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Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2024年2月19日

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  • Ken Suzuki,
  • Konstantinos Hatzikotoulas,
  • Lorraine Southam,
  • Henry J. Taylor,
  • Xianyong Yin,
  • Kim M. Lorenz,
  • Ravi Mandla,
  • Alicia Huerta-Chagoya,
  • Giorgio E. M. Melloni,
  • Stavroula Kanoni,
  • Nigel W. Rayner,
  • Ozvan Bocher,
  • Ana Luiza Arruda,
  • Kyuto Sonehara,
  • Shinichi Namba,
  • Simon S. K. Lee,
  • Michael H. Preuss,
  • Lauren E. Petty,
  • Philip Schroeder,
  • Brett Vanderwerff,
  • Mart Kals,
  • Fiona Bragg,
  • Kuang Lin,
  • Xiuqing Guo,
  • Weihua Zhang,
  • Jie Yao,
  • Young Jin Kim,
  • Mariaelisa Graff,
  • Fumihiko Takeuchi,
  • Jana Nano,
  • Amel Lamri,
  • Masahiro Nakatochi,
  • Sanghoon Moon,
  • Robert A. Scott,
  • James P. Cook,
  • Jung-Jin Lee,
  • Ian Pan,
  • Daniel Taliun,
  • Esteban J. Parra,
  • Jin-Fang Chai,
  • Lawrence F. Bielak,
  • Yasuharu Tabara,
  • Yang Hai,
  • Gudmar Thorleifsson,
  • Niels Grarup,
  • Tamar Sofer,
  • Matthias Wuttke,
  • Chloé Sarnowski,
  • Christian Gieger,
  • Darryl Nousome,
  • Stella Trompet,
  • Soo-Heon Kwak,
  • Jirong Long,
  • Meng Sun,
  • Lin Tong,
  • Wei-Min Chen,
  • Suraj S. Nongmaithem,
  • Raymond Noordam,
  • Victor J. Y. Lim,
  • Claudia H. T. Tam,
  • Yoonjung Yoonie Joo,
  • Chien-Hsiun Chen,
  • Laura M. Raffield,
  • Bram Peter Prins,
  • Aude Nicolas,
  • Lisa R. Yanek,
  • Guanjie Chen,
  • Jennifer A. Brody,
  • Edmond Kabagambe,
  • Ping An,
  • Anny H. Xiang,
  • Hyeok Sun Choi,
  • Brian E. Cade,
  • Jingyi Tan,
  • K. Alaine Broadaway,
  • Alice Williamson,
  • Zoha Kamali,
  • Jinrui Cui,
  • Manonanthini Thangam,
  • Linda S. Adair,
  • Adebowale Adeyemo,
  • Carlos A. Aguilar-Salinas,
  • Tarunveer S. Ahluwalia,
  • Sonia S. Anand,
  • Alain Bertoni,
  • Jette Bork-Jensen,
  • Ivan Brandslund,
  • Thomas A. Buchanan,
  • Charles F. Burant,
  • Adam S. Butterworth,
  • Mickaël Canouil,
  • Juliana C. N. Chan,
  • Li-Ching Chang,
  • Miao-Li Chee,
  • Ji Chen,
  • Shyh-Huei Chen,
  • Yuan-Tsong Chen,
  • Zhengming Chen,
  • Lee-Ming Chuang,
  • Mary Cushman,
  • John Danesh,
  • 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,
  • Oscar H. Franco,
  • Timothy M. Frayling,
  • Barry I. Freedman,
  • Pauline Genter,
  • Hertzel C. Gerstein,
  • Vilmantas Giedraitis,
  • Clicerio González-Villalpando,
  • Maria Elena González-Villalpando,
  • Penny Gordon-Larsen,
  • Myron Gross,
  • Lindsay A. Guare,
  • Sophie Hackinger,
  • Liisa Hakaste,
  • Sohee Han,
  • Andrew T. Hattersley,
  • Christian Herder,
  • Momoko Horikoshi,
  • 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,
  • Torben Jørgensen,
  • Frederick K. Kamanu,
  • 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,
  • Florian Kronenberg,
  • Johanna Kuusisto,
  • Kristi Läll,
  • Leslie A. Lange,
  • Kyung Min Lee,
  • 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,
  • Julie A. Lynch,
  • Valeriya Lyssenko,
  • Shiro Maeda,
  • Vasiliki Mamakou,
  • Sohail Rafik Mansuri,
  • Koichi Matsuda,
  • Thomas Meitinger,
  • Olle Melander,
  • Andres Metspalu,
  • Huan Mo,
  • Andrew D. Morris,
  • Filipe A. Moura,
  • Jerry L. Nadler,
  • Michael A. Nalls,
  • Uma Nayak,
  • Ioanna Ntalla,
  • Yukinori Okada,
  • Lorena Orozco,
  • Sanjay R. Patel,
  • Snehal Patil,
  • Pei Pei,
  • Mark A. Pereira,
  • Annette Peters,
  • Fraser J. Pirie,
  • Hannah G. Polikowsky,
  • Bianca Porneala,
  • Gauri Prasad,
  • Laura J. Rasmussen-Torvik,
  • Alexander P. Reiner,
  • Michael Roden,
  • Rebecca Rohde,
  • Katheryn Roll,
  • Charumathi Sabanayagam,
  • Kevin Sandow,
  • Alagu Sankareswaran,
  • Naveed Sattar,
  • Sebastian Schönherr,
  • Mohammad Shahriar,
  • Botong Shen,
  • Jinxiu Shi,
  • Dong Mun Shin,
  • Nobuhiro Shojima,
  • Jennifer A. Smith,
  • Wing Yee So,
  • Alena Stančáková,
  • Valgerdur Steinthorsdottir,
  • Adrienne M. Stilp,
  • Konstantin Strauch,
  • Kent D. Taylor,
  • Barbara Thorand,
  • Unnur Thorsteinsdottir,
  • Brian Tomlinson,
  • Tam C. Tran,
  • Fuu-Jen Tsai,
  • Jaakko Tuomilehto,
  • Teresa Tusie-Luna,
  • Miriam S. Udler,
  • Adan Valladares-Salgado,
  • Rob M. van Dam,
  • Jan B. van Klinken,
  • Rohit Varma,
  • Niels Wacher-Rodarte,
  • Eleanor Wheeler,
  • Ananda R. Wickremasinghe,
  • Ko Willems van Dijk,
  • Daniel R. Witte,
  • Chittaranjan S. Yajnik,
  • Ken Yamamoto,
  • Kenichi Yamamoto,
  • Kyungheon Yoon,
  • Canqing Yu,
  • Jian-Min Yuan,
  • Salim Yusuf,
  • Matthew Zawistowski,
  • Liang Zhang,
  • Wei Zheng,
  • Stavroula Kanona,
  • David A. van Heel,
  • Leslie J. Raffel,
  • Michiya Igase,
  • Eli Ipp,
  • Susan Redline,
  • Yoon Shin Cho,
  • Lars Lind,
  • Michael A. Province,
  • Myriam Fornage,
  • Craig L. Hanis,
  • Erik Ingelsson,
  • Alan B. Zonderman,
  • Bruce M. Psaty,
  • Ya-Xing Wang,
  • Charles N. Rotimi,
  • Diane M. Becker,
  • Fumihiko Matsuda,
  • Yongmei Liu,
  • Mitsuhiro Yokota,
  • Sharon L. R. Kardia,
  • Patricia A. Peyser,
  • James S. Pankow,
  • James C. Engert,
  • Amélie Bonnefond,
  • Philippe Froguel,
  • James G. Wilson,
  • Wayne H. H. Sheu,
  • Jer-Yuarn Wu,
  • M. Geoffrey Hayes,
  • Ronald C. W. Ma,
  • Tien-Yin Wong,
  • Dennis O. Mook-Kanamori,
  • Tiinamaija Tuomi,
  • 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,
  • Yii-Der Ida Chen,
  • Stephen S. Rich,
  • Roberta McKean-Cowdin,
  • Harald Grallert,
  • Ching-Yu Cheng,
  • Mohsen Ghanbari,
  • E-Shyong Tai,
  • Josee Dupuis,
  • Norihiro Kato,
  • Markku Laakso,
  • Anna Köttgen,
  • Woon-Puay Koh,
  • Donald W. Bowden,
  • Colin N. A. Palmer,
  • Jaspal S. Kooner,
  • Charles Kooperberg,
  • Simin Liu,
  • Kari E. North,
  • Danish Saleheen,
  • Torben Hansen,
  • Oluf Pedersen,
  • Nicholas J. Wareham,
  • Juyoung Lee,
  • Bong-Jo Kim,
  • Iona Y. Millwood,
  • Robin G. Walters,
  • Kari Stefansson,
  • Emma Ahlqvist,
  • Mark O. Goodarzi,
  • Karen L. Mohlke,
  • Claudia Langenberg,
  • Christopher A. Haiman,
  • Ruth J. F. Loos,
  • Jose C. Florez,
  • Daniel J. Rader,
  • Marylyn D. Ritchie,
  • Sebastian Zöllner,
  • Reedik Mägi,
  • Nicholas A. Marston,
  • Christian T. Ruff,
  • David A. van Heel,
  • Sarah Finer,
  • Joshua C. Denny,
  • Toshimasa Yamauchi,
  • Takashi Kadowaki,
  • John C. Chambers,
  • Maggie C. Y. Ng,
  • Xueling Sim,
  • Jennifer E. Below,
  • Philip S. Tsao,
  • Kyong-Mi Chang,
  • Mark I. McCarthy,
  • James B. Meigs,
  • Anubha Mahajan,
  • Cassandra N. Spracklen,
  • Josep M. Mercader,
  • Michael Boehnke,
  • Jerome I. Rotter,
  • Marijana Vujkovic,
  • Benjamin F. Voight,
  • Andrew P. Morris,
  • Eleftheria Zeggini

摘要

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10−8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.