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Genetic susceptibility to type 2 diabetes and obesity: from genome-wide association studies to rare variants and beyond

DIABETOLOGIA (2014)

期刊

DIABETOLOGIA

卷 57, 期 8, 页码 1528-1541

出版社

SPRINGER

DOI: 10.1007/s00125-014-3270-4

关键词

Adiposity; Body mass index; Genetics; Genome-wide association; Glycaemic traits; Obesity; Review; Sequencing; Type 2 diabetes

类别

Endocrinology & Metabolism

资金

Lundbeck Foundation Centre
Novo Nordisk Foundation

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Reagent

摘要

During the past 7 years, genome-wide association studies have shed light on the contribution of common genomic variants to the genetic architecture of type 2 diabetes, obesity and related intermediate phenotypes. The discoveries have firmly established more than 175 genomic loci associated with these phenotypes. Despite the tight correlation between type 2 diabetes and obesity, these conditions do not appear to share a common genetic background, since they have few genetic risk loci in common. The recent genetic discoveries do however highlight specific details of the interplay between the pathogenesis of type 2 diabetes, insulin resistance and obesity. The focus is currently shifting towards investigations of data from targeted array-based genotyping and exome and genome sequencing to study the individual and combined effect of low-frequency and rare variants in metabolic disease. Here we review recent progress as regards the concepts, methodologies and derived outcomes of studies of the genetics of type 2 diabetes and obesity, and discuss avenues to be investigated in the future within this research field.

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Cade, Hui Cai, Qiuyin Cai, Archie Campbell, Marisa Canadas-Garre, Eulalia Catamo, Jin-Fang Chai, Xiaoran Chai, Li-Ching Chang, Yi-Cheng Chang, Chien-Hsiun Chen, Alessandra Chesi, Seung Hoan Choi, Ren-Hua Chung, Massimiliano Cocca, Maria Pina Concas, Christian Couture, Gabriel Cuellar-Partida, Rebecca Danning, E. Warwick Daw, Frauke Degenhard, Graciela E. Delgado, Alessandro Delitala, Ayse Demirkan, Xuan Deng, Poornima Devineni, Alexander Dietl, Maria Dimitriou, Latchezar Dimitrov, Rajkumar Dorajoo, Arif B. Ekici, Jorgen E. Engmann, Zammy Fairhurst-Hunter, Aliki-Eleni Farmaki, Jessica D. Faul, Juan-Carlos Fernandez-Lopez, Lukas Forer, Margherita Francescatto, Sandra Freitag-Wolf, Christian Fuchsberger, Tessel E. Galesloot, Yan Gao, Zishan Gao, Frank Geller, Olga Giannakopoulou, Franco Giulianini, Anette P. Gjesing, Anuj Goel, Scott D. Gordon, Mathias Gorski, Jakob Grove, Xiuqing Guo, Stefan Gustafsson, Jeffrey Haessler, Thomas F. Hansen, Aki S. Havulinna, Simon J. Haworth, Jing He, Nancy Heard-Costa, Prashantha Hebbar, George Hindy, Yuk-Lam A. Ho, Edith Hofer, Elizabeth Holliday, Katrin Horn, Whitney E. Hornsby, Jouke-Jan Hottenga, Hongyan Huang, Jie Huang, Alicia Huerta-Chagoya, Jennifer E. Huffman, Yi-Jen Hung, Shaofeng Huo, Mi Yeong Hwang, Hiroyuki Iha, Daisuke D. Ikeda, Masato Isono, Anne U. Jackson, Susanne Jager, Iris E. Jansen, Ingegerd Johansson, Jost B. Jonas, Anna Jonsson, Torben Jorgensen, Ioanna-Panagiota Kalafati, Masahiro Kanai, Stavroula Kanoni, Line L. Karhus, Anuradhani Kasturiratne, Tomohiro Katsuya, Takahisa Kawaguchi, Rachel L. Kember, Katherine A. Kentistou, Han-Na Kim, Young Jin Kim, Marcus E. Kleber, Maria J. Knol, Azra Kurbasic, Marie Lauzon, Phuong Le, Rodney Lea, Jong-Young Lee, Hampton L. Leonard, Shengchao A. Li, Xiaohui Li, Xiaoyin Li, Jingjing Liang, Honghuang Lin, Shih-Yi Lin, Jun Liu, Xueping Liu, Ken Sin Lo, Jirong Long, Laura Lores-Motta, Jian'an Luan, Valeriya Lyssenko, Leo-Pekka Lyytikainen, Anubha Mahajan, Vasiliki Mamakou, Massimo Mangino, Ani Manichaikul, Jonathan Marten, Manuel Mattheisen, Laven Mavarani, Aaron F. McDaid, Karina Meidtner, Tori L. Melendez, Josep M. Mercader, Yuri Milaneschi, Jason E. Miller, Iona Y. Millwood, Pashupati P. Mishra, Ruth E. Mitchell, Line T. Mollehave, Anna Morgan, Soeren Mucha, Matthias Munz, Masahiro Nakatochi, Christopher P. Nelson, Maria Nethander, Chu Won Nho, Aneta A. Nielsen, Ilja M. Nolte, Suraj S. Nongmaithem, Raymond Noordam, Ioanna Ntalla, Teresa Nutile, Anita Pandit, Paraskevi Christofidou, Katri Parna, Marc Pauper, Eva R. B. Petersen, Liselotte Petersen, Niina Pitkanen, Ozren Polasek, Alaitz Poveda, Michael H. Preuss, Saiju Pyarajan, Laura M. Raffield, Hiromi Rakugi, Julia Ramirez, Asif Rasheed, Dennis Raven, Nigel W. Rayner, Carlos Riveros, Rebecca Rohde, Daniela Ruggiero, Sanni E. Ruotsalainen, Kathleen A. Ryan, Maria Sabater-Lleal, Richa Saxena, Markus Scholz, Anoop Sendamarai, Botong Shen, Jingchunzi Shi, Jae Hun Shin, Carlo Sidore, Colleen M. Sitlani, Roderic K. C. Slieker, Roelof A. J. Smit, Albert Smith, Jennifer A. Smith, Laura J. Smyth, Lorrain E. Southam, Valgerdur Steinthorsdottir, Liang Sun, Fumihiko Takeuchi, Divyasripriyanka Tallapragada, Kent D. Taylor, Bamidele O. Tayo, Catherine Tcheandjieu, Natalie Terzikhan, Paola Tesolin, Alexander Teumer, Elizabeth Theusch, Deborah J. Thompson, Gudmar Thorleifsson, Paul R. H. J. Timmers, Stella Trompet, Constance Turman, Simona Vaccargiu, Sander W. van der Laan, Peter J. van der Most, Jan B. van Klinken, Jessica van Setten, Shefali S. Verma, Niek Verweij, Yogasudha Veturi, Carol A. Wang, Chaolong Wang, Lihua Wang, Zhe Wang, Helen R. Warren, Wen Bin Wei, Ananda R. Wickremasinghe, Matthias Wielscher, Kerri L. Wiggins, Bendik S. Winsvold, Andrew Wong, Yang Wu, Matthias Wuttke, Rui Xia, Tian Xie, Ken Yamamoto, Jingyun Yang, Jie Yao, Hannah Young, Noha A. Yousri, Lei Yu, Lingyao Zeng, Weihua Zhang, Xinyuan Zhang, Jing-Hua Zhao, Wei Zhao, Wei Zhou, Martina E. Zimmermann, Magdalena Zoledziewska, Linda S. Adair, Hieab H. H. Adams, Carlos A. Aguilar-Salinas, Fahd Al-Mulla, Donna K. Arnett, Folkert W. Asselbergs, Bjorn Olav Asvold, John Attia, Bernhard Banas, Stefania Bandinelli, David A. Bennett, Tobias Bergler, Dwaipayan Bharadwaj, Ginevra Biino, Hans Bisgaard, Eric Boerwinkle, Carsten A. Boger, Klaus Bonnelykke, Dorret Boomsma, Anders D. Borglum, Judith B. Borja, Claude Bouchard, Donald W. Bowden, Ivan Brandslund, Ben Brumpton, Julie E. Buring, Mark J. Caulfield, John C. Chambers, Giriraj R. Chandak, Stephen J. Chanock, Nish Chaturvedi, Yii-Der Ida Chen, Zhengming Chen, Ching-Yu Cheng, Ingrid E. Christophersen, Marina Ciullo, John W. Cole, Francis S. Collins, Richard S. Cooper, Miguel Cruz, Francesco Cucca, L. Adrienne Cupples, Michael J. Cutler, Scott M. Damrauer, Thomas M. Dantoft, Gert J. de Borst, Lisette C. P. G. M. de Groot, Philip L. De Jager, Dominique P. de Kleijn, H. Janaka de Silva, George Dedoussis, Anneke den Hollander, Shufa Du, Douglas F. Easton, Petra J. M. Elders, A. Heather Eliassen, Patrick T. Ellinor, Solve Elmstahl, Jeanette Erdmann, Michele K. Evans, Diane Fatkin, Bjarke Feenstra, Mary F. Feitosa, Luigi Ferrucci, Ian Ford, Myriam Fornage, Andre Franke, Paul W. Franks, Barry Freedman, Paolo Gasparini, Christian Gieger, Giorgia Girotto, Michael E. Goddard, Yvonne M. Golightly, Clicerio Gonzalez-Villalpando, Penny Gordon-Larsen, Harald Grallert, Struan F. A. Grant, Niels Grarup, Lyn Griffiths, Vilmundur Gudnason, Christopher Haiman, Hakon Hakonarson, Torben Hansen, Catharina A. Hartman, Andrew T. Hattersley, Caroline Hayward, Susan R. Heckbert, Chew-Kiat Heng, Christian Hengstenberg, Alex W. Hewitt, Haretsugu Hishigaki, Carel B. Hoyng, Paul L. Huang, Wei Huang, Steven C. Hunt, Kristian Hveem, Elina Hypponen, William G. Iacono, Sahoko Ichihara, M. Arfan Ikram, Carmen R. Isasi, Rebecca D. Jackson, Marjo-Riitta Jarvelin, Zi-Bing Jin, Karl-Heinz Jockel, Peter K. Joshi, Pekka Jousilahti, J. Wouter Jukema, Mika Kahonen, Yoichiro Kamatani, Kui Dong Kang, Jaakko Kaprio, Sharon L. R. Kardia, Fredrik Karpe, Norihiro Kato, Frank Kee, Thorsten Kessler, Amit Khera, Chiea Chuen Khor, Lambertus A. L. M. Kiemeney, Bong-Jo Kim, Eung Kweon Kim, Hyung-Lae Kim, Paulus Kirchhof, Mika Kivimaki, Woon-Puay Koh, Heikki A. Koistinen, Genovefa D. Kolovou, Jaspal S. Kooner, Charles Kooperberg, Anna Kottgen, Peter Kovacs, Adriaan Kraaijeveld, Peter Kraft, Ronald M. Krauss, Meena Kumari, Zoltan Kutalik, Markku Laakso, Leslie A. Lange, Claudia Langenberg, Lenore J. Launer, Loic Le Marchand, Hyejin Lee, Nanette R. Lee, Terho Lehtimaki, Huaixing Li, Liming Li, Wolfgang Lieb, Xu Lin, Lars Lind, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Markus Loeffler, Barry London, Steven A. Lubitz, Stephen J. Lye, David A. Mackey, Reedik Magi, Patrik K. E. Magnusson, Gregory M. Marcus, Pedro Marques Vidal, Nicholas G. Martin, Winfried Marz, Fumihiko Matsuda, Robert W. McGarrah, Matt McGue, Amy Jayne McKnight, Sarah E. Medland, Dan Mellstrom, Andres Metspalu, Braxton D. Mitchell, Paul Mitchell, Dennis O. Mook-Kanamori, Andrew D. Morris, Lorelei A. Mucci, Patricia B. Munroe, Mike A. Nalls, Saman Nazarian, Amanda E. Nelson, Matt J. Neville, Christopher Newton-Cheh, Christopher S. Nielsen, Markus M. Nothen, Claes Ohlsson, Albertine J. Oldehinkel, Lorena Orozco, Katja Pahkala, Paivi Pajukanta, Colin N. A. Palmer, Esteban J. Parra, Cristian Pattaro, Oluf Pedersen, Craig E. Pennell, Brenda W. J. H. Penninx, Louis Perusse, Annette Peters, Patricia A. Peyser, David J. Porteous, Danielle Posthuma, Chris Power, Peter P. Pramstaller, Michael A. Province, Qibin Qi, Jia Qu, Daniel J. Rader, Olli T. Raitakari, Sarju Ralhan, Loukianos S. Rallidis, Dabeeru C. Rao, Susan Redline, Dermot F. Reilly, Alexander P. Reiner, Sang Youl Rhee, Paul M. Ridker, Michiel Rienstra, Samuli Ripatti, Marylyn D. Ritchie, Dan M. Roden, Frits R. Rosendaal, Jerome Rotter, Igor Rudan, Femke Rutters, Charumathi Sabanayagam, Danish Saleheen, Veikko Salomaa, Nilesh J. Samani, Dharambir K. Sanghera, Naveed Sattar, Borge Schmidt, Helena Schmidt, Reinhold Schmidt, Matthias B. Schulze, Heribert Schunkert, Laura J. Scott, Rodney J. Scott, Peter Sever, Eric J. Shiroma, M. Benjamin Shoemaker, Xiao-Ou Shu, Eleanor M. Simonsick, Mario Sims, Jai Rup Singh, Andrew B. Singleton, Moritz F. Sinner, J. Gustav Smith, Harold Snieder, Tim D. Spector, Meir J. Stampfer, Klaus J. Stark, David P. Strachan, Leen M. t' Hart, Yasuharu Tabara, Hua Tang, Jean-Claude Tardif, Thangavel A. Thanaraj, Nicholas J. Timpson, Anke Tonjes, Angelo Tremblay, Tiinamaija Tuomi, Jaakko Tuomilehto, Maria-Teresa Tusie-Luna, Andre G. Uitterlinden, Rob M. van Dam, Pim van der Harst, Nathalie Van der Velde, Cornelia M. van Duijn, Natasja M. van Schoor, Veronique Vitart, Uwe Volker, Peter Vollenweider, Henry Volzke, Niels H. Wacher-Rodarte, Mark Walker, Ya Xing Wang, Nicholas J. Wareham, Richard M. Watanabe, Hugh Watkins, David R. Weir, Thomas M. Werge, Elisabeth Widen, Lynne R. Wilkens, Gonneke Willemsen, Walter C. Willett, James F. Wilson, Tien-Yin Wong, Jeong-Taek Woo, Alan F. Wright, Jer-Yuarn Wu, Huichun Xu, Chittaranjan S. Yajnik, Mitsuhiro Yokota, Jian-Min Yuan, Eleftheria Zeggini, Babette S. Zemel, Wei Zheng, Xiaofeng Zhu, Joseph M. Zmuda, Alan B. Zonderman, John-Anker Zwart, Daniel Chasman, Yoon Shin Cho, Iris M. Heid, Mark McCarthy, Maggie C. Y. Ng, Christopher J. O'Donnell, Fernando Rivadeneira, Unnur Thorsteinsdottir, Yan Sun, E. Shyong Tai, Michael Boehnke, Panos Deloukas, Anne E. Justice, Cecilia M. Lindgren, Ruth J. F. Loos, Karen L. Mohlke, Kari E. North, Kari Stefansson, Robin G. Walters, Thomas W. Winkler, Kristin L. Young, Po-Ru Loh, Jian Yang, Tonu Esko, Themistocles L. Assimes, Adam Auton, Goncalo R. Abecasis, Cristen J. Willer, Adam E. Locke, Sonja Berndt, Guillaume Lettre, Timothy M. Frayling, Yukinori Okada, Andrew R. Wood, Peter M. Visscher, Joel N. Hirschhorn

Summary: A large genome-wide association study of more than 5 million individuals reveals that 12,111 independent SNPs account for nearly all the heritability of height attributable to common genetic variants. These SNPs are clustered within non-overlapping genomic segments and the phenotypic variance explained varies across populations.

NATURE (2022)

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Article Genetics & Heredity

Loci for insulin processing and secretion provide insight into type 2 diabetes risk

K. Alaine Broadaway, Xianyong Yin, Alice Williamson, Victoria A. Parsons, Emma P. Wilson, Anne H. Moxley, Swarooparani Vadlamudi, Arushi Varshney, Anne U. Jackson, Vasudha Ahuja, Stefan R. Bornstein, Laura J. Corbin, Graciela E. Delgado, Om P. Dwivedi, Lilian Fernandes Silva, Timothy M. Frayling, Harald Grallert, Stefan Gustafsson, Liisa Hakaste, Ulf Hammar, Christian Herder, Sandra Herrmann, Kurt Hojlund, David A. Hughes, Marcus E. Kleber, Cecilia M. Lindgren, Ching-Ti Liu, Jian'an Luan, Anni Malmberg, Angela P. Moissl, Andrew P. Morris, Nikolaos Perakakis, Annette Peters, John R. Petrie, Michael Roden, Peter E. H. Schwarz, Sapna Sharma, Angela Silveira, Rona J. Strawbridge, Tiinamaija Tuomi, Andrew R. Wood, Peitao Wu, Bjorn Zethelius, Damiano Baldassarre, Johan G. Eriksson, Tove Fall, Jose C. Florez, Andreas Fritsche, Bruna Gigante, Anders Hamsten, Eero Kajantie, Markku Laakso, Jari Lahti, Deborah A. Lawlor, Lars Lind, Winfried Maerz, James B. Meigs, Johan Sundstrom, Nicholas J. Timpson, Robert Wagner, Mark Walker, Nicholas J. Wareham, Hugh Watkins, Ines Barroso, Stephen O'Rahilly, Niels Grarup, Stephen CJ. Parker, Michael Boehnke, Claudia Langenberg, Eleanor Wheeler, Karen L. Mohlke

Summary: Insufficient insulin secretion and increased proinsulin levels indicate beta-cell stress and insulin resistance. A meta-analysis of European-ancestry individuals identified 36 independent signals at 30 loci associated with fasting proinsulin. These loci are involved in various mechanisms that affect insulin processing and beta-cell function. Colocalization analysis provided potential candidate genes and regulatory mechanisms for proinsulin production and glucose regulation. This study highlights the importance of genetic studies for understanding disease predisposition.

AMERICAN JOURNAL OF HUMAN GENETICS (2023)

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Article Endocrinology & Metabolism

Physical Activity and Insulin Sensitivity Independently Attenuate the Effect of FTO rs9939609 on Obesity

Mette K. Andersen, Lars Angquist, Jette Bork-Jensen, Anna E. Jonsson, Sara E. Stinson, Camilla H. Sandholt, Malte Thodberg, Laura Maarit Pikkupeura, Emily L. Ongstad, Niels Grarup, Arne Astrup, Oluf Pedersen, Kristine Williams, Romain Barres, Thorkild I. A. Sorensen, Allan Linneberg, Joseph Grimsby, Christopher J. Rhodes, Torben Hansen

Summary: The association between FTO rs9939609 and obesity is modified by physical activity and insulin sensitivity, and these modifications are independent. High physical activity and insulin sensitivity can attenuate the effect of the FTO rs9939609 A allele on BMI. Moreover, greater physical activity and insulin sensitivity may weaken the associations between the FTO rs9939609 A allele and all-cause mortality and certain cardiometabolic outcomes. The FTO rs9939609 A allele is associated with higher expression of FTO in skeletal muscle.

DIABETES CARE (2023)

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Article Endocrinology & Metabolism

Low birthweight is associated with a higher incidence of type 2 diabetes over two decades independent of adult BMI and genetic predisposition

Rasmus Wibaek, Gregers S. Andersen, Allan Linneberg, Torben Hansen, Niels Grarup, Anne Cathrine B. Thuesen, Rasmus T. Jensen, Jonathan C. K. Wells, Kasper A. Pilgaard, Charlotte Brons, Dorte Vistisen, Allan A. Vaag

Summary: Low birthweight is a risk factor for type 2 diabetes. This study aimed to examine the associations between birthweight and age-specific incidence rates of type 2 diabetes. The results showed that a lower birthweight was associated with an increased risk of developing type 2 diabetes.

DIABETOLOGIA (2023)

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Article Gastroenterology & Hepatology

An adult-based genetic risk score for liver fat associates with liver and plasma lipid traits in children and adolescents

Yun Huang, Sara E. Stinson, Helene Baek Juel, Morten A. V. Lund, Louise Aas Holm, Cilius E. Fonvig, Trine Nielsen, Niels Grarup, Oluf Pedersen, Michael Christiansen, Elizaveta Chabanova, Henrik S. Thomsen, Aleksander Krag, Stefan Stender, Jens-Christian Holm, Torben Hansen

Summary: This study investigated the effects of eight previously reported genome-wide significant steatogenic variants on liver and cardiometabolic traits in children and adolescents. The results showed that these variants were associated with higher liver fat and distinct patterns of plasma lipids. The genetic risk score (GRS) based on these variants was also associated with higher prevalence of hepatic steatosis and had potential clinical utility for risk stratification.

LIVER INTERNATIONAL (2023)

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Article Genetics & Heredity

Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake

Alice Williamson, Dougall M. Norris, Xianyong Yin, K. Alaine Broadaway, Anne H. Moxley, Swarooparani Vadlamudi, Emma P. Wilson, Anne U. Jackson, Vasudha Ahuja, Mette K. Andersen, Zorayr Arzumanyan, Lori L. Bonnycastle, Stefan R. Bornstein, Maxi P. Bretschneider, Thomas A. Buchanan, Yi-Cheng Chang, Lee-Ming Chuang, Ren-Hua Chung, Tine D. Clausen, Peter Damm, Graciela E. Delgado, Vanessa D. de Mello, Josee Dupuis, Om P. Dwivedi, Michael R. Erdos, Lilian Fernandes Silva, Timothy M. Frayling, Christian Gieger, Mark O. Goodarzi, Xiuqing Guo, Stefan Gustafsson, Liisa Hakaste, Ulf Hammar, Gad Hatem, Sandra Herrmann, Kurt Hojlund, Katrin Horn, Willa A. Hsueh, Yi-Jen Hung, Chii-Min Hwu, Anna Jonsson, Line L. Karhus, Marcus E. Kleber, Peter Kovacs, Timo A. Lakka, Marie Lauzon, I-Te Lee, Cecilia M. Lindgren, Jaana Lindstroem, Allan Linneberg, Ching-Ti Liu, Jian'an Luan, Dina Mansour Aly, Elisabeth Mathiesen, Angela P. Moissl, Andrew P. Morris, Narisu Narisu, Nikolaos Perakakis, Annette Peters, Rashmi B. Prasad, Roman N. Rodionov, Kathryn Roll, Carsten F. Rundsten, Chloe Sarnowski, Kai Savonen, Markus Scholz, Sapna Sharma, Sara E. Stinson, Sufyan Suleman, Jingyi Tan, Kent D. Taylor, Matti Uusitupa, Dorte Vistisen, Daniel R. Witte, Romy Walther, Peitao Wu, Anny H. Xiang, Bjoern Zethelius, Emma Ahlqvist, Richard N. Bergman, Yii-Der Ida Chen, Francis S. Collins, Tove Fall, Jose C. Florez, Andreas Fritsche, Harald Grallert, Leif Groop, Torben Hansen, Heikki A. Koistinen, Pirjo Komulainen, Markku Laakso, Lars Lind, Markus Loeffler, Winfried Marz, James B. Meigs, Leslie J. Raffel, Rainer Rauramaa, Jerome I. Rotter, Peter E. H. Schwarz, Michael Stumvoll, Johan Sundstrom, Anke Toenjes, Tiinamaija Tuomi, Jaakko Tuomilehto, Robert Wagner, Ines Barroso, Mark Walker, Niels Grarup, Michael Boehnke, Nicholas J. Wareham, Karen L. Mohlke, Eleanor Wheeler, Stephen O'Rahilly, Daniel J. Fazakerley, Claudia Langenberg

Summary: Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Genome-wide association analyses of two oral glucose tolerance test-derived measures of postprandial insulin resistance discover ten new loci. Functional characterization identifies nine candidate genes implicated in the regulation of GLUT4.

NATURE GENETICS (2023)

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Article Multidisciplinary Sciences

Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease

William J. Young, Jeffrey Haessler, Jan-Walter Benjamins, Linda Repetto, Jie Yao, Aaron Isaacs, Andrew R. Harper, Julia Ramirez, Sophie Garnier, Stefan van Duijvenboden, Antoine R. Baldassari, Maria Pina Concas, ThuyVy Duong, Luisa Foco, Jonas L. Isaksen, Hao Mei, Raymond Noordam, Casia Nursyifa, Anne Richmond, Meddly L. Santolalla, Colleen M. Sitlani, Negin Soroush, Sebastien Theriault, Stella Trompet, Stefanie Aeschbacher, Fariba Ahmadizar, Alvaro Alonso, Jennifer A. Brody, Archie Campbell, Adolfo Correa, Dawood Darbar, Antonio De Luca, Jean-Francois Deleuze, Christina Ellervik, Christian Fuchsberger, Anuj Goel, Christopher Grace, Xiuqing Guo, Torben Hansen, Susan R. Heckbert, Rebecca D. Jackson, Jan A. Kors, Maria Fernanda Lima-Costa, Allan Linneberg, Peter W. Macfarlane, Alanna C. Morrison, Pau Navarro, David J. Porteous, Peter P. Pramstaller, Alexander P. Reiner, Lorenz Risch, Ulrich Schotten, Xia Shen, Gianfranco Sinagra, Elsayed Z. Soliman, Monika Stoll, Eduardo Tarazona-Santos, Andrew Tinker, Katerina Trajanoska, Eric Villard, Helen R. Warren, Eric A. Whitsel, Kerri L. Wiggins, Dan E. Arking, Christy L. Avery, David Conen, Giorgia Girotto, Niels Grarup, Caroline Hayward, J. Wouter Jukema, Dennis O. Mook-Kanamori, Morten Salling Olesen, Sandosh Padmanabhan, Bruce M. Psaty, Cristian Pattaro, Antonio Luiz P. Ribeiro, Jerome I. Rotter, Bruno H. Stricker, Pim van der Harst, Cornelia M. van Duijn, Niek Verweij, James G. Wilson, Michele Orini, Philippe Charron, Hugh Watkins, Charles Kooperberg, Henry J. Lin, James F. Wilson, Jrgen K. Kanters, Nona Sotoodehnia, Borbala Mifsud, Pier D. Lambiase, Larisa G. Tereshchenko, Patricia B. Munroe

Summary: Using multi-ancestry genome-wide association studies, this research identified 61 loci related to spatial QRS-T angle and 11 loci related to frontal QRS-T angle. These loci also showed shared genetic influences with classical ECG traits and were associated with cardiovascular diseases. The findings provide insights into the biology of QRS-T angles and their relationships with cardiovascular traits and diseases, which can inform future research and risk prediction.

NATURE COMMUNICATIONS (2023)

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Article Genetics & Heredity

Identification of pathogenic GCK variants in patients with common type 2 diabetes can lead to discontinuation of pharmacological treatment

Anne Cathrine Baun Thuesen, Rasmus Tanderup Jensen, Henrik Maagensen, Maja Refshauge Kristiansen, Henrik Toft Sorensen, Allan Vaag, Henning Beck-Nielsen, Oluf B. Pedersen, Niels Grarup, Jens Steen Nielsen, Jorgen Rungby, Anette Prior Gjesing, Heidi Storgaard, Tina Vilsboll, Torben Hansen

Summary: This study investigated the glycemic phenotype and treatment response of patients with type 2 diabetes carrying rare GCK variants consistent with GCK-diabetes. Carriers of pathogenic and likely pathogenic variants had lower fasting glucose and C-peptide levels. Stopping medication did not lead to worsening of HbA1c or fasting glucose. Variants of uncertain significance should be interpreted carefully.

MOLECULAR GENETICS AND METABOLISM REPORTS (2023)

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Article Multidisciplinary Sciences

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

Ashley Budu-Aggrey, Anna Kilanowski, Maria K. Sobczyk, Suyash S. Shringarpure, Ruth Mitchell, Kadri Reis, Anu Reigo, Reedik Maegi, Mari Nelis, Nao Tanaka, Ben M. Brumpton, Laurent F. Thomas, Pol Sole-Navais, Christopher Flatley, Antonio Espuela-Ortiz, Esther Herrera-Luis, Jesus V. T. Lominchar, Jette Bork-Jensen, Ingo Marenholz, Aleix Arnau-Soler, Ayoung Jeong, Katherine A. Fawcett, Hansjorg Baurecht, Elke Rodriguez, Alexessander Couto Alves, Ashish Kumar, Patrick M. Sleiman, Xiao Chang, Carolina Medina-Gomez, Chen Hu, Cheng-jian Xu, Cancan Qi, Sarah El-Heis, Philip Titcombe, Elie Antoun, Joao Fadista, Carol A. Wang, Elisabeth Thiering, Baojun Wu, Sara Kress, Dilini M. Kothalawala, Latha Kadalayil, Jiasong Duan, Hongmei Zhang, Sabelo Hadebe, Thomas Hoffmann, Eric Jorgenson, Helene Choquet, Neil Risch, Pal Njolstad, Ole A. Andreassen, Stefan Johansson, Catarina Almqvist, Tong Gong, Vilhelmina Ullemar, Robert Karlsson, Patrik K. E. Magnusson, Agnieszka Szwajda, Esteban G. Burchard, Jacob P. Thyssen, Torben Hansen, Line L. Karhus, Thomas M. Dantoft, Alexander C. S. N. Jeanrenaud, Ahla Ghauri, Andreas Arnold, Georg Homuth, Susanne Lau, Markus M. Noethen, Norbert Huebner, Medea Imboden, Alessia Visconti, Mario Falchi, Veronique Bataille, Pirro Hysi, Natalia Ballardini, Dorret I. Boomsma, Jouke J. Hottenga, Martina Mueller-Nurasyid, Tarunveer S. Ahluwalia, Jakob Stokholm, Bo Chawes, Ann-Marie M. Schoos, Ana Esplugues, Mariona Bustamante, Benjamin Raby, Syed Arshad, Chris German, Tonu Esko, Lili A. Milani, Andres Metspalu, Chikashi Terao, Katrina Abuabara, Mari Loset, Kristian Hveem, Bo Jacobsson, Maria Pino-Yanes, David P. Strachan, Niels Grarup, Allan Linneberg, Young-Ae Lee, Nicole Probst-Hensch, Stephan Weidinger, Marjo-Riitta Jarvelin, Erik Melen, Hakon Hakonarson, Alan D. Irvine, Deborah Jarvis, Tamar Nijsten, Liesbeth Duijts, Judith M. Vonk, Gerard H. Koppelmann, Keith M. Godfrey, Sheila J. Barton, Bjarke Feenstra, Craig E. Pennell, Peter D. Sly, Patrick G. Holt, L. Keoki Williams, Hans Bisgaard, Klaus Bonnelykke, John Curtin, Angela Simpson, Clare Murray, Tamara Schikowski, Supinda Bunyavanich, Scott T. Weiss, John W. Holloway, Josine L. Min, Sara J. Brown, Marie Standl, Lavinia Paternoster

Summary: This study conducted the largest genome-wide association study (GWAS) on atopic dermatitis (AD) to date, identifying 81 replicated AD-associated loci in Europeans and 10 additional loci in a multi-ancestry analysis. The implicated genes are predominantly involved in immune pathways relevant to atopic inflammation and may offer drug repurposing opportunities.

NATURE COMMUNICATIONS (2023)

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Article Multidisciplinary Sciences

Genetic insights into resting heart rate and its role in cardiovascular disease

Yordi van de Vegte, Ruben P. Eppinga, M. Yldau van der Ende, Yanick Hagemeijer, Yuvaraj V. Mahendran, Elias Y. Salfati, Albert E. Smith, Vanessa Tan, Dan V. Arking, Ioanna Ntalla, Emil A. Appel, Claudia Schurmann, Jennifer Brody, Rico Rueedi, Ozren Polasek, Gardar Sveinbjornsson, Cecile Lecoeur, Claes Ladenvall, Jing Hua Zhao, Aaron Isaacs, Lihua Wang, Jian'an Luan, Shih-Jen Hwang, Nina U. Mononen, Kirsi F. Auro, Anne Jackson, Lawrence Bielak, Linyao Zeng, Nabi Shah, Maria Nethander, Archie Campbell, Tuomo Rankinen, Sonali Pechlivanis, Lu Qi, Wei Zhao, Federica Rizzi, Toshiko Tanaka, Antonietta Robino, Massimiliano Cocca, Leslie Lange, Martina Mueller-Nurasyid, Carolina E. Roselli, Weihua Zhang, Marcus J. Kleber, Xiuqing Guo, Henry E. Lin, Francesca Pavani, Tessel Galesloot, Raymond E. Noordam, Yuri Milaneschi, Katharina Schraut, Marcel den Hoed, Frauke E. Degenhardt, Stella Trompet, Marten van den Berg, Giorgio Pistis, Yih-Chung S. Tham, Stefan L. Weiss, Xueling J. Sim, Hengtong M. Li, Peter van der Most, Ilja Nolte, Leo-Pekka R. Lyytikaeinen, M. Abdullah Said, Daniel Witte, Carlos M. Iribarren, Lenore S. Launer, Susan Ring, Paul de Vries, Peter P. Sever, Allan Linneberg, Erwin M. Bottinger, Sandosh Padmanabhan, Bruce Psaty, Nona Sotoodehnia, Ivana Kolcic, Delnaz D. Roshandel, Andrew O. Paterson, David F. Arnar, Daniel Gudbjartsson, Hilma Holm, Beverley T. Balkau, Claudia H. Silva, Christopher Newton-Cheh, Kjell Nikus, Perttu L. Salo, Karen A. Mohlke, Patricia Peyser, Heribert Schunkert, Mattias Lorentzon, Jari C. Lahti, Dabeeru C. Rao, Marilyn D. Cornelis, Jessica A. Faul, Jennifer Smith, Katarzyna Stolarz-Skrzypek, Stefania Bandinelli, Maria Pina Concas, Gianfranco Sinagra, Thomas Meitinger, Melanie F. Waldenberger, Moritz Sinner, Konstantin E. Strauch, Graciela D. Delgado, Kent Taylor, Jie Yao, Luisa Foco, Olle Melander, Jacqueline de Graaf, Renee de Mutsert, Eco J. C. de Geus, Asa K. Johansson, Peter K. Joshi, Lars Lind, Andre W. Franke, Peter V. Macfarlane, Kirill Tarasov, Nicholas B. Tan, Stephan Felix, E-Shyong Q. Tai, Debra Quek, Harold Snieder, Johan Ormel, Martin Ingelsson, Cecilia P. Lindgren, Andrew T. Morris, Olli Raitakari, Torben Hansen, Themistocles Assimes, Vilmundur J. Gudnason, Nicholas C. Timpson, Alanna B. Morrison, Patricia P. Munroe, David Strachan, Niels Grarup, Ruth J. F. R. Loos, Susan Heckbert, Peter Vollenweider, Caroline Hayward, Kari Stefansson, Philippe Froguel, Leif J. Groop, Nicholas M. Wareham, Cornelia F. van Duijn, Mary J. Feitosa, Christopher O'Donnell, Mika Kaehoenen, Markus Perola, Michael Boehnke, Sharon L. R. Kardia, Jeanette Erdmann, Colin N. A. Palmer, Claes J. Ohlsson, David G. Porteous, Johan Eriksson, Claude Bouchard, Susanne Moebus, Peter R. Kraft, David Weir, Daniele Cusi, Luigi Ferrucci, Sheila Ulivi, Giorgia Girotto, Adolfo Correa, Stefan Kaeaeb, Annette C. Peters, John S. Chambers, Jaspal Kooner, Winfried I. Maerz, Jerome A. Rotter, Andrew Hicks, J. Gustav Smith, Lambertus A. L. M. O. Kiemeney, Dennis Mook-Kanamori, Brenda W. J. H. Penninx, Ulf F. Gyllensten, James Wilson, Stephen Burgess, Johan Sundstroem, Wolfgang Lieb, J. Wouter Jukema, Mark Eijgelsheim, Edward L. M. Lakatta, Ching-Yu Cheng, Marcus Doerr, Tien-Yin Wong, Charumathi J. Sabanayagam, Albertine Oldehinkel, Harriette Riese, Terho Lehtimaeki, Niek Verweij, Pim van der Harst

Summary: This study identifies new genetic variants associated with resting heart rate (RHR) and demonstrates that higher genetically predicted RHR is associated with a decreased risk of atrial fibrillation and ischemic stroke. Genome-wide analysis reveals multiple genetic variants in cardiomyocyte-related genes and provides insights into their electrocardiogram (ECG) signature. Mendelian randomization analyses indicate that higher genetically predicted RHR increases the risk of dilated cardiomyopathy, but reduces the risk of atrial fibrillation, ischemic stroke, and cardio-embolic stroke.

NATURE COMMUNICATIONS (2023)

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Article Biochemistry & Molecular Biology

Genetics of Plasma Bilirubin and Associations between Bilirubin and Cardiometabolic Risk Profiles in Danish Children and Adolescents

Asmat Ullah, Evelina Stankevic, Louise Aas Holm, Sara E. Stinson, Helene Baek Juel, Cilius E. Fonvig, Morten A. V. Lund, Caecilie Trier, Line Engelbrechtsen, Lars Angquist, Anna E. Jonsson, Oluf Pedersen, Niels Grarup, Jens-Christian Holm, Torben Hansen

Summary: Bilirubin is inversely associated with cardiovascular disease, type 2 diabetes, and all-cause mortality in adults. This study found that bilirubin is also negatively associated with cardiometabolic risk factors and inflammation in children and adolescents. Genome-wide association studies identified genetic loci associated with plasma bilirubin concentrations.

ANTIOXIDANTS (2023)

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Article Health Care Sciences & Services

A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland

Anne Cathrine Baun Thuesen, Frederik Filip Staeger, Alba Kaci, Marie Holm Solheim, Ingvild Aukrust, Emil Jorsboe, Cindy G. Santander, Mette K. Andersen, Zilong Li, Arthur Gilly, Sara Elizabeth Stinson, Anette Prior Gjesing, Peter Bjerregaard, Michael Lynge Pedersen, Christina Viskum Lytken Larsen, Niels Grarup, Marit E. Jorgensen, Eleftheria Zeggini, Lise Bjorkhaug, Pal Rasmus Njolstad, Anders Albrechtsen, Ida Moltke, Torben Hansen

Summary: This study aimed to identify and characterize novel variants in genes associated with MODY in the Greenlandic population. Through screening data from Greenlandic population cohorts, researchers identified a novel variant in the known MODY gene HNF1A that is specific to the Greenlandic Inuit population. The variant was found to be associated with diabetes and glucose levels, and had a significant impact on diabetes prevalence in Greenland.

LANCET REGIONAL HEALTH-EUROPE (2023)

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Article Public, Environmental & Occupational Health

The effect of diabetes and the diabetogenic TBC1D4 p.Arg684ter variant on kidney function in Inuit in Greenland

Maria Overvad, Lars Jorge Diaz, Peter Bjerregaard, Michael Lynge Pedersen, Christina Viskum Lytken Larsen, Niels Grarup, Torben Hansen, Peter Rossing, Marit Eika Jorgensen

Summary: The aim of this study was to investigate the impact of diabetes and the diabetogenic TBC1D4 variant on kidney function in a population-based setting in Greenland. Data from a health survey and TBC1D4 genotypes of 5,336 Greenlanders were analyzed to assess the odds ratios (ORs) of albuminuria and chronic kidney disease (CKD) in individuals with and without diabetes, taking into account the effect of the TBC1D4 variant. The results showed that diabetes was associated with an elevated risk of albuminuria, while the TBC1D4 variant was protective against the development of albuminuria. However, neither diabetes nor the TBC1D4 variant were significantly associated with CKD. The findings suggest a potential renoprotective effect of the TBC1D4 variant on albuminuria, warranting further investigation.

INTERNATIONAL JOURNAL OF CIRCUMPOLAR HEALTH (2023)

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