luan, Jian'An, Lyytikäinen, Leo-Pekka, Matoba, Nana, Nolte, Ilja M, Pietzner, Maik, Riaz, Muhammad, Said, M Abdullah, Scott, Robert A, Sofer, Tamar, Stancáková, Alena, Takeuchi, Fumihiko, Tayo, Bamidele O, van der Most, Peter J, Varga, Tibor V, Wang, Yajuan, Ware, Erin B, Wen, Wanqing, Yanek, Lisa R, Zhang, Weihua, Zhao, Jing Hua, Afaq, Saima, Amin, Najaf, Amini, Marzyeh, Arking, Dan E, Aung, Tin, Ballantyne, Christie, Boerwinkle, Eric, Broeckel, Ulrich, Campbell, Archie, Canouil, Mickaël, Charumathi, Sabanayagam, Chen, Yii-Der Ida, Connell, John M, de Faire, Ulf, de Las Fuentes, Lisa, de Mutsert, Renée, de Silva, H Janaka, Ding, Jingzhong, Dominiczak, Anna F, Duan, Qing, Eaton, Charles B, Eppinga, Ruben N, Faul, Jessica D, Fisher, Virginia, Forrester, Terrence, Franco, Oscar H, Friedlander, Yechiel, Ghanbari, Mohsen, Giulianini, Franco, Grabe, Hans J, Grove, Megan L, Gu, C Charle, Harris, Tamara B, Heikkinen, Sami, Heng, Chew-Kiat, Hirata, Makoto, Hixson, James E, Howard, Barbara V, Ikram, M Arfan, Jacobs, David R, Johnson, Craig, Jonas, Jost Bruno, Kammerer, Candace M, Katsuya, Tomohiro, Khor, Chiea Chuen, Kilpeläinen, Tuomas O, Koh, Woon-Puay, Koistinen, Heikki A, Kolcic, Ivana, Kooperberg, Charle, Krieger, Jose E, Kritchevsky, Steve B, Kubo, Michiaki, Kuusisto, Johanna, Lakka, Timo A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lehne, Benjamin, Lemaitre, Rozenn N, Li, Yize, Liang, Jingjing, Liu, Jianjun, Liu, Kiang, Loh, Marie, Louie, Tin, Mägi, Reedik, Manichaikul, Ani W, Mckenzie, Colin A, Meitinger, Thoma, Metspalu, Andre, Milaneschi, Yuri, Milani, Lili, Mohlke, Karen L, Mosley, Thomas H, Mukamal, Kenneth J, Nalls, Mike A, Nauck, Matthia, Nelson, Christopher P, Sotoodehnia, Nona, O'Connell, Jeff R, Palmer, Nicholette D, Pazoki, Raha, Pedersen, Nancy L, Peters, Annette, Peyser, Patricia A, Polasek, Ozren, Poulter, Neil, Raffel, Leslie J, Raitakari, Olli T, Reiner, Alex P, Rice, Treva K, Rich, Stephen S, Robino, Antonietta, Robinson, Jennifer G, Rose, Lynda M, Rudan, Igor, Schmidt, Carsten O, Schreiner, Pamela J, Scott, William R, Sever, Peter, Shi, Yuan, Sidney, Stephen, Sims, Mario, Smith, Blair H, Smith, Jennifer A, Snieder, Harold, Starr, John M, Strauch, Konstantin, Tan, Nichola, Taylor, Kent D, Teo, Yik Ying, Tham, Yih Chung, Uitterlinden, André G, van Heemst, Diana, Vuckovic, Dragana, Waldenberger, Melanie, Wang, Lihua, Wang, Yujie, Wang, Zhe, Wei, Wen Bin, Williams, Christine, Wilson, Gregory, Wojczynski, Mary K, Yao, Jie, Yu, Bing, Yu, Caizheng, Yuan, Jian-Min, Zhao, Wei, Zonderman, Alan B, Becker, Diane M, Boehnke, Michael, Bowden, Donald W, Chambers, John C, Deary, Ian J, Esko, Tõnu, Farrall, Martin, Franks, Paul W, Freedman, Barry I, Froguel, Philippe, Gasparini, Paolo, Gieger, Christian, Horta, Bernardo L, Kamatani, Yoichiro, Kato, Norihiro, Kooner, Jaspal S, Laakso, Markku, Leander, Karin, Lehtimäki, Terho, Magnusson, Patrik K E, Penninx, Brenda, Pereira, Alexandre C, Rauramaa, Rainer, Samani, Nilesh J, Scott, Jame, Shu, Xiao-Ou, van der Harst, Pim, Wagenknecht, Lynne E, Wang, Ya Xing, Wareham, Nicholas J, Watkins, Hugh, Weir, David R, Wickremasinghe, Ananda R, Zheng, Wei, Elliott, Paul, North, Kari E, Bouchard, Claude, Evans, Michele K, Gudnason, Vilmundur, Liu, Ching-Ti, Liu, Yongmei, Psaty, Bruce M, Ridker, Paul M, van Dam, Rob M, Kardia, Sharon L R, Zhu, Xiaofeng, Rotimi, Charles N, Mook-Kanamori, Dennis O, Fornage, Myriam, Kelly, Tanika N, Fox, Ervin R, Hayward, Caroline, van Duijn, Cornelia M, Tai, E Shyong, Wong, Tien Yin, Liu, Jingmin, Rotter, Jerome I, Gauderman, W Jame, Province, Michael A, Munroe, Patricia B, Rice, Kenneth, Chasman, Daniel I, Cupples, L Adrienne, Rao, Dabeeru C, Morrison, Alanna C, and Academic Medical Center
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Male ,Epidemiology ,Genome-wide association study ,Cardiovascular ,MESH: Genotype ,Substance Misuse ,Alcohol Use and Health ,0302 clinical medicine ,Aetiology ,triglycerides ,11 Medical and Health Sciences ,Public, Environmental & Occupational Health ,[STAT.AP]Statistics [stat]/Applications [stat.AP] ,MESH: Middle Aged ,MESH: Life Style ,genome wide ,gene-alcohol interaction ,lipid levels ,Lipid Measurement ,Lifelines Cohort ,DENSITY-LIPOPROTEIN CHOLESTEROL ,MESH: Young Adult ,030220 oncology & carcinogenesis ,Kexin ,LOW-FREQUENCY ,MESH: Cholesterol, HDL ,MESH: Cholesterol, LDL ,MESH: Triglycerides ,HDL ,Alcohol Drinking ,Genotype ,alcohol consumption ,MESH: Phenotype ,LDL ,lipids ,03 medical and health sciences ,Genetics ,Humans ,Life Style ,METAANALYSIS ,01 Mathematical Sciences ,Aged ,MESH: Adolescent ,HDL CHOLESTEROL ,MESH: Humans ,Science & Technology ,Cholesterol ,APOBEC1 ,Lifelines Cohort, Groningen, The Netherlands (Lifelines Cohort Study) ,MESH: Vascular Endothelial Growth Factor B ,Racial Groups ,cholesterol ,The Netherlands ,MESH: Adult ,CONSUMPTION ,chemistry ,MESH: Genome-Wide Association Study ,[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] ,Lipid profile ,MESH: Female ,MESH: Alcohol Drinking ,MESH: Continental Population Groups ,Vascular Endothelial Growth Factor B ,Original Contributions ,Blood lipids ,VEGF-B ,Medical and Health Sciences ,Mathematical Sciences ,BLOOD-LIPIDS ,chemistry.chemical_compound ,2.1 Biological and endogenous factors ,030212 general & internal medicine ,MESH: Aged ,medicine.diagnostic_test ,PLASMA ,gene-environment interactions ,Middle Aged ,3142 Public health care science, environmental and occupational health ,Alcoholism ,Phenotype ,Female ,gene-lifestyle interactions ,genome-wide association studies ,[STAT.ME]Statistics [stat]/Methodology [stat.ME] ,Life Sciences & Biomedicine ,Groningen ,Adult ,Adolescent ,Biology ,Young Adult ,medicine ,CORONARY-HEART-DISEASE ,Human Genome ,Cholesterol, HDL ,Lipid metabolism ,Cholesterol, LDL ,InterAct Consortium ,MESH: Lipids ,MESH: Male ,INDIVIDUALS ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Genome-Wide Association Study - Abstract
© The Author(s) 2019. A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-Alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2- degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10?6) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 × 10?8 using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models. National Heart, Lung, and Blood Institute; American Heart Association Grant
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- 2019
32. Proof of concept for quantitative urine NMR metabolomics pipeline for large-scale epidemiology and genetics
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Johannes Kettunen, Jaspal S. Kooner, Pauli Ohukainen, Minna Männikkö, Olga Anufrieva, Qin Wang, Michael Hill, Marjo-Riitta Järvelin, Mika Ala-Korpela, Jussi Ekholm, John C Chambers, George Davey Smith, Tuulia Tynkkynen, Jouko Vepsäläinen, Susan M. Ring, Michael V. Holmes, Matthew Goodwin, and Sirkka Keinänen-Kiukaanniemi
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0301 basic medicine ,medicine.medical_specialty ,Magnetic Resonance Spectroscopy ,genome-wide analyses ,Epidemiology ,multicentre ,Metabolite ,Population ,Urine ,030204 cardiovascular system & hematology ,Biology ,Proof of Concept Study ,1117 Public Health and Health Services ,03 medical and health sciences ,chemistry.chemical_compound ,Metabolomics ,0302 clinical medicine ,medicine ,Humans ,Spectral analysis ,education ,Nmr based metabolomics ,030304 developmental biology ,Genetics ,open access ,0303 health sciences ,education.field_of_study ,Shape fitting ,0104 Statistics ,General Medicine ,urine ,Metabolomics data ,Miscellaneous ,Epidemiologic Studies ,030104 developmental biology ,chemistry ,Fully automated ,serum ,Genome-Wide Association Study - Abstract
Background Quantitative molecular data from urine are rare in epidemiology and genetics. NMR spectroscopy could provide these data in high throughput, and it has already been applied in epidemiological settings to analyse urine samples. However, quantitative protocols for large-scale applications are not available. Methods We describe in detail how to prepare urine samples and perform NMR experiments to obtain quantitative metabolic information. Semi-automated quantitative line shape fitting analyses were set up for 43 metabolites and applied to data from various analytical test samples and from 1004 individuals from a population-based epidemiological cohort. Novel analyses on how urine metabolites associate with quantitative serum NMR metabolomics data (61 metabolic measures; n = 995) were performed. In addition, confirmatory genome-wide analyses of urine metabolites were conducted (n = 578). The fully automated quantitative regression-based spectral analysis is demonstrated for creatinine and glucose (n = 4548). Results Intra-assay metabolite variations were mostly Conclusion Quantitative urine metabolomics data suggest broad novelty for systems epidemiology. A roadmap for an open access methodology is provided.
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- 2019
33. Disentangling the genetics of lean mass
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Tuomas O. Kilpeläinen, Jacqueline S. L. Kloth, Nam H. Cho, Peter Vollenweider, Georg Homuth, Unnur Thorsteinsdottir, Nicole C. Wright, Wen-Chi Chou, Yongmei Liu, Kari Stefansson, Kim M. Huffman, Ida Malkin, Andrew P. Morris, Robert Luben, Shad B. Smith, Lei Yu, Joel Eriksson, Aarno Palotie, Veikko Salomaa, Michael J. Econs, Liesbeth Vandenput, Elizabeth A. Streeten, Albert Hofman, Elisabeth Widen, Emmi Tikkanen, Braxton D. Mitchell, Natasja M. van Schoor, Caroline Hayward, Liisa Byberg, Joanne M. Jordan, Bruce M. Psaty, Elisabeth Steinhagen-Thiessen, Magnus Karlsson, Harry Campbell, John C. Chambers, Fernando Rivadeneira, Johan G. Eriksson, Jari Lahti, Reiner Biffar, James F. Wilson, Luda Diatchenko, Jerome I. Rotter, Eric S. Orwoll, Launer J. Lenore, Cornelia M. van Duijn, Frances M K Williams, Munro Peacock, David A. Bennett, Annette Peters, Ali A. Aghdassi, Gudny Eiriksdottir, Weihua Zhang, Östen Ljunggren, Daniel L. Koller, Nicole Soranzo, Patricia A. Thompson, Jane A. Cauley, John A Robbins, Mattias Lorentzon, Igor Rudan, Thomas Illig, Claes Ohlsson, Ilja Demuth, Zoltán Kutalik, Aron S. Buchman, Jian'an Luan, Erik Ingelsson, Natalia Campos-Obando, Karol Estrada, Chan Soo Shin, Lisette Stolk, Gudmar Thorleifsson, Douglas P. Kiel, Michael N. Weedon, Lars Bertram, Fiona E. McGuigan, Ben A. Oostra, Thomas Meitinger, Mary F. Feitosa, Christian Gieger, Jean Wactawski-Wende, Yanhua Zhou, Serkalem Demissie, Najaf Amin, Anke W. Enneman, Håkan Melhus, Stuart H. Ralston, Johanna Kuusisto, Markku Laakso, Mark Walker, Tim D. Spector, Karl Michaëlsson, John-Olov Jansson, Richard L. Prince, Leif Mosekilde, Sabine Schipf, Carolina Medina-Gomez, Antti Jula, Carrie M. Nielson, Bente L. Langdahl, André G. Uitterlinden, Kay-Tee Khaw, Ruth J. F. Loos, Kristina Åkesson, Albert V. Smith, Tamara B. Harris, Cynthia A. Thomson, Karin M. A. Swart, Unnur Styrkarsdottir, Yi-Hsiang Hsu, Anne B. Newman, Murielle Bochud, M. Carola Zillikens, Alena Stančáková, Markus M. Lerch, Maria Nethander, Gregory Livshits, Dawn Waterworth, Christina M. Lill, Henry Völzke, Steven R. Cummings, Lise B. Husted, Cecilia M. Lindgren, Jaspal S. Kooner, Joshua R. Lewis, Katri Räikkönen, Linda Broer, Inês Barroso, Teemu Kuulasmaa, Jeffery R. O'Connell, Harald Grallert, William E. Kraus, Nicholas J. Wareham, Lars Lind, David Karasik, H-Erich Wichmann, Gregory J. Tranah, Mao Fu, Toby Johnson, Samuli Ripatti, Dan Mellström, Suzanne Satterfield, Jing Hua Zhao, Hyung Jin Choi, Vilmundur Gudnason, Lisette C. P. G. M. de Groot, Stephen B. Kritchevsky, Zhao Chen, Norman Klopp, Till Ittermann, Daniel S. Evans, Phillip L. De Jager, Ingrid B. Borecki, Laura M. Yerges-Armstrong, Peggy M. Cawthon, Thomas Lang, Markus Perola, Internal Medicine, Epidemiology, Clinical Genetics, General practice, APH - Societal Participation & Health, APH - Aging & Later Life, Epidemiology and Data Science, and APH - Personalized Medicine
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Adipose Tissue/metabolism ,Male ,0301 basic medicine ,Medicine (miscellaneous) ,Body Fluid Compartments/metabolism ,Genome-wide association study ,FTO gene ,ADAMTS Proteins ,Absorptiometry, Photon ,Versicans ,0302 clinical medicine ,Electric Impedance ,European Continental Ancestry Group/genetics ,Aged, 80 and over ,2. Zero hunger ,Genetics ,Extracellular Matrix Proteins ,Nutrition and Dietetics ,ADAMTS Proteins/genetics ,RNA-Binding Proteins ,Body Fluid Compartments ,Middle Aged ,metabolic profile ,Nutritional Biology ,body fat ,Original Research Communications ,Phenotype ,Adipose Tissue ,Body Composition ,Receptor, Melanocortin, Type 4 ,Female ,Bioelectrical impedance analysis ,Adult ,meta-analysis of genome-wide association studies ,Versicans/genetics ,Adolescent ,Alpha-Ketoglutarate-Dependent Dioxygenase FTO ,030209 endocrinology & metabolism ,Locus (genetics) ,Single-nucleotide polymorphism ,Biology ,Extracellular Matrix Proteins/genetics ,meta-Analysis of genome-wide association studies ,Polymorphism, Single Nucleotide ,White People ,Young Adult ,03 medical and health sciences ,Humans ,Receptor, Melanocortin, Type 4/genetics ,skeletal muscle ,Allele ,Muscle, Skeletal ,VLAG ,Aged ,Global Nutrition ,Wereldvoeding ,Body Composition/genetics ,body composition ,Muscle, Skeletal/metabolism ,030109 nutrition & dietetics ,Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics ,RNA-Binding Proteins/genetics ,Genetic architecture ,Lean body mass ,Genome-Wide Association Study - Abstract
Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.
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- 2019
34. Association of maternal prenatal smoking GFI1-locus and cardio-metabolic phenotypes in 18,212 adultsResearch in context
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Priyanka Parmar, Estelle Lowry, Giovanni Cugliari, Matthew Suderman, Rory Wilson, Ville Karhunen, Toby Andrew, Petri Wiklund, Matthias Wielscher, Simonetta Guarrera, Alexander Teumer, Benjamin Lehne, Lili Milani, Niek de Klein, Pashupati P. Mishra, Phillip E. Melton, Pooja R. Mandaviya, Silva Kasela, Jana Nano, Weihua Zhang, Yan Zhang, Andre G. Uitterlinden, Annette Peters, Ben Schöttker, Christian Gieger, Denise Anderson, Dorret I. Boomsma, Hans J. Grabe, Salvatore Panico, Jan H. Veldink, Joyce B.J. van Meurs, Leonard van den Berg, Lawrence J. Beilin, Lude Franke, Marie Loh, Marleen M.J. van Greevenbroek, Matthias Nauck, Mika Kähönen, Mikko A. Hurme, Olli T. Raitakari, Oscar H. Franco, P.Eline Slagboom, Pim van der Harst, Sonja Kunze, Stephan B. Felix, Tao Zhang, Wei Chen, Trevor A. Mori, Amelie Bonnefond, Bastiaan T. Heijmans, Taulant Muka, Jaspal S. Kooner, Krista Fischer, Melanie Waldenberger, Philippe Froguel, Rae-Chi Huang, Terho Lehtimäki, Wolfgang Rathmann, Caroline L. Relton, Giuseppe Matullo, Hermann Brenner, Niek Verweij, Shengxu Li, John C. Chambers, Marjo-Riitta Järvelin, and Sylvain Sebert
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lcsh:R5-920 ,lcsh:R ,lcsh:Medicine ,lcsh:Medicine (General) - Abstract
Background: DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health. Methods: We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n = 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL—C), triglycerides (TG), diastolic, and systolic blood pressure (BP). Findings: Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P
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- 2018
35. The trans-ancestral genomic architecture of glycemic traits
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Albertine J. Oldehinkel, Wieland Kiess, Xueling Sim, Norihiro Kato, Philippe Froguel, Astrid van Hylckama Vlieg, Josée Dupuis, Nanette R. Lee, Symen Ligthart, Harry Campbell, Marta E. Alarcón-Riquelme, P. Eline Slagboom, Massimo Mangino, Tian Xie, Niek Verweij, James B. Meigs, Chaolong Wang, Michael Y. Tsai, Erik Ingelsson, Colin N. A. Palmer, Erik B. van den Akker, Fumihiko Matsuda, Rainer Rauramaa, Yi-Cheng Chang, Lars Lind, Stefan R. Bornstein, Mandy Vogel, Sven Bergmann, Ya X. Wang, Ching-Ti Liu, Annette Schürmann, Michael Boehnke, David J. Porteous, Kazuya Setoh, Qibin Qi, Ayse Demirkan, Francesco Cucca, Allan Linneberg, Claire J. Steves, Jun Liu, Leslie A. Lange, Noël P. Burtt, Diana Kuh, Cassandra N. Spracklen, Ken K. Ong, Charumathi Sabanayagam, Jost B. Jonas, Ele Ferrannini, Lawrence J. Beilin, Qing Duan, Blair H. Smith, Isobel D. Stewart, Alexander P. Reiner, Simon P. Mooijaart, Tim D. Spector, Paul W. Franks, E. Shyong Tai, Mark I. McCarthy, Anna L. Gloyn, D.I. Boomsma, Dennis Raven, Nicholas J. Timpson, Rona J. Strawbridge, George Dedoussis, Susan Redline, Jaeyoung Hong, Harald Grallert, Jagadish Vangipurapu, Rico Rueedi, Diane M. Becker, Marian Beekman, Claudia P. Cabrera, Johannes Waage, Jin Fang Chai, Yii-Der Ida Chen, Graciela E. Delgado, Thibaud S. Boutin, Yang Hai, Yoriko Heianza, Wei Zhao, Andres Metspalu, Tien Yin Wong, Mila Desi Anasanti, Inger Njølstad, Hans Bisgaard, Valeriya Lyssenko, Denis Rybin, Wanqing Wen, Torben Hansen, James F. Wilson, Sameline Grimsgaard, Annette Peters, Michele K. Evans, Damia Noce, Sarah C. Nelson, May E. Montasser, Nan Wang, Geltrude Mingrone, Gudny Eiriksdottir, Nicholas J. Wareham, Fouad Kandeel, Linda S. Adair, Kelvin Lam, Jaana Lindström, Eco J. C. de Geus, Debbie A Lawlor, Sara M. Willems, Xu Lin, Harold Snieder, Matt J. Neville, Naveed Sattar, Chelsea K. Raulerson, Paul M. Ridker, Jer-Yuarn Wu, Weihua Zhang, H. Janaka de Silva, Jana V. van Vliet-Ostaptchouk, Elena Tremoli, Toru Nabika, Jing Hua Zhao, Vilmundur Gudnason, Tao Huang, Robert C. Kaplan, Sohee Han, Mohammad Hadi Zafarmand, Aaron Leong, Yen-Feng Chiu, Kumaraswamy Naidu Chitrala, Ivana Kolcic, Franco Giulianini, Tao Wang, Lu Qi, Stephan J. L. Bakker, Laura J Corbin, Zoltán Kutalik, Bruna Gigante, Willa A. Hsueh, Peter J. van der Most, Tin Louie, Yujie Wang, Stella Trompet, Fernando Rivideneira, Yasumasa Ohyagi, Lynne E. Wagenknecht, Jerry L. Nadler, Michael Stumvoll, Mark O. Goodarzi, Sahoko Ichihara, Jeffrey R. O'Connell, Tomohiro Katsuya, Giorgio Pistis, Alice Stanton, Sirkka Keinänen-Kiukaanniemi, Momoko Horikoshi, Honglan Li, Tanja G. M. Vrijkotte, Caroline Hayward, Karen L. Mohlke, Carola Marzi, Girish N. Nadkarni, Laura J. Rasmussen-Torvik, Alain G. Bertoni, Andrew R. Wood, Annique Claringbould, Mi Yeong Hwang, Hugh Watkins, Heikki A. Koistinen, Mattias Frånberg, Jani Heikkinen, Elizabeth Selvin, Donald W. Bowden, Abbas Dehghan, Christian Fuchsberger, Audrey Y. Chu, Kent D. Taylor, Katherine A. Kentistou, Johanna Kuusisto, Jingyi Tan, Huaixing Li, Eric Boerwinkle, Catharina A. Hartman, Archie Campbell, Kari E. North, Oluf Pedersen, Sölve Elmståhl, Emil V. R. Appel, Chang-Hsun Hsieh, Dennis O. Mook-Kanamori, Rob M. van Dam, Pontiano Kaleebu, Corri Black, Jennifer A. Brody, Bengt Sennblad, Shaofeng Huo, M. Larissa Avilés-Santa, Ruth J. F. Loos, Patricia B. Munroe, Chien-Hsiun Chen, Liang Sun, Zorayr Arzumanyan, Rebecca Rohde, Yasuharu Tabara, Albert V. Smith, Betina H. Thuesen, Niels Grarup, Jorgen Engmann, Tatijana Zemunik, M. Arfan Ikram, Marit E. Jørgensen, Christian Herder, Ching-Yu Cheng, Serena Sanna, Damiano Baldassarre, Tarunveer S. Ahluwalia, Mark J. Caulfield, Anne Ndungu, Carl D. Langefeld, Lisa R. Yanek, Luigi Ferrucci, Ananda R. Wickremasinghe, Raymond Noordam, Trevor A. Mori, Tom Wilsgaard, Mika Kivimäki, Rita R. Kalyani, Alan B. Zonderman, Veronique Vitart, Patricia A. Peyser, Shuiqing Lai, Richa Saxena, Li-Ching Chang, Karin Leander, Wei Huang, Peter Vollenweider, Tanya M. Teslovich, Ying Wu, Shufa Du, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Stephen C. J. Parker, Tamar Sofer, Winfried März, Sharon L.R. Kardia, Peter K. Joshi, Neil R. Robertson, Anny H. Xiang, Fumihiko Takeuchi, N. Amin, Jouke-Jan Hottenga, Carol A. Wang, Stefan Gustafsson, Jung Ho Gong, Penny Gordon-Larsen, Yu-Tang Gao, Abhishek Nag, Gonneke Willemsen, Michael A. Province, Aliki-Eleni Farmaki, Segun Fatumo, Antje Körner, Pim van der Harst, Marie Loh, Kei Hang Katie Chan, Gonçalo R. Abecasis, Nicholette D. Palmer, Simin Liu, Ishminder K. Kooner, Javier Gayán, Arne Astrup, Laura J. Scott, Erwin P. Bottinger, Andrew Wong, Inga Prokopenko, Ping An, Markku Laakso, Matthias Blüher, Susan R. Heckbert, Thomas A. Buchanan, Tatsuaki Matsubara, Andrew P. Morris, Brian H. Chen, Kristi Läll, Teresa Tusie, Timo A. Lakka, Jie Yao, Michael Preuss, Teemu Kuulasmaa, Carlos Lorenzo, Stephen S. Rich, Marie Lauzon, Laura M. Raffield, Pankow S. James, Takahisa Kawaguchi, Kathleen A. Ryan, Wei Zheng, Igor Rudan, Thomas Sparsø, Hugoline G. de Haan, Sandosh Padmanabhan, Richard M. Watanabe, Alicia Huerta-Chagoya, Anette P. Gjesing, Andrew A. Hicks, Richard N. Bergman, Mitsuhiro Yokota, Heather M. Stringham, Bruce M. Psaty, Jian'an Luan, Anuj Goel, Eleanor Wheeler, Masahiro Nakatochi, Young-Jin Kim, Xiao-Ou Shu, Mickaël Canouil, Robert A. Scott, Marika Kaakinen, Mari Nelis, Adolfo Correa, Jaspal S. Kooner, Michiya Igase, Anubha Mahajan, Peter E. H. Schwarz, Craig E. Pennell, Claudia Schurmann, Xiaoran Chai, Ji Chen, Lori L. Bonnycastle, Peter S. Sever, Thorkild I. A. Sørensen, André G. Uitterlinden, Ilja M. Nolte, Gaëlle Marenne, Timothy M. Frayling, Bong-Jo Kim, Kerrin S. Small, Cecilia M. Lindgren, Bernhard O. Böhm, Shih-Yi Lin, Katharina E. Schraut, Cornelia M. van Duijn, Sanghoon Moon, Mark Walker, Chiea Chuen Khor, Ruifang Li-Gao, Qiuyin Cai, Neil Schneiderman, Ko Willems van Dijk, Ozren Polasek, W. Craig Johnson, Dermot F. Reilly, Inês Barroso, Anke Tönjes, Manjinder S. Sandhu, Wen B. Wei, Jose C. Florez, Lorraine Southam, Leif Groop, Lawrence F. Bielak, Peter Kovacs, Jianjun Liu, Jouko Saramies, Helen R. Warren, Man Li, Daniel I. Chasman, Eleftheria Zeggini, Xiaoshuai Zhang, Loic Yengo, Shi Jinxiu, Jirong Long, Xiuqing Guo, Meena Kumari, Leslie J. Raffel, Jill M. Norris, Henrik Vestergaard, Jing He, Peter P. Pramstaller, Diana van Heemst, Kevin Sandow, Marjo-Ritta Jarvelin, Carlos A. Aguilar-Salinas, Peitao Wu, Hortensia Moreno-Macías, Jerome I. Rotter, Kathryn Roll, Frits R. Rosendaal, Bernardo L. Horta, Heming Wang, Fernando Pires Hartwig, Richard A. Jensen, Matti Uusitupa, Rozenn N. Lemaitre, Paul R. H. J. Timmers, Timo Saaristo, Jaakko Tuomilehto, Reedik Mägi, Debashree Ray, J. Wouter Jukema, Claudia Langenberg, Marcus E. Kleber, Francis S. Collins, Klaus Bønnelykke, Lenore J. Launer, Arushi Varshney, Anders Hamsten, European Commission, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Sanger Institute, Wellcome Trust, Marenne, Gaëlle [0000-0002-4363-7170], Varshney, Arushi [0000-0001-9177-9707], Corbin, Laura J [0000-0002-4032-9500], Parker, Stephen CJ [0000-0001-8122-0117], Langenberg, Claudia [0000-0002-5017-7344], Wheeler, Eleanor [0000-0002-8616-6444], Morris, Andrew P [0000-0002-6805-6014], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Lifelines Cohort Study, Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC), de Haan, H.G., van den Akker, E., van der Most, P.J., de Geus, EJC, van Dam, R.M., van Heemst, D., van Hylckama Vlieg, A., van Willems van Dijk, K., de Silva, H.J., van der Harst, P., van Duijn, C., Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Institute for Molecular Medicine Finland, Leif Groop Research Group, HUS Internal Medicine and Rehabilitation, Department of Medicine, Department of Biochemistry and Developmental Biology, Helsinki University Hospital Area, University of Helsinki, Clinicum, Department of Public Health, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Physiology, AMS - Musculoskeletal Health, AMS - Tissue Function & Regeneration, APH - Mental Health, Nutrition and Health, APH - Methodology, Epidemiology and Data Science, ACS - Atherosclerosis & ischemic syndromes, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, Public and occupational health, Epidemiology, Internal Medicine, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Cardiovascular Centre (CVC)
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Blood Glucose ,Disease risk ,Multifactorial Inheritance ,Glycated Hemoglobin A ,[SDV]Life Sciences [q-bio] ,Meta-Analysis of Glucose and Insulin-related Traits Consortium (MAGIC) ,LOCI ,Genome-wide association study ,Type 2 diabetes ,VARIANTS ,GLUCOSE ,Epigenesis, Genetic ,chemistry.chemical_compound ,0302 clinical medicine ,Mechanisms ,WIDE ASSOCIATION ,genetics ,Gene-expression ,HEMOGLOBIN ,ComputingMilieux_MISCELLANEOUS ,11 Medical and Health Sciences ,GENE-EXPRESSION ,Genetics ,Genetics & Heredity ,0303 health sciences ,INSULIN-RESISTANCE ,Genome ,Loci ,1184 Genetics, developmental biology, physiology ,Variants ,ALSPAC ,Physical Chromosome Mapping ,Life Sciences & Biomedicine ,Human ,Quantitative Trait Loci ,Wide association study ,Biology ,Quantitative trait locus ,Article ,White People ,diseases ,MECHANISMS ,Quantitative Trait ,03 medical and health sciences ,Insulin resistance ,Quantitative Trait, Heritable ,SDG 3 - Good Health and Well-being ,Genetic ,Lifelines Cohort Study ,Diabetes mellitus ,medicine ,Humans ,Hemoglobin ,Heritable ,METAANALYSIS ,Alleles ,030304 developmental biology ,Genetic association ,Glycemic ,Glycated Hemoglobin ,Science & Technology ,Genome, Human ,Whites ,Gene Expression Profiling ,DISEASE RISK ,Settore MED/13 - ENDOCRINOLOGIA ,Insulin-resistance ,06 Biological Sciences ,medicine.disease ,Glucose ,chemistry ,Blood Glucose/genetics ,European Continental Ancestry Group/genetics ,Genome-Wide Association Study ,Glycated Hemoglobin A/metabolism ,Multifactorial Inheritance/genetics ,Quantitative Trait Loci/genetics ,Glycated hemoglobin ,030217 neurology & neurosurgery ,Meta analysis ,Epigenesis ,Developmental Biology - Abstract
Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.
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36. COVID-19 and its impact on the cardiovascular system
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Michael Bellamy, Gulammehdi Haji, Lilit Baghdasaryan, Ghada W. Mikhail, Francesco Lo Giudice, Rodney A. Foale, Brian Wang, Amarjit Sethi, Neil Ruparelia, Ahmed M M Hassan, Perviz Asaria, Poornima Mohan, Petros Nihoyannopoulos, Prapa Kanagaratnam, Darrel P. Francis, Nilesh Sutaria, Andrew Chukwuemeka, Rasha Al-Lamee, Carla M. Plymen, Rachel J. Davies, Gajen Kanaganayagam, Ramzi Khamis, Jon Anderson, Luke Howard, Gemma Bowsher, Iqbal S. Malik, Christopher S. Baker, Richard J. Jabbour, Amanda Varnava, Kevin Fox, Sayan Sen, Bushra Rana, Jaspal S. Kooner, Theodora Bampouri, Saud Ahmed Khawaja, Punam A Pabari, Farhan Huq, Ricardo Petraco, Sukhjinder Nijjer, Graham D. Cole, National Institute for Health Research, British Heart Foundation, and Imperial College Healthcare NHS Trust- BRC Funding
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Male ,medicine.medical_specialty ,Acute coronary syndrome ,myocardial disease ,Myocarditis ,Cardiac & Cardiovascular Systems ,cardiac ,Disease ,Comorbidity ,030204 cardiovascular system & hematology ,acute coronary syndrome ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Epidemiology ,London ,medicine ,Diseases of the circulatory (Cardiovascular) system ,Humans ,030212 general & internal medicine ,Hospital Mortality ,Pandemics ,Aged ,Retrospective Studies ,Science & Technology ,business.industry ,SARS-CoV-2 ,Incidence (epidemiology) ,Incidence ,COVID-19 ,Retrospective cohort study ,medicine.disease ,Cardiac Risk Factors and Prevention ,Survival Rate ,Cardiovascular Diseases ,RC666-701 ,Cohort ,Cardiovascular System & Cardiology ,RNA, Viral ,Female ,myocarditis ,Cardiology and Cardiovascular Medicine ,business ,Life Sciences & Biomedicine ,arrhythmias - Abstract
ObjectivesThe clinical impact of SARS-CoV-2 has varied across countries with varying cardiovascular manifestations. We review the cardiac presentations, in-hospital outcomes and development of cardiovascular complications in the initial cohort of SARS-CoV-2 positive patients at Imperial College Healthcare National Health Service Trust, UK.MethodsWe retrospectively analysed 498 COVID-19 positive adult admissions to our institute from 7 March to 7 April 2020. Patient data were collected for baseline demographics, comorbidities and in-hospital outcomes, especially relating to cardiovascular intervention.ResultsMean age was 67.4±16.1 years and 62.2% (n=310) were male. 64.1% (n=319) of our cohort had underlying cardiovascular disease (CVD) with 53.4% (n=266) having hypertension. 43.2%(n=215) developed acute myocardial injury. Mortality was significantly increased in those patients with myocardial injury (47.4% vs 18.4%, pConclusionHypertension, pre-existing CVD and acute myocardial injury were associated with increased in-hospital mortality in our cohort of COVID-19 patients. However, only a low number of patients required invasive cardiac intervention.
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37. Low uptake of COVID-19 prevention behaviours and high socioeconomic impact of lockdown measures in South Asia: Evidence from a large-scale multi-country surveillance programme
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Khadija Irfan Khawaja, Vindya P. Rajakaruna, Rajendra Pradeepa, Sajjad Ahmad, Chamini K. De Silva, Anuradhani Kasturiratne, Mehedi Hasan, Asma Tassawar, Balachandran Kumarendran, Malabika Sarker, Sujeet Jha, Prasad Katulanda, Abu Am Hanif, Sara Mahmood, Menka Loomba, John C. Chambers, Manoja Gamage, Franco Sassi, Dian Kusuma, Ranjit Mohan Anjana, Marie Loh, Malay K Mridha, Akansha Tyagi, Swati Waghdhare, Ian Y. Goon, Syed Mohsin Ali Shah, Archa Misra, Samreen Siddiqui, Jaspal S. Kooner, Saira Burney, Viswanathan Mohan, Laksara de Silva, Rajan Kamalesh, Wellcome Trust, and National Institute for Health Research
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Health (social science) ,media_common.quotation_subject ,Preventative measures ,South Asia ,Article ,1117 Public Health and Health Services ,Health(social science) ,03 medical and health sciences ,0302 clinical medicine ,Hygiene ,Environmental health ,Pandemic ,medicine ,030212 general & internal medicine ,Economic impact analysis ,NIHR Global Health Research Unit for Diabetes and Cardiovascular Disease in South Asia ,lcsh:Social sciences (General) ,Socioeconomic status ,Depression (differential diagnoses) ,Surveillance system ,media_common ,030505 public health ,business.industry ,lcsh:Public aspects of medicine ,Health Policy ,Public Health, Environmental and Occupational Health ,COVID-19 ,lcsh:RA1-1270 ,medicine.disease ,Mental health ,Obesity ,Disadvantaged ,Socioeconomic impact ,Scale (social sciences) ,Household income ,Anxiety ,lcsh:H1-99 ,medicine.symptom ,0305 other medical science ,business - Abstract
Background South Asia has become a major epicentre of the COVID-19 pandemic. Understanding South Asians’ awareness, attitudes and experiences of early measures for the prevention of COVID-19 is key to improving the effectiveness and mitigating the social and economic impacts of pandemic responses at a critical time for the Region. Methods We assessed the knowledge, behaviours, health and socio-economic circumstances of 29,809 adult men and women, at 93 locations across four South Asian countries. Data were collected during the national lockdowns implemented from March to July 2020, and compared with data collected prior to the pandemic as part of an ongoing prospective surveillance initiative. Results Participants were 61% female, mean age 45.1 years. Almost half had one or more chronic disease, including diabetes (16%), hypertension (23%) or obesity (16%). Knowledge of the primary COVID-19 symptoms and transmission routes was high, but access to hygiene and personal protection resources was low (running water 63%, hand sanitisers 53%, paper tissues 48%). Key preventive measures were not widely adopted. Knowledge, access to, and uptake of COVID-19 prevention measures were low amongst people from disadvantaged socio-economic groups. Fifteen percent of people receiving treatment for chronic diseases reported loss of access to long-term medications; 40% reported symptoms suggestive of anxiety or depression. The prevalence of unemployment rose from 9.3% to 39.4% (P, Highlights • South Asia has become a major epicentre of the COVID-19 pandemic and faces multiple challenges (health, economic, social). • Our findings identified important knowledge, access and uptake barriers to the prevention of COVID-19 in the region. • We demonstrated adverse impacts on chronic disease treatment, mental health, health behaviours, employment, finances. • There is a need for immediate large-scale action to close gaps in knowledge and access to essential resources for prevention. • Along with measures to safeguard economic production and mitigate socio-economic impacts on the young and the poor.
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38. Data resource profile: Understanding the patterns and determinants of health in South Asians—the South Asia Biobank
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Khadija Irfan Khawaja, Franco Sassi, Nita G. Forouhi, Prasad Katulanda, Ananya Gupta, Anuradhani Kasturiratne, Ananda R. Wickremasinghe, Rajendra Pradeepa, Sajjad Ahmed, Sujeet Jha, Jaspal S. Kooner, Mehedi Hasan, Samreen Siddiqui, Gary Frost, Nicholas J. Wareham, Ian Y. Goon, Peige Song, Ranjit Mohan Anjana, Marie Loh, Malay K Mridha, Soren Brage, Sara Mahmood, John C. Chambers, Marisa Miraldo, Dian Kusuma, National Institute for Health Research, Song, Peige [0000-0002-0196-9759], Frost, Gary S [0000-0003-0529-6325], Kusuma, Dian [0000-0002-1909-9341], Brage, Soren [0000-0002-1265-7355], Mridha, Malay K [0000-0001-9226-457X], and Apollo - University of Cambridge Repository
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South asia ,Resource (biology) ,Asia ,business.industry ,Epidemiology ,0104 Statistics ,MEDLINE ,South Asia Biobank. Remaining authors are listed at the end of the article ,General Medicine ,Biobank ,1117 Public Health and Health Services ,Asian People ,RA0421 ,Risk Factors ,Medicine ,Humans ,AcademicSubjects/MED00860 ,Social determinants of health ,Data Resource Profiles ,Socioeconomics ,business ,RC ,Biological Specimen Banks - Abstract
Funder: Singapore Ministry of Health's National Medical Research Council, Funder: National Institute for Health Research, Funder: Wellcome Trust or the Department of Health, Funder: NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme; Grant(s): IS-BRC-1215-20014
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39. APOC3 genetic variation, serum triglycerides, and risk of coronary artery disease in Asian Indians, Europeans, and other ethnic groups
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Yosuke Tanigawa, Megan R. Lerner, Rob M. van Dam, Marvin D. Peyton, Charumathi Sabanayagam, Manuel A. Rivas, Piers R. Blackett, Narinder K. Mehra, Sarju Ralhan, Gurpreet Singh Wander, Weihua Zhang, Jai Rup Singh, Jin-Fang Chai, E. Shyong Tai, Ravindranath Duggirala, Shiwali Goyal, Chanel Seraphin, Marcio Almeida, Juan M. Peralta, Jonathan Garcia Ramiu, April Vaughan, John C. Chambers, Blair Apple, Joanne E. Curran, Donna M. Lehman, Dharambir K. Sanghera, Ching-Yu Cheng, James Muniu, Juliane Chainakul, John Blangero, Xueling Sim, Christopher E. Aston, Jaspal S. Kooner, Evgeny Sidorov, and Lee Kong Chian School of Medicine (LKCMedicine)
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Male ,Apolipoprotein B ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Coronary Artery Disease ,Gastroenterology ,Triglyceride ,Coronary artery disease ,Endocrinology ,Mendelian Randomization ,Nutritional diseases. Deficiency diseases ,biology ,Middle Aged ,Europe ,Coronary artery disease risk ,Female ,Lipidology ,Risk ,Heterozygote ,medicine.medical_specialty ,RC620-627 ,Genotype ,Clinical chemistry ,Rare and common variants ,India ,Clinical nutrition ,Internal medicine ,Mendelian randomization ,medicine ,Humans ,Medicine [Science] ,Asian Indians ,Risk factor ,Alleles ,Genetic Association Studies ,Triglycerides ,Aged ,Apolipoprotein C-III ,business.industry ,Research ,Biochemistry (medical) ,Hypertriglyceridemia ,Genetic Variation ,Sequence Analysis, DNA ,Mendelian Randomization Analysis ,medicine.disease ,ApoC-III ,Mutation ,biology.protein ,business - Abstract
Background: Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk. Methods: We performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD. Results: One rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10− 424. Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p = 0.042). Conclusions: Our results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk. Ministry of Health (MOH) National Medical Research Council (NMRC) Published version AIDHS/SDS: The Sikh Diabetes Study/ Asian Indian Diabetic Heart Study was supported by NIH grants-R01DK082766; R01DK118427 (NIDDK) and NOT-HG11-009 (NHGRI) and grants from Presbyterian Health Foundation and Harald Hamm Diabetes Center of Oklahoma. Sequencing services were provided through the RS&G Service by the Northwest Genomics Center at the University of Washington, Department of Genome Sciences, under US Federal Government contract number HHSN268201100037C from the National Heart, Lung, and Blood Institute of the NIH. LOLIPOP: The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS. Trust, the British Heart Foundation (S.P./04/002), the Medical Research Council (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z, 090532 & 098381) the NIHR (RP-PG-0407-10371), the NIHR Official Development Assistance (ODA, award 16/136/68), the European Union FP7 (EpiMigrant, 279143) and H2020 programs (iHealth-T2D, 643774). We acknowledge the support of the MRC-PHE Centre for Environment and Health, and the NIHR Health Protection Research Unit on Health Impact of Environmental Hazards. The work was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the Imperial College Healthcare NHS. Trust, the NHS, the NIHR, or the Department of Health. We thank the participants and research staff who made the study possible. JC is supported by the Singapore Ministry of Health’s National Medical Research Council under its Singapore Translational Research Investigator (STaR) Award (NMRC/ STaR/0028/2017). SAMAFS: SAMAFS is supported in part by National Institutes of Health (NIH) grants P01 HL045522, R01 DK047482, DK053889, R01 HL113323, R37 MH059490, and T2D-GENES Consortium grants (U01 DK085524, U01 DK085584, U01 DK085501, U01 DK085526, and U01 DK085545). We thank the participants of the San Antonio Family Heart Study and the San Antonio Family Diabetes/Gallbladder Study for their continued cooperation and participation in our research programs. MISS-OLIVER: The OLIVER and MISS are partly supported by NIH grants -R01DK082766 funded by the National Institute of Health (NIDDK), Presbyterian Health Foundation Grants, the College of Medicine Alumni Association grant, and Leinbach Seed Grant from the University of Oklahoma Health Sciences Center. The authors thank all the participants of MISS-OLIVER participants and are grateful for their contribution to this study. UKBB: YT is supported by a Funai Overseas Scholarship from the Funai Foundation for Information Technology and the Stanford University School of Medicine. MAR is partially supported by Stanford University and a National Institute of Health center for Multi-and Trans-ethnic Mapping of Mendelian and Complex Diseases grant (5 U01 HG009080) and partially supported by the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH) under award R01HG010140.
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40. Impact of BMI and waist circumference on epigenome-wide DNA methylation and identification of epigenetic biomarkers in blood: An EWAS in multi-ethnic Asian individuals
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Xueling Sim, Suk Hiang Lau, Yik Ying Teo, Annette Peters, Irfahan Kassam, John C. Chambers, Rory P. Wilson, Rob M. van Dam, Chiea Chuen Khor, Jaspal S. Kooner, Juliane Winkelmann, Vincent T. K. Chow, Yuqing Chen, Marie Loh, and Lee Kong Chian School of Medicine (LKCMedicine)
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Waist ,Bioinformatics ,Body Mass Index ,Asian People ,Epigenome-wide association study ,Mendelian randomization ,Genetics ,Metabolites ,Medicine ,Humans ,Medicine [Science] ,Obesity ,Molecular Biology ,Genetics (clinical) ,Inflammation ,Analysis of Variance ,DNA methylation ,business.industry ,Research ,Epigenome ,Methylation ,Epigenome-Wide Association Study ,DNA Methylation ,medicine.disease ,Human genetics ,ddc ,Waist circumference ,Dna Methylation ,Epigenome-wide Association Study ,Waist Circumference ,business ,Body mass index ,Biomarkers ,Developmental Biology ,Genome-Wide Association Study - Abstract
Background The prevalence of obesity and its related chronic diseases have been increasing especially in Asian countries. Obesity-related genetic variants have been identified, but these explain little of the variation in BMI. Recent studies reported associations between DNA methylation and obesity, mostly in non-Asian populations. Methods We performed an epigenome-wide association study (EWAS) on general adiposity (body mass index, BMI) and abdominal adiposity (waist circumference, WC) in 409 multi-ethnic Asian individuals and replicated BMI and waist-associated DNA methylation CpGs identified in other populations. The cross-lagged panel model and Mendelian randomization were used to assess the temporal relationship between methylation and BMI. The temporal relationship between the identified CpGs and inflammation and metabolic markers was also examined. Results EWAS identified 116 DNA methylation CpGs independently associated with BMI and eight independently associated with WC at false discovery rate PFDR Conclusion Our study provides evidence of an association between obesity and DNA methylation in multi-ethnic Asians and suggests that obesity can drive methylation change. The results also suggested possible causal influence that obesity-related methylation changes might have on inflammation and lipoprotein levels.
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41. Alcohol consumption is associated with widespread changes in blood DNA methylation: Analysis of cross-sectional and longitudinal data
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Daniel F. Schmidt, Rory P. Wilson, Melanie Waldenberger, Laura Baglietto, Harindra Jayasekara, Benjamin Lehne, Graham G. Giles, Pierre Antoine Dugué, Jaspal S. Kooner, Melissa C. Southey, Xiaochuan Wang, Annette Peters, Karl-Heinz Ladwig, Dallas R. English, John C Chambers, Jihoon E. Joo, Christian Gieger, Roger L. Milne, Chol-Hee Jung, Gianluca Severi, Enes Makalic, Cancer Epidemiology Centre & Cancer Council Victoria [Melbourne, Australia], University of Melbourne-Melbourne School for Population and Global Health, Melbourne School of Population and Global Health [Melbourne], University of Melbourne, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Department of Epidemiology and Biostatistics, Imperial College London, St Mary's Campus, London, W2 1PG, Melbourne Bioinformatics [Australia], The University of MelbourneParkville, VIC, Australia., Department of Clinical and Experimental Medicine, University of Pisa, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), München, Technische Universität München, German Research Center for Cardiovascular Disease (DZHK), Partner site Munich Heart Alliance, Institute of Epidemiology and Medical Biometry, University of Ulm, Munich, Germany, Ealing Hospital, Imperial College Healthcare NHS Trust, Monash University [Clayton], Nanyang Technological University [Singapour], Imperial College Healthcare NHS Trust Oregon Department of Agriculture, ODA: 16/136/68 279143 Wellcome Trust, WT: 084723/Z/08/Z, 090532, RP‐PG‐0407‐10371, 098381 Cancer Council Victoria: 1026892, 1027505, 251553, 209057, 1050198, 1011618, 1074383, 504711, 1043616 Bundesministerium für Bildung und Forschung, BMBF VicHealth British Heart Foundation, BHF: SP/04/002 Münchner Zentrum für Gesundheitswissenschaften, Ludwig-Maximilians-Universität München National Institute for Health Research, NIHR National Health and Medical Research Council, NHMRC: 1088405 Horizon 2020 Framework Programme, H2020: 643774 ERAB: The European Foundation for Alcohol Research, ERAB: ERAB 2018 – EA1817 Medical Research Council, MRC: G0601966, G0700931 National Medical Research Council, NMRC: NMRC/STaR/0028/2017, and This work (MCCS) was supported by the Australian National Health and Medical Research Council (NHMRC) (Grant 1088405). MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC Grants 209057, 251553, and 504711 and by infrastructure provided by Cancer Council Victoria. Cases were ascertained through the Victorian Cancer Registry (VCR) and the Australian Cancer Database (Australian Institute of Health and Welfare). The nested case‐control methylation studies were supported by the NHMRC Grants 1011618, 1026892, 1027505, 1050198, 1043616, and 1074383. M.C.S. is an NHMRC Senior Research Fellow (1061177). The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research has been supported within the Munich Center of Health Sciences (MC‐Health), Ludwig‐Maximilians‐Universität, as part of LMUinnovativ. This work has received funding from the European Foundation for Alcohol Research (ERAB 2018 – EA1817). We thank all members of field staffs who were involved in the planning and conduct of the MONICA/KORA Augsburg studies. The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z, 090532, and 098381), the NIHR (RP‐PG‐0407‐10371), the NIHR Official Development Assistance (ODA, award 16/136/68), the European Union FP7 (EpiMigrant, 279143), and H2020 programs (iHealth‐T2D, 643774). We acknowledge support of the MRC‐PHE Centre for Environment and Health and the NIHR Health Protection Research Unit on Health Impact of Environmental Hazards. The work was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the Imperial College Healthcare NHS Trust, the NHS, the NIHR, or the Department of Health. We thank the participants and research staff who made the study possible. JC is supported by the Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research Investigator (STaR) Award (NMRC/STaR/0028/2017).
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Male ,longitudinal data ,[SDV]Life Sciences [q-bio] ,Medicine (miscellaneous) ,Physiology ,Alcohol ,Disease ,Epigenesis, Genetic ,Cohort Studies ,chemistry.chemical_compound ,0302 clinical medicine ,Medicine ,Prospective Studies ,education.field_of_study ,0303 health sciences ,DNA methylation ,Confounding ,Regression analysis ,Methylation ,Middle Aged ,epigenome-wide association study ,Substance abuse ,Psychiatry and Mental health ,030220 oncology & carcinogenesis ,Female ,Alcohol consumption ,Cohort study ,Adult ,Alcohol Drinking ,Longitudinal data ,alcohol consumption ,Population ,03 medical and health sciences ,Genetic ,cross-sectional data ,EWAS ,HM450 assay ,Aged ,CpG Islands ,Cross-Sectional Studies ,Genome-Wide Association Study ,Humans ,DNA Methylation ,Epigenetics ,education ,030304 developmental biology ,Pharmacology ,business.industry ,Alcohol Consumption ,Cross-sectional Data ,Dna Methylation ,Epigenome-wide Association Study ,Ewas ,Hm450 Assay ,Longitudinal Data ,medicine.disease ,030227 psychiatry ,chemistry ,business ,030217 neurology & neurosurgery ,Epigenesis - Abstract
Background:DNA methylation may be one of the mechanisms by which alcohol consumption is associated with the risk of disease. We conducted a large-scale, cross-sectional, genome-wide DNA methylation association study of alcohol consumption and a longitudinal analysis of repeated measurements taken several years apart.Methods:Using the Illumina Infinium HumanMethylation450 BeadChip, DNA methylation measures were determined using baseline peripheral blood samples from 5,606 adult Melbourne Collaborative Cohort Study (MCCS) participants. For a subset of 1,088 of them, these measures were repeated using blood samples collected at follow-up, a median of 11 years later. Associations between alcohol intake and blood DNA methylation were assessed using linear mixed-effects regression models adjusted for batch effects and potential confounders. Independent data from the LOLIPOP (N=4,042) and KORA (N=1,662) cohorts were used to replicate associations discovered in the MCCS.Results:Cross-sectional analyses identified 1,414 CpGs associated with alcohol intake at P-7, 1,243 of which had not been reported previously. Of these 1,243 novel associations, 1,078 were replicated (PConclusion:Our study indicates that, for middle-aged and older adults, alcohol intake is associated with widespread changes in DNA methylation across the genome. Longitudinal analyses showed that the methylation status of alcohol-associated CpGs may change with changes in alcohol consumption.
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- 2021
42. Association of ApoCIII common variants with risk of coronary artery disease: A Mendelian randomization study
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John C. Chambers, Blair Apple, Piers R. Blackett, X. Sim, A. Vaughan, Yosuke Tanigawa, E. S. Tai, C. Jin-Fang, Marvin D. Peyton, Narinder K. Mehra, Juan M. Peralta, J. Muniu, Sarju Ralhan, Jai Rup Singh, Marcio Almeida, Donna M. Lehman, Gurpreet Singh Wander, Megan R. Lerner, Joanne E. Curran, Shiwali Goyal, Weihua Zhang, Manuel A. Rivas, Juliane Chainakul, J.G. Ramiu, John Blangero, Jaspal S. Kooner, Ravindranath Duggirala, Evgeny Sidorov, C. Seraphin, Charumathi Sabanayagam, R.M. Van Dam, Dharambir K. Sanghera, and Ching-Yu Cheng
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Coronary artery disease ,medicine.medical_specialty ,business.industry ,Association (object-oriented programming) ,Internal medicine ,Mendelian randomization ,Cardiology ,Medicine ,Cardiology and Cardiovascular Medicine ,business ,medicine.disease - Published
- 2021
43. The iHealth-T2D study: Statistical analysis plan for a cluster randomised controlled trial with intensive family-based lifestyle modification programme to reduce type 2 diabetes risk amongst South Asians
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Sajjad Ahmed, Jaspal S. Kooner, Samreen Siddiqui, Gary Frost, Ananda R. Wickremasinghe, Saranya Palaniswamy, Sujeet Jha, Mirthe Muilwijk, Marjo-Riitta Järvelin, Prasad Katulanda, R.P. Rannan-Eliya, Irene G. M. van Valkengoed, Marie Loh, Anuradhani Kasturiratne, Sara Mahmood, John C. Chambers, Heather Gage, Wnurinham Silva, and Khadija Irfan Khawaja
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medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Type 2 diabetes ,Anthropometry ,medicine.disease ,law.invention ,Statistical Analysis Plan ,Randomized controlled trial ,law ,Family medicine ,Intervention (counseling) ,medicine ,Prediabetes ,Cluster randomised controlled trial ,business - Abstract
BackgroundSouth Asians are at high risk of type 2 diabetes (T2D). Lifestyle modification is effective at preventing T2D amongst South Asians, but the approaches to screening and intervention are limited by high-costs, poor scalability and thus low impact on T2D burden. An intensive family-based lifestyle modification programme for prevention of T2D was developed. The aim of the iHealth-T2D trial is to compare the effectiveness of this programme with usual care.MethodsThe iHealth-T2D trial is designed as a cluster randomised controlled trial (RCT) conducted at 120 locations across India, Pakistan, Sri Lanka and the UK. A total of 3,682 South Asian men and women with age between 40-70 years without T2D but at elevated risk for T2D [defined by central obesity (waist circumference ≥95cm in Sri Lanka, or ≥100cm in India, Pakistan and UK) and/or prediabetes (HbA1c ≥6.0%)] were included in the trial. Here we describe in detail the statistical analysis plan (SAP), which was finalised before outcomes were available to the investigators. The primary outcome will be evaluated after three years of follow-up after enrolment to the study, and is defined as T2D incidence in the intervention arm compared to usual care. Secondary outcomes are evaluated both after one and three years of follow-up and include biochemical measurements, anthropometric measurements, behavioural components and treatment compliance.DiscussionThe iHealth-T2D trial will provide evidence whether an intensive family-based lifestyle modification programme in South Asians who are at high risk for T2D is effective in the prevention of T2D. The data from the trial will be analysed according to this pre-specified SAP.Ethics and disseminationThe trial was approved by the international review board of each participating study site. Study findings will be disseminated through peer-reviewed publications and in conference presentations.Trial registrationEudraCT 2016-001350-18. Registered 14 April 2016 https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/ihealth-t2d/; ClinicalTrials.govNCT02949739. Registered 31 October 2016, https://clinicaltrials.gov/ct2/show/NCT02949739, First posted 31/10/2016.
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- 2020
44. The iHealth-T2D study: rationale and design of a cluster randomised trial for prevention of Type 2 Diabetes amongst South Asians with central obesity and prediabetes
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Samreen Siddiqui, Khurram Shahzad, Jonathan Valabhji, Gary Frost, Saranya Palaniswamy, Madawanarachchi S, Sajjad Ahmad, Batool T, Sara Mahmood, John C. Chambers, Baldeesh Rai, Sattar I, Mirthe Muilwijk, Prasad Katulanda, van Valkengoed Ig, Bamunuarachchi, R.P. Rannan-Eliya, Panda M, Anuradhani Kasturiratne, Marjo-Riitta Järvelin, Marie Loh, Sujeet Jha, Ranil Jayawardena, Swati Waghdhare, L.K. Athauda, Matthew Glover, Heather Gage, Wnurinham Silva, Khadija Irfan Khawaja, Jaspal S. Kooner, Saira Burney, and Ananda R. Wickremasinghe
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medicine.medical_specialty ,Waist ,business.industry ,Type 2 diabetes ,medicine.disease ,Obesity ,Clinical trial ,Family medicine ,Community health ,medicine ,Prediabetes ,Underweight ,medicine.symptom ,business ,Body mass index - Abstract
BackgroundPeople from South Asia are at increased risk of type 2 diabetes (T2D). There is an urgent need to develop approaches for prevention of T2D in South Asians, that are cost-effective, generalisable and scalable across settings.HypothesisCompared to usual care, risk of T2D can be reduced amongst South Asians with central obesity or raised HbA1c, through a 12 month lifestyle modification programme delivered by community health workers.DesignCluster randomised clinical trial (1:1 allocation to Intervention or Usual care), carried out in India, Pakistan, Sri Lanka, and UK, with 30 sites per country (120 sites total). Target recruitment 3,600 (30 participants per site) with annual follow-up for three years.Entry criteriaSouth Asian, men or women, age 40-70 years with i. Central obesity (waist circumference ≥100cm in India and Pakistan; ≥90cm in Sri Lanka) and / or ii. Prediabetes (HbA1c 6.0-6.4% inclusive). Exclusion criteria: known type 1 or 2 diabetes, normal or underweight (body mass indexEndpointsThe primary end point is new onset T2D at 3 years, defined as: i. HbA1c≥6.5% or ii. Physician diagnosis and on treatment for T2D. Secondary endpoints at 1 and 3 years are: i. Physical measures: waist circumference, weight and blood pressure; ii. Lifestyle measures: smoking status, alcohol intake, physical activity, dietary intake; iii. Biochemical measures: Fasting glucose, insulin and lipids (total and HDL cholesterol, triglycerides); and iv. Treatment compliance.InterventionLifestyle intervention (60 sites) or Usual care (60 sites). Lifestyle intervention was delivered by a trained community health worker over 12 months (5 one-one session, 4 group sessions, 13 telephone sessions) with the goal of the participants achieving e a 7% reduction in body mass index and a 10 cm reduction in waist circumference through i. improved diet and ii. increased physical activity. Usual care comprised a single 30 minute session of lifestyle modification advice from the community health worker.ResultsWe screened 33,212 people for inclusion into the study. We identified 10,930 people who met study entry criteria, amongst whom, 3,682 agreed to take part in the intervention. Study participants are 49.2% female and aged 52.8 (SD 8.2) years. Clinical characteristics are well balanced between Intervention and Usual care sites. More than 90% of follow-up visits are scheduled to be complete December 2020. Based on follow-up to end 2019, the observed incidence of T2D in the study population is in line with expectations (6.1% per annum).ConclusionThe iHealth-T2D study will advance understanding of strategies for prevention of diabetes amongst South Asians, use approaches for screening and intervention that are adapted for low-resource settings. Our study will thus inform the implementation of strategies for improving the health and well-being of this major global ethnic group.IRB approval16/WM/0171Trial registrationEudraCT 2016-001350-18. Registered 14 April 2016 https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/ihealth-t2d/ ; ClinicalTrials.gov NCT02949739. Registered 31 October 2016, https://clinicaltrials.gov/ct2/show/NCT02949739, First posted 31/10/2016.FunderEuropean Commission (award 643774) and National Institute for Health Research (award 16/136/68)
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- 2020
45. Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes
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Ma Elena Gonzalez, Marit E. Jørgensen, Edmund Chan, Eric Boerwinkle, Craig L. Hanis, Tim M. Strom, Young-Jin Kim, Alanna C. Morrison, Abigail Sveden, Zachary Zappala, Jianjun Liu, Markku Laakso, Russell P. Tracy, Andrew D. Morris, Farook Thameem, Ruth J. F. Loos, Robert Sladek, Moriel Singer-Berk, Jason Flannick, Stephen S. Rich, Angélica Martínez-Hernández, Rob M. van Dam, Wendy S. Post, Michael Boehnke, Peter M. Nilsson, Humberto García-Ortiz, Clicerio González-Villalpando, Samantha Baxter, Yoon Shin Cho, Sergio Islas-Andrade, Colin N. A. Palmer, Claudia H. T. Tam, Nicholas A. Watts, Lizz Caulkins, Rachel Son, Daniel G. MacArthur, Toni I. Pollin, Juan Manuel Malacara Hernandez, Jong-Young Lee, Bruce M. Psaty, Ravindranath Duggirala, Erwin P. Bottinger, Nancy L. Heard-Costa, Donna M. Lehman, Carlos A. Aguilar-Salinas, Juyoung Lee, Haichen Zhang, Mark I. McCarthy, Brian Tomlinson, Leslie A. Lange, Cecilia Contreras-Cubas, Johanna Kuusisto, Danish Saleheen, Juliana C.N. Chan, Andrew Dahl, Konstantin Strauch, Noël P. Burtt, Tien Yin Wong, Niels Grarup, Jerome I. Rotter, Ronald C.W. Ma, Julia K. Goodrich, Anne H. O’Donnell-Luria, Jose C. Florez, Miriam S. Udler-Aubrey, Kristin A. Maloney, James G. Wilson, Ramachandran S. Vasan, Bong-Jo Kim, Leif Groop, Noah Zaitlen, Kerrin S. Small, Heikki A. Koistinen, Donald W. Bowden, Wing-Yee So, Jaakko Tuomilehto, Oluf Pedersen, John C. Chambers, Mi Yeong Hwang, Karen L. Mohlke, John Blangero, Eleina M. England, Elvia Mendoza-Caamal, James B. Meigs, Federico Centeno-Cruz, Michael Preuss, Ralph A. DeFronzo, Joanne B. Cole, Jordan Wood, Allan Linneberg, Benjamin Glaser, Lorena Orozco, Jaspal S. Kooner, Valeriya Lyssenko, Sohee Han, Gil Atzmon, Ma. Eugenia Garay-Sevilla, Tiinamaija Tuomi, Brian E. Henderson, Christopher J. O'Donnell, Hyun Min Kang, Teresa Tusié-Luna, Nir Barzilai, Thomas Meitinger, Christian Gieger, Ben Weisburd, Alexander P. Reiner, Tim D. Spector, Myron D. Gross, E. Shyong Tai, Yik Ying Teo, for Amp-T D-Genes Consortia, Xueling Sim, Emilio J. Cordova, Cristina Revilla-Monsalve, Daniel R. Witte, Francisco Barajas-Olmos, Claudia Schurmann, Lori L. Bonnycastle, Josep M. Mercader, Adolfo Correa, Torben Hansen, Kyong Soo Park, Ching-Yu Cheng, Soo Heon Kwak, Nathalie Chami, Christopher A. Haiman, Xavier Soberón, Josée Dupuis, and Maggie C.Y. Ng
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Genetics ,0303 health sciences ,Genetic variants ,Disease ,030204 cardiovascular system & hematology ,Biology ,medicine.disease ,Penetrance ,3. Good health ,Biomarker (cell) ,03 medical and health sciences ,0302 clinical medicine ,Diabetes mellitus ,Genotype ,medicine ,Exome sequencing ,030304 developmental biology ,Monogenic Diabetes - Abstract
Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier will develop the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we applied clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias displayed effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers averaged below 60% in both studies for all conditions except monogenic diabetes. We assessed additional epidemiologic and genetic factors contributing to risk prediction, demonstrating that inclusion of common polygenic variation significantly improved biomarker estimation for two monogenic dyslipidemias.
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- 2020
46. Trans-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
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Anubha Mahajan, Cassandra N Spracklen, Weihua Zhang, Maggie CY Ng, Lauren E Petty, Hidetoshi Kitajima, Grace Z Yu, Sina Rüeger, Leo Speidel, Young Jin Kim, Momoko Horikoshi, Josep M Mercader, Daniel Taliun, Sanghoon Moon, Soo-Heon Kwak, Neil R Robertson, Nigel W Rayner, Marie Loh, Bong-Jo Kim, Joshua Chiou, Irene Miguel-Escalada, Pietro della Briotta Parolo, Kuang Lin, Fiona Bragg, Michael H Preuss, Fumihiko Takeuchi, Jana Nano, Xiuqing Guo, Amel Lamri, Masahiro Nakatochi, Robert A Scott, Jung-Jin Lee, Alicia Huerta-Chagoya, Mariaelisa Graff, Jin-Fang Chai, Esteban J Parra, Jie Yao, Lawrence F Bielak, Yasuharu Tabara, Yang Hai, Valgerdur Steinthorsdottir, James P Cook, Mart Kals, Niels Grarup, Ellen M Schmidt, Ian Pan, Tamar Sofer, Matthias Wuttke, Chloe Sarnowski, Christian Gieger, Darryl Nousome, Stella Trompet, Jirong Long, Meng Sun, Lin Tong, Wei-Min Chen, Meraj Ahmad, Raymond Noordam, Victor JY Lim, Claudia HT Tam, Yoonjung Yoonie Joo, Chien-Hsiun Chen, Laura M Raffield, Cécile Lecoeur, Nisa M Maruthur, Bram Peter Prins, Aude Nicolas, Lisa R Yanek, Guanjie Chen, Richard A Jensen, Salman Tajuddin, Edmond Kabagambe, Ping An, Anny H Xiang, Hyeok Sun Choi, Brian E Cade, Jingyi Tan, Fernando Abaitua, Linda S Adair, Adebowale Adeyemo, Carlos A Aguilar-Salinas, Masato Akiyama, Sonia S Anand, Alain Bertoni, Zheng Bian, Jette Bork-Jensen, Ivan Brandslund, Jennifer A Brody, Chad M Brummett, Thomas A Buchanan, Mickaël Canouil, Juliana CN Chan, Li-Ching Chang, Miao-Li Chee, Ji Chen, Shyh-Huei Chen, Yuan-Tsong Chen, Zhengming Chen, Lee-Ming Chuang, Mary Cushman, Swapan K Das, H. Janaka de Silva, George Dedoussis, Latchezar Dimitrov, Ayo P Doumatey, Shufa Du, Qing Duan, Kai-Uwe Eckardt, Leslie S Emery, Daniel S Evans, Michele K Evans, Krista Fischer, James S Floyd, Ian Ford, Myriam Fornage, Oscar H Franco, Timothy M Frayling, Barry I Freedman, Christian Fuchsberger, Pauline Genter, Hertzel C Gerstein, Vilmantas Giedraitis, Clicerio González-Villalpando, Maria Elena González-Villalpando, Mark O Goodarzi, Penny Gordon-Larsen, David Gorkin, Myron Gross, Yu Guo, Sophie Hackinger, Sohee Han, Andrew T Hattersley, Christian Herder, Annie-Green Howard, Willa Hsueh, Mengna Huang, Wei Huang, Yi-Jen Hung, Mi Yeong Hwang, Chii-Min Hwu, Sahoko Ichihara, Mohammad Arfan Ikram, Martin Ingelsson, Md. Tariqul Islam, Masato Isono, Hye-Mi Jang, Farzana Jasmine, Guozhi Jiang, Jost B Jonas, Marit E Jørgensen, Torben Jørgensen, Yoichiro Kamatani, Fouad R Kandeel, Anuradhani Kasturiratne, Tomohiro Katsuya, Varinderpal Kaur, Takahisa Kawaguchi, Jacob M Keaton, Abel N Kho, Chiea-Chuen Khor, Muhammad G Kibriya, Duk-Hwan Kim, Katsuhiko Kohara, Jennifer Kriebel, Florian Kronenberg, Johanna Kuusisto, Kristi Läll, Leslie A Lange, Myung-Shik Lee, Nanette R Lee, Aaron Leong, Liming Li, Yun Li, Ruifang Li-Gao, Symen Ligthart, Cecilia M Lindgren, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Adam E Locke, Tin Louie, Jian’an Luan, Andrea O Luk, Xi Luo, Jun Lv, Valeriya Lyssenko, Vasiliki Mamakou, K Radha Mani, Thomas Meitinger, Andres Metspalu, Andrew D Morris, Girish N. Nadkarni, Jerry L Nadler, Michael A Nalls, Uma Nayak, Ioanna Ntalla, Yukinori Okada, Lorena Orozco, Sanjay R Patel, Mark A Pereira, Annette Peters, Fraser J Pirie, Bianca Porneala, Gauri Prasad, Sebastian Preissl, Laura J Rasmussen-Torvik, Alexander P Reiner, Michael Roden, Rebecca Rohde, Katheryn Roll, Charumathi Sabanayagam, Maike Sander, Kevin Sandow, Naveed Sattar, Sebastian Schönherr, Claudia Schurmann, Mohammad Shahriar, Jinxiu Shi, Dong Mun Shin, Daniel Shriner, Jennifer A Smith, Wing Yee So, Alena Stančáková, Adrienne M Stilp, Konstantin Strauch, Ken Suzuki, Atsushi Takahashi, Kent D Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Brian Tomlinson, Jason M Torres, Fuu-Jen Tsai, Jaakko Tuomilehto, Teresa Tusie-Luna, Miriam S Udler, Adan Valladares-Salgado, Rob M van Dam, Jan B van Klinken, Rohit Varma, Marijana Vujkovic, Niels Wacher-Rodarte, Ellie Wheeler, Eric A Whitsel, Ananda R Wickremasinghe, Konstantin Willems van Dijk, Daniel R Witte, Chittaranjan S Yajnik, Ken Yamamoto, Toshimasa Yamauchi, Loïc Yengo, Kyungheon Yoon, Canqing Yu, Jian-Min Yuan, Salim Yusuf, Liang Zhang, Wei Zheng, null FinnGen, Leslie J Raffel, Michiya Igase, Eli Ipp, Susan Redline, Yoon Shin Cho, Lars Lind, Michael A Province, Craig L Hanis, Patricia A Peyser, Erik Ingelsson, Alan B Zonderman, Bruce M Psaty, Ya-Xing Wang, Charles N Rotimi, Diane M Becker, Fumihiko Matsuda, Yongmei Liu, Eleftheria Zeggini, Mitsuhiro Yokota, Stephen S Rich, Charles Kooperberg, James S Pankow, James C Engert, Yii-Der Ida Chen, Philippe Froguel, James G Wilson, Wayne HH Sheu, Sharon LR Kardia, Jer-Yuarn Wu, M Geoffrey Hayes, Ronald CW Ma, Tien-Yin Wong, Leif Groop, Dennis O Mook-Kanamori, Giriraj R Chandak, Francis S Collins, Dwaipayan Bharadwaj, Guillaume Paré, Michèle M Sale, Habibul Ahsan, Ayesha A Motala, Xiao-Ou Shu, Kyong-Soo Park, J Wouter Jukema, Miguel Cruz, Roberta McKean-Cowdin, Harald Grallert, Ching-Yu Cheng, Erwin P Bottinger, Abbas Dehghan, E-Shyong Tai, Josee Dupuis, Norihiro Kato, Markku Laakso, Anna Köttgen, Woon-Puay Koh, Colin NA Palmer, Simin Liu, Goncalo Abecasis, Jaspal S Kooner, Ruth JF Loos, Kari E North, Christopher A Haiman, Jose C Florez, Danish Saleheen, Torben Hansen, Oluf Pedersen, Reedik Mägi, Claudia Langenberg, Nicholas J Wareham, Shiro Maeda, Takashi Kadowaki, Juyoung Lee, Iona Y Millwood, Robin G Walters, Kari Stefansson, Simon R Myers, Jorge Ferrer, Kyle J Gaulton, James B Meigs, Karen L Mohlke, Anna L Gloyn, Donald W Bowden, Jennifer E Below, John C Chambers, Xueling Sim, Michael Boehnke, Jerome I Rotter, Mark I McCarthy, and Andrew P Morris
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0303 health sciences ,Transferability ,Translation (biology) ,Type 2 diabetes ,Biology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Evolutionary biology ,Global health ,medicine ,Genetic risk ,Gene ,030217 neurology & neurosurgery ,030304 developmental biology ,Genetic association - Abstract
We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p-8), including 237 attaining a more stringent trans-ancestry threshold (p-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.
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- 2020
47. DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures
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Ilkka Seppälä, John C. Chambers, Marjo-Riitta Järvelin, Thomas Meitinger, Simone Wahl, Mika Ala-Korpela, Annette Peters, Michael Roden, Martina Müller-Nurasyid, Weihua Zhang, Wolfgang Rathmann, Pamela R. Matias-Garcia, Jaspal S. Kooner, Anja Kretschmer, Holger Prokisch, Johannes Kettunen, Christian Herder, Monica del C. Gomez-Alonso, Melanie Waldenberger, Mikko Hurme, Marie Loh, Sylvain Sebert, Rory P. Wilson, Olli T. Raitakari, Liliane Pfeiffer, Ville Karhunen, Kirstin Mittelstraß, Luis R. Serrano-Garcia, Terho Lehtimäki, Sacha Horn, Christian Gieger, Tampere University, Department of Clinical Chemistry, Clinical Medicine, BioMediTech, and Lee Kong Chian School of Medicine (LKCMedicine)
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0301 basic medicine ,Male ,Very low-density lipoprotein ,Myocardial Infarction ,Blood lipids ,030204 cardiovascular system & hematology ,Epigenesis, Genetic ,Cohort Studies ,chemistry.chemical_compound ,0302 clinical medicine ,Germany ,Genetics (clinical) ,2. Zero hunger ,Aged, 80 and over ,Middle Aged ,CpG site ,ddc ,Cpg Site ,Fatty Acids ,Hdl ,Ldl ,Lipoprotein Composition ,Lipoprotein Sizes ,Nmr ,Obesity ,Vldl ,DNA methylation ,Metabolome ,lipids (amino acids, peptides, and proteins) ,Female ,VLDL ,Adult ,medicine.medical_specialty ,HDL ,Biology ,3121 Internal medicine ,LDL ,03 medical and health sciences ,Lipoprotein composition ,Lipoprotein sizes ,Internal medicine ,Genetics ,medicine ,Humans ,Medicine [Science] ,Epigenetics ,CpG Site ,Fatty acids ,Molecular Biology ,Aged ,Cholesterol ,Research ,Lipid metabolism ,DNA Methylation ,Lipid Metabolism ,NMR ,Myocardial infarction ,030104 developmental biology ,Endocrinology ,chemistry ,3111 Biomedicine ,Developmental Biology ,Lipoprotein ,Genome-Wide Association Study - Abstract
Background The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances. Results We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value −10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations. Conclusion Our study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.
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- 2020
48. Data Resource Profile: Understanding the patterns and determinants of health in South Asians - South Asia Biobank
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Jaspal S. Kooner, Anuradhani Kasturiratne, Malabika Sarker, Marisa Miraldo, Samreen Siddiqui, Fred Hersch, Rajendra Pradeepa, Sujeet Jha, Ranjit Mohan Anjana, Marie Loh, Franco Sassi, Malay K Mridha, Sophie E. Day, Garudam R Aarthi, Polly Page, Jonathan Valabhji, Mehedi Hasan, Soren Brage, Ian Y. Goon, Sara Mahmood, Rajan Kamalesh, John C. Chambers, Wnurinham Silva, Ananda R. Wickremasinghe, Peige Song, Khadija Irfan Khawaja, Gary Frost, Sajjad Ahmed, Nicholas J. Wareham, Baldeesh Rai, Ananya Gupta, Saira Afzal, Bridget A. Holmes, Prasad Katulanda, Dian Kusuma, Elisa Pineda, and Nita G. Forouhi
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education.field_of_study ,Waist ,business.industry ,Population ,Disease ,medicine.disease ,Biobank ,Obesity ,Environmental health ,medicine ,Medical history ,Social determinants of health ,education ,business ,Socioeconomic status - Abstract
Background and aimsThis paper describes the data resource profile of South Asia Biobank (SAB), which was set up in South Asia from November 2018 to March 2020, to identify the risk factors and their complex interactions underlying the development of type-2 diabetes mellitus, cardiovascular disease and other chronic diseases in South Asians.Data resource basicsThis cross-sectional population-based study has recruited 52713 South Asian adults from 118 surveillance sites at five centres of excellence in South Asia (Bangladesh, North India, South India, Pakistan and Sri Lanka). Structured assessments of participants included six complementary domains: i). Registration and consent; ii). Questionnaire (information on behavioural risk factors, personal and family medical history, medications, socioeconomic status); iii). Physical measurements (height, weight, waist and hip circumference and bio-impedance for body fat composition, blood pressure, cardiac evaluation, retinal photography, respiratory evaluation); iv). Biological samples (blood and urine); v). Physical activity monitoring and vi). Dietary intake by a 24-hour recall. Aliquots of whole blood, serum, plasma, and urine were put into storage at −80°C for further analysis.Key resultsThe prevalence of obesity is 6.6% in Bangladesh, 19.7% in India, 33.9% in Pakistan and 15.7% in Sri Lanka. The prevalence of diabetes is 11.5%, 27.7%, 25.3%, and 24.8%, and the prevalence of hypertension is 26.7%, 36.9%, 44.5%, 35.0% in Bangladesh, India, Pakistan and Sri Lanka respectively.Collaboration and data accessSAB is the first comprehensive biobank of South Asian individuals. Collected data are available to the global scientific community upon request.
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- 2020
49. The Trans-Ancestral Genomic Architecture of Glycaemic Traits
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Hugoline G. de Haan, Andrew A. Hicks, Achilleas Pitsilides, Fernando Pires Hartwig, Richard A. Jensen, Matti Uusitupa, Anders Hamsten, Dennis O. Mook-Kanamori, Zorayr Arzumanyan, Betina H. Thuesen, Karin Leander, Fernando Rivideneira, Lynne E. Wagenknecht, Andrew R. Wood, Annique Claringbould, Ele Ferranni, Sölve Elmståhl, Eleanor Wheeler, Sharon L.R. Kardia, Richa Saxena, Tatijana Zemunik, Cassandra N. Spracklen, Ken K. Ong, Xiao-Ou Shu, Johannes Waage, Blair H. Smith, Rozenn N. Lemaitre, Torben Hansen, Peter K. Joshi, Lisa R. Yanek, Neil R. Robertson, Sven Bergmann, Mila Desi Anasanti, Inger Njølstad, Ananda R. Wickremasinghe, Xu Lin, Harold Snieder, Wanqing Wen, Veronique Vitart, Paul R. H. J. Timmers, Timo Saaristo, James F. Wilson, Tian Xie, Tao Huang, Rainer Rauramaa, Kei Hang, Rebecca Rohde, Li-Ching Chang, Jing Hua Zhao, Kazuya Setoh, Yasuharu Tabara, Michael Stumvoll, Mark O. Goodarzi, Igor Rudan, James B. Meigs, Jaakko Tuomilehto, Richard M. Watanabe, Ruth J. F. Loos, Reedik Mägi, Jouke-Jan Hottenga, Ozren Polasek, Michael Y. Tsai, Donald W. Bowden, Diana Kuh, Erik B. van den Akker, Yii-Der Ida Chen, Daniel I. Chasman, Weihua Zhang, Nicholette D. Palmer, Marcus E. Kleber, Anny H. Xiang, Chang-Hsun Hsieh, Alan B. Zonderman, Stefan Gustafsson, Timo A. Lakka, Brian H. Chen, Dermot F. Reilly, Francis S. Collins, Oluf Pedersen, Corri Black, Yang Hai, Zoltán Kutalik, Yoriko Heianza, Willa A. Hsueh, Vilmundur Gudnason, Robert C. Kaplan, Jun Liu, Michael A. Province, Aliki-Eleni Farmaki, Stephen S. Rich, Jian'an Luan, Erik Ingelsson, Marie Loh, Michael Preuss, Lars Lind, Stefan R. Bornstein, Mandy Vogel, Colin N. A. Palmer, Fumihiko Matsuda, Takahisa Kawaguchi, Sohee Han, Ching-Ti Liu, Young-Jin Kim, L. Southam, Sara M. Willems, Mickaël Canouil, Robert A. Scott, Marika Kaakinen, Stephan J. L. Bakker, Momoko Horikoshi, Tarunveer S. Ahluwalia, Annette Schürmann, Graciela E. Delgado, Thibaud S. Boutin, Thomas Sparsø, Sandosh Padmanabhan, Fouad Kandeel, Eco J. C. de Geus, Anubha Mahajan, Claudia Schurmann, Klaus Bønnelykke, Leslie A. Lange, Qing Duan, Rona J. Strawbridge, Dennis Raven, Gonçalo R. Abecasis, Mitsuhiro Yokota, Jani Heikkinen, Elizabeth Selvin, Audrey Y. Chu, Anke Tönjes, Marta E. Alarcón-Riquelme, Hans Bisgaard, P. Eline Slagboom, Eric Boerwinkle, Massimo Mangino, Catharina A. Hartman, Geltrude Mingrone, Lenore J. Launer, Michael Boehnke, Emil V. R. Appel, Niels Grarup, Arushi Varshney, Archie Campbell, Kari E. North, W. Craig Johnson, Inês Barroso, Ya X. Wang, Carola Marzi, Anuj Goel, Eleftheria Zeggini, Lu Qi, Yasumasa Ohyagi, Tien Yin Wong, Tanja G. M. Vrijkotte, Gudny Eiriksdottir, Harald Grallert, Ishminder K. Kooner, Trevor A. Mori, Jagadish Vangipurapu, Laura J Corbin, Tomohiro Katsuya, Wen B. Wei, Segun Fatumo, Debashree Ray, Annette Peters, Lori L. Bonnycastle, Ilja M. Nolte, M. Arfan Ikram, Manjinder S. Sandhu, Marit E. Jørgensen, Christian Herder, Damia Noce, Sarah C. Nelson, Chien-Hsiun Chen, Heather M. Stringham, Yong-Bing Xiang, Bruce M. Psaty, Alain G. Bertoni, Gaëlle Marenne, Timothy M. Frayling, Jose C. Florez, Penny Gordon-Larsen, Yu-Tang Gao, Abhishek Nag, Damiano Baldassarre, J. Wouter Jukema, Wei Huang, Yi-Cheng Chang, Albertine J. Oldehinkel, Xiaoshuai Zhang, Yujie Wang, Shaofeng Huo, Xueling Sim, Norihiro Kato, Bernhard O. Böhm, Lorraine Southam, Mari Nelis, Gonneke Willemsen, Laura J. Rasmussen-Torvik, Philippe Froguel, Charumathi Sabanayagam, Leif Groop, Loic Yengo, Shi Jinxiu, Adolfo Correa, Serena Sanna, Arne Astrup, Teemu Kuulasmaa, Symen Ligthart, Shih-Yi Lin, David J. Porteous, Harry Campbell, Peter Vollenweider, Mark J. Caulfield, Kristi Läll, Anne Ndungu, Carl D. Langefeld, Tanya M. Teslovich, Heikki A. Koistinen, Ying Wu, Mattias Frånberg, D.I. Boomsma, Lawrence F. Bielak, Diana van Heemst, Peter Kovacs, Markku Laakso, Leslie J. Raffel, Katharina E. Schraut, Noël P. Burtt, Michiya Igase, Craig E. Pennell, Claudia Langenberg, Huaixing Li, Teresa Tusie, Laura M. Raffield, Jorgen Engmann, Stephen C. J. Parker, Michele K. Evans, Chaolong Wang, Rico Rueedi, Jianjun Liu, Pankow S. James, Hortensia Moreno-Macías, Fumihiko Takeuchi, Cornelia M. van Duijn, Sanghoon Moon, Susan R. Heckbert, Thomas A. Buchanan, Ko Willems van Dijk, Toru Nabika, May E. Montasser, Caroline Hayward, Jie Yao, Aaron Leong, Antje Körner, Jouko Saramies, Jost B. Jonas, Pim van der Harst, Naveed Sattar, Helen R. Warren, Alice Stanton, Yen-Feng Chiu, Kumaraswamy Naidu Chitrala, Mi Yeong Hwang, Jin Fang Chai, Alicia Huerta-Chagoya, Anette P. Gjesing, Ching-Yu Cheng, Debbie A Lawlor, Simin Liu, Man Li, Ivana Kolcic, Erwin P. Bottinger, Andrew Wong, Stella Trompet, Heming Wang, Jirong Long, Xiuqing Guo, Jeffrey R. O'Connell, Meena Kumari, Sirkka Keinänen-Kiukaanniemi, Rita R. Kalyani, Bengt Sennblad, Mohammad Hadi Zafarmand, Kent D. Taylor, Katherine A. Kentistou, Carol A. Wang, Shuiqing Lai, Patricia B. Munroe, Patricia A. Peyser, Lawrence J. Beilin, Niek Verweij, Inga Prokopenko, Brian E. Cade, Patrik K. E. Magnusson, John C. Chambers, Tamar Sofer, Ping An, Matthias Blüher, Isobel D. Stewart, Alexander P. Reiner, Anna L. Gloyn, Simon P. Mooijaart, Tim D. Spector, Paul W. Franks, Wei Zhao, Andres Metspalu, Wieland Kiess, Kathleen A. Ryan, Astrid van Hylckama Vlieg, Jaana Lindström, Wei Zheng, E. Shyong Tai, Josée Dupuis, Nanette R. Lee, Laura J. Scott, Nicholas J. Timpson, George Dedoussis, Mark I. McCarthy, Tatsuaki Matsubara, Carlos Lorenzo, Denis Rybin, Luigi Ferruci, Chelsea K. Raulerson, Mika Kivimäki, Paul M. Ridker, Jer-Yuarn Wu, Shufa Du, Jaeyoung Hong, Linda S. Adair, Tin Louie, Valeriya Lyssenko, Susan Redline, Kelvin Lam, Qibin Qi, H. Janaka de Silva, Jana V. van Vliet-Ostaptchouk, Peter J. van der Most, Sahoko Ichihara, Nicholas J. Wareham, Ayse Demirkan, Francesco Cucca, Allan Linneberg, Rob M. van Dam, Claire J. Steves, Liang Sun, Albert V. Smith, Raymond Noordam, Tom Wilsgaard, Winfried März, Jung Ho Gong, Matt J. Neville, Jerry L. Nadler, Giorgio Pistis, Karen L. Mohlke, Bruna Gigante, Jennifer A. Brody, Andrew P. Morris, Marie Lauzon, Peter E. H. Schwarz, Bernardo L. Horta, Xiaoran Chai, Ji Chen, Peter S. Sever, Thorkild I. A. Sørensen, André G. Uitterlinden, Javier Gayán, Elena Tremoli, Girish N. Nadkarni, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Jingyi Tan, Sameline Grimsgaard, Bong-Jo Kim, Kerrin S. Small, Jill M. Norris, Cecilia M. Lindgren, Richard N. Bergman, Mark Walker, Henrik Vestergaard, Larissa Aviles-Santa, Jing He, Masahiro Nakatochi, Peter P. Pramstaller, Chiea Chuen Khor, Ruifang Li-Gao, Qiuyin Cai, Neil Schneiderman, Kevin Sandow, Jaspal S. Kooner, Carlos A. Aguilar-Salinas, Peitao Wu, Jerome I. Rotter, Kathryn Roll, Frits R. Rosendaal, Diane M. Becker, Marian Beekman, Claudia P. Cabrera, Nan Wang, Franco Giulianini, Tao Wang, Honglan Li, Abbas Dehghan, Christian Fuchsberger, and Pontiano Kaleebu
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0303 health sciences ,medicine.medical_specialty ,business.industry ,Type 2 diabetes ,medicine.disease ,Fasting insulin ,Fasting glucose ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Diabetes mellitus ,medicine ,Genomic architecture ,business ,Glycated haemoglobin ,030217 neurology & neurosurgery ,030304 developmental biology ,Genetic association - Abstract
Glycaemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To date, most genetic studies of glycaemic traits have focused on individuals of European ancestry. Here, we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated haemoglobin, and fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase understanding of diabetes pathophysiology by use of trans-ancestry studies for improved power and resolution.
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- 2020
50. Management of Acute Coronary Syndromes During the Coronavirus Disease 2019 Pandemic: Deviations from Guidelines and Pragmatic Considerations for Patients and Healthcare Workers
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Henry Seligman, Ricardo Petraco, Sukhjinder Nijjer, Ghada W. Mikhail, Michael Bellamy, Rasha Al-Lamee, Iqbal S. Malik, Ramzi Khamis, Nearchos Hadjiloizou, Rodney A. Foale, Jaspal S. Kooner, Raffi Kaprielian, Piers Clifford, Jamil Mayet, Amarjit Sethi, Christopher S. Baker, Masood Khan, Punit Ramrakha, Darrel P. Francis, Sayan Sen, and British Heart Foundation
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safety ,medicine.medical_specialty ,Acute coronary syndrome ,thrombolysis ,Management of acute coronary syndrome ,RD1-811 ,Coronavirus disease 2019 (COVID-19) ,business.industry ,angioplasty ,Guideline ,medicine.disease ,acute coronary syndrome ,RC666-701 ,Health care ,Pandemic ,Diseases of the circulatory (Cardiovascular) system ,Medicine ,Surgery ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,Intensive care medicine ,Covid-19 ,Personal protective equipment - Abstract
Coronavirus disease 2019 (COVID-19) is forcing cardiology departments to rapidly adapt existing clinical guidelines to a new reality and this is especially the case for acute coronary syndrome pathways. In this focused review, the authors discuss how COVID-19 is affecting acute cardiology care and propose pragmatic guideline modifications for the diagnosis and management of acute coronary syndrome patients, particularly around the appropriateness of invasive strategies as well as length of hospital stay. The authors also discuss the use of personal protective equipment for healthcare workers in cardiology. Based on shared global experiences and growing peer-reviewed literature, it is possible to put in place modified acute coronary syndrome treatment pathways to offer safe pragmatic decisions to patients and staff.
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- 2020
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