open access publication

Article, Early Access, 2024

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

NATURE, ISSN 0028-0836, 0028-0836, 10.1038/s41586-024-07019-6

Contributors

Suzuki, Ken 0000-0003-1065-3593 [1] [2] [3] Hatzikotoulas, Konstantinos (Corresponding author) [4] [5] Southam, Lorraine 0000-0002-7546-9650 [4] [5] Taylor, Henry J. [6] [7] [8] Yin, Xian-Yong 0000-0001-6454-2384 [9] [10] [11] Lorenz, Kim M. [12] [13] Mandla, Ravi [14] [15] [16] [17] Huerta-Chagoya, Alicia [15] [16] [17] Melloni, Giorgio E. M. [17] [18] [19] Kanoni, Stavroula 0000-0002-1691-9615 [20] [21] Rayner, N. W. [4] [5] Bocher, Ozvan [4] [5] Arruda, Ana Luiza [4] [5] [22] [23] Sonehara, Kyuto [1] [2] [24] Namba, Shinichi [1] Lee, Simon S. K. [25] Preuss, Michael H. [25] Petty, Lauren E. [26] Schroeder, Philip [14] [15] [16] [17] Vanderwerff, B. [10] [11] Kals, Mart [27] B 0000-0002-9170-8447 [28] [29] [30] Lin, Kuang [28] Guo, Xiuqing [31] [32] [33] Zhang, Weiwei 0000-0002-8850-5235 [34] [35] Yao, Jie 0000-0002-8822-0651 [31] [32] [33] Kim, Young Jin 0000-0002-4271-5771 [36] [37] Graff, M. [38] [39] Takeuchi, Fumihiko 0000-0003-3185-5661 [40] Nano, J. [4] [5] Lamri, Amel [41] [42] Nakatochi, Masahiro 0000-0002-1838-4837 [43] Moon, Sanghoon [36] [37] SCOTT, RA 0000-0002-0406-9617 [6] Cook, James P. [44] Lee, Jung-Jin 0000-0003-1025-8980 [13] Pan, Ian [45] Taliun, D. [10] [11] Parra, Esteban J 0000-0002-2057-8577 [46] [47] Chai, Jin Fang 0000-0003-3770-1137 [48] Bielak, L. F. 0000-0002-3443-8030 [10] [11] Tabara, Yasuharu [49] Hai, Yang 0000-0002-2039-5367 [31] [32] [33] Thorleifsson, Gudmar [50] Grarup, Niels 0000-0001-5526-1070 [51] [52] Sofer, Tamar 0000-0001-8520-8860 [17] [18] Wuttke, Matthias [53] Sarnowski, Chloe 0000-0002-6090-7099 [54] [55] [56] Gieger, Christian 0000-0001-6986-9554 [4] [5] [57] Nousome, Darryl [58] Trompet, Stella 0000-0001-5006-0528 [59] [60] [61] Kwak, Soo Heon 0000-0003-1230-0919 [62] [63] Long, Jirong [26] Sun, Meng [28] Tong, Lin [64] Chen, Wei-Min 0000-0002-2643-2333 [65] Nongmaithem, Suraj S. [66] [67] Noordam, Raymond 0000-0001-7801-809X [59] [60] [61] Lim, Victor Jun Yu 0000-0003-3051-4857 [48] Tam, C. H. T. 0000-0002-9169-0013 [68] Joo, Yoonjung Yoonie [69] [70] [71] [72] [73] Chen, Chien-Hsiun [74] Raffield, Laura M. [38] [39] Prins, Bram [75] Nicolas, Aude [7] [76] Yanek, Lisa R. [77] Chen, Guanjie 0000-0001-5946-6452 [7] [8] Brody, J. A. 0000-0001-8509-148X [78] [79] Kabagambe, Edmond [26] [80] An, Ping [81] Xiang, Anny H. [82] Choi, Hyeok Sun [83] Cade, B. E. 0000-0003-1424-0673 [17] [18] [19] Tan, Jingyi 0000-0001-8494-9536 [31] [32] [33] Broadaway, K Alaine [38] [39] Williamson, Alice 0000-0002-7599-9301 [6] Kamali, Zoha [84] [85] Cui, Jinrui [86] Thangam, Manonanthini 0000-0002-7164-6525 [87] [88] Adair, Linda S. [38] [39] Adeyemo, Adebowale [7] [8] Aguilar-Salinas, Carlos A. [89] Ahluwalia, Tarunveer S. [51] [90] Anand, S. S. [41] [42] Bertoni, A. G. [91] Bork-Jensen, Jette [51] [52] Brandslund, Ivan [92] [93] Buchanan, T. A. 0000-0001-7892-5132 [58] Burant, Charles F. 0000-0001-9189-5003 [10] [11] Butterworth, Adam S. [6] [74] [94] [95] Canouil, Mickael 0000-0002-3396-4549 [96] [97] [98] [99] [100] [101] [102] Chan, Juliana C. N. [68] Chang, Li-Ching [74] Chee, M. [48] [103] Chen, Ji [75] [104] Chen, Shyh-Huei [91] Chen, Yuan-Tsong [74] Chen, Zhengming [28] [29] [30] Chuang, Lee-Ming [91] [105] [106] Cushman, Mary [107] Danesh, John [6] [74] [75] [94] [95] Das, Swapan K. [91] de Silva, H. Janaka [108] Dedoussis, George 0000-0002-7798-6221 [109] Dimitrov, Latchezar [91] Doumatey, Ayo P. [7] [8] Du, Shufa [38] [39] Duan, Qing 0000-0003-1792-7091 [38] [39] Eckardt, K.-U. 0000-0003-3823-0920 [110] [111] [112] [113] Emery, Leslie 0000-0002-9070-9886 [78] [79] Evans, Daniel S [114] [115] Evans, Michele K. [7] [76] Fischer, K. [27] Floyd, James S. [78] [79] Ford, Ian [116] Franco, Oscar H. 0000-0002-4606-4929 [117] [118] Frayling, Timothy M. [104] Freedman, B. I. 0000-0003-0275-5530 [91] Genter, Pauline M. 0000-0003-1154-1921 [31] [32] [33] Gerstein, H. C. 0000-0001-8072-2836 [41] [42] Giedraitis, V. 0000-0003-3423-2021 [119] Gonzalez-Villalpando, Clicerio [120] Gonzalez-Villalpando, Maria Elena [120] Gordon-Larsen, P. 0000-0001-5322-4188 [38] [39] Gross, Myron [121] [122] Guare, Lindsay A. [13] Hackinger, Sophie 0000-0002-5896-0608 [75] Hakaste, Liisa [123] [124] Han, Sohee [36] [37] Hattersley, Andrew T. [104] Herder, Christian [57] [125] [126] [127] Horikoshi, Momoko [24] Howard, Annie Green 0000-0003-0837-8166 [38] [39] Hsueh, W. [128] [129] Huang, Mengna 0000-0002-4626-4816 [45] [130] Huang, Wei [131] Hung, Yi-Jen [130] [132] Hwang, Mi Yeong [36] [37] Hwu, CM 0000-0002-8209-9627 [133] [134] Ichihara, Sahoko 0000-0002-7224-0949 [135] Ikram, M. Arfan [117] [118] Ingelsson, Martin 0000-0001-5466-8370 [119] Islam, Md Tariqul [136] Isono, M. [40] Rotter, Jerome 0000-0001-7191-1723 [36] [37] Foo, Jasmine 0000-0002-5980-1174 [64] Jiang, Guozhi [68] Jonas, Jost B. [137] Jorgensen, Torben [51] [138] [139] Kamanu, Frederick K. [17] [18] [19] Kandeel, Fouad R. [140] Kasturiratne, A. 0000-0001-5260-2394 [108] Katsuya, Tomohiro [1] Kaur, Varinderpal [14] [17] Kawaguchi, Takahisa [49] Keaton, Jacob M. [7] [8] [26] [91] Kho, Abel N. [70] [71] Khor, Chiea Chuen 0000-0002-1128-4729 [141] [142] Kibriya, Muhammad 0000-0001-9784-6958 [64] Kim, Duk-Hwan [72] Kronenberg, Florian 0000-0003-2229-1120 [143] K. Kuusisto, Jussi [144] [145] Lall, Kristi [27] Lange, L. A. [146] [147] [148] Lee, Kyung Min 0000-0001-8995-0448 [149] [150] [151] Lee, Myung-Shik [72] [73] [152] Lee, Nanette R. [153] Leong, Aaron [14] [17] [19] Li, Liming 0000-0002-3988-2130 [154] Li, Yun [38] [39] Li-Gao, Ruifang [59] [60] [61] Ligthart, Symen [117] [118] Lindgren, Cecilia M. [15] [16] [17] [28] [155] Linneberg, Allan [51] [139] Liu, Ching-Ti 0000-0002-0703-0742 [156] Liu, Jian-Jun 0000-0002-3255-3019 [48] [141] [142] Locke, Adam E. [81] [157] Louie, T. L. [78] [79] Luan, Jian'an [6] Luk, Andrea O. Y. [68] Luo, Xi [54] [55] [56] Lv, Jun [154] Lynch, Julie A. [149] [150] [151] Lyssenko, Valeriya [87] [158] Maeda, Shiro [24] [159] Mamakou, Vasiliki [160] Mansuri, Sohail Rafik [66] [67] [161] Matsuda, Koichi [2] Meitinger, Thomas [4] [5] [23] [162] [163] Melander, Olle 0000-0002-2581-484X [87] [88] Metspalu, Andres 0000-0002-3718-796X [27] Mo, Huan 0000-0001-6029-458X [7] [8] Morris, Andrew D. [164] Moura, Filipe A. 0000-0001-8017-1675 [17] [18] [19] Nadler, J. L. [165] Nalls, M. A. [7] [76] [166] Nayak, Uma [65] Ntalla, Ioanna [20] [21] Okada, Yukinori [1] [2] [24] Orozco, L. [167] Patel, Sanjay R. [168] [169] Patil, Snehal [10] [11] Pei, Pei [154] Pereira, Mark A. [121] [122] 't Hoen, Peter 0000-0003-4450-3112 [4] [5] [57] [162] [163] [170] Pirie, Fraser [171] Polikowsky, Hannah G. [26] Porneala, B. C. [14] [17] Prasad, Gauri [66] [161] [172] Rasmussen-Torvik, Laura J. [70] [71] Reiner, A. P. [173] Roden, Michael [57] [125] [126] [127] Rohde, Rebecca [38] [39] Roll, Katheryn [31] [32] [33] Sabanayagam, Chanimati 0000-0002-4042-4719 [48] [103] Sandow, K [31] [32] [33] Sankareswaran, Alagu [66] [67] [161] Sattar, Naveed 0000-0002-1604-2593 [116] Schoenherr, Sebastian [143] Shahriar, Mohammad [64] Shen, Bo [7] [76] Shi, Jin-Xiu [131] Shin, Dong Mun [36] [37] Shojima, Nobuhiro 0000-0002-4078-3308 [2] Smith, Jennifer A. 0000-0003-1652-7299 [10] [11] So, Wing Yee 0000-0001-8078-7402 [68] Stancakova, Alena [144] [145] Steinthorsdottir, Valgerdur 0000-0003-1846-6274 [50] Stilp, Adrienne [78] [79] Strauch, Konstantin [4] [5] [170] [174] Taylor, Kent D 0000-0002-2756-4370 [31] [32] [33] Thorand, Barbara 0000-0002-8416-6440 [4] [5] [57] Thorsteinsdottir, Unnur [50] [175] Tomlinson, Brian [68] [176] Tran, Tam C. [7] [8] Tsai, Fuu-Jen [177] [178] Tuomilehto, J [123] [179] [180] [181] Tusie-Luna, Teresa [89] [182] Udler, M. S. [14] [15] [16] [17] [19] Valladares-Salgado, Adan [183] van Dam, Rob M. [48] van Klinken, Jan Bert 0000-0002-9855-3548 [59] [60] [61] [184] [185] Varma, Rohit 0000-0002-9224-2909 [186] Wacher-Rodarte, Niels [183] Wheeler, E. 0000-0002-8616-6444 [6] Wickremasinghe, Ananda R. 0000-0002-6174-6784 [108] van Dijk, Ko Willems [59] [60] [61] Witte, Daniel 0000-0002-0769-2922 [187] [188] Yajnik, Chittaranjan [189] Yamamoto, Ken Yamamoto, Kenichi [1] Yoon, Kyungheon [36] [37] Ravina, B. 0000-0001-6107-6672 [154] Yuan, Jian-Min [168] [169] Yusuf, Salim [41] [42] Zawistowski, M. 0000-0002-3005-083X [10] [11] Zhang, Liang [48] [103] Zheng, Wei [26] Raffel, L. J. [190] Igase, Michiya [191] Ipp, Eli 0000-0003-1588-0146 [31] [32] [33] Redline, Susan [17] [18] [19] [192] Cho, Yoon Shin [83] Lind, Lars 0000-0003-2335-8542 [119] Province, Michael A. [81] Fornage, Myriam [54] [55] [56] Hanis, C. [55] [56] Ingelsson, Erik [119] [193] [194] Zonderman, Alan B. [7] [76] Psaty, Bruce 0000-0002-7278-2190 [78] [79] Wang, Ya Xing 0000-0002-1842-339X [195] Rotimi, Charles N. [7] [8] Becker, Diane M. [77] Matsuda, F. [49] Chou, Y. [91] [196] Yokota, Mitsuhiro [193] Kardia, Sharon L. [10] [11] Peyser, Patricia A [10] [11] Pankow, James S. [121] [122] Engert, James C. 0000-0001-8411-4790 [197] Bonnefond, Amelie [34] [96] [97] [98] [99] [100] [101] [102] Froguel, Philippe [34] [96] [97] [98] [99] [100] [101] [102] Wilson, James G. [17] [192] Sheu, Wayne H-H 0000-0002-8805-8340 [132] [134] [198] Wu, Jer-Yuarn [74] Hayes, M. Geoffrey 0000-0002-4617-3981 [70] [71] Ma, Ronald 0000-0002-1227-803X [68] Wong, Tien-Yin [48] [103] Mook-Kanamori, Dennis O. [59] [60] [61] Tuomi, Tiinamaija [87] [88] [123] [124] [199] Chandak, Giriraj Ratan [66] [67] [200] [201] Collins, F. S. [7] [8] Bharadwaj, Dwaipayan [202] Pare, Guillaume [41] [42] Sale, Michele M. 0000-0001-6225-8240 [65] Ahsan, Habibul [64] Motala, Ayesha A. [171] Shu, Xiao Ou [26] Park, Kyong-Soo [62] [63] Jukema, J. Wouter [59] [60] [61] [203] Cruz, Miguel [183] Chen, Yii-Der Ida [31] [32] [33] Rich, Stephen S. 0000-0003-3872-7793 [65] McKean-Cowdin, Roberta 0000-0002-6121-688X [58] Grallert, Harald [4] [5] [57] Cheng, Ching-Yu [48] [103] Ghanbari, Mohsen [117] [118] Tai, E-Shyong [48] Dupuis, Josee [156] [197] Kato, Norihiro [40] Laakso, M. [144] [145] Koettgen, Anna [53] Koh, Woon-Puay 0000-0002-5674-6341 [48] [142] [204] Bowden, Donald W. [91] Palmer, Colin N. A. [205] Kooner, J. [34] [35] Kooperberg, C. [173] Liu, Simin [45] North, K. E. 0000-0002-8903-0366 [38] [39] Saleheen, D. [206] [207] [208] Hansen, T. 0000-0001-7476-671X [51] [52] Pedersen, Oluf [51] [52] Wareham, Nicholas J. [6] Lee, Juyoung [36] [37] Kim, Bong-Jo 0000-0003-3562-2654 [36] [37] Millwood, I.Y [28] [29] [30] Guo, Yu 0000-0002-9179-0321 [28] [29] [30] Stefansson, Kari [50] [175] Ahlqvist, E. 0000-0002-6513-2384 [87] [88] Goodarzi, M. O. [86] Mohlke, K. L. [38] [39] Langenberg, Claudia [6] [20] [21] [111] [112] [113] [209] Haiman, C. A. [58] Loos, Ruth J. F. [25] [51] [52] Florez, Jose C. [14] [15] [16] [17] [19] Rader, D. J. 0000-0002-9245-9876 [13] Ritchie, Marylyn [13] Zollner, Sebastian [10] [11] Magi, Reedik [27] Marston, N. A. 0000-0001-6164-4617 [17] [18] [19] Ruff, Christian T. [17] [18] [19] van Heel, David A. [20] [21] Finer, Sarah 0000-0002-2684-4653 [20] [21] Denny, Joshua C. [7] [8] Yamauchi, Toshimasa [2] Kadowaki, Takashi [2] [210] Chambers, John C. [34] [35] [211] Ng, Maggie C. Y. [26] [91] Sim, Xueling 0000-0002-1233-7642 [48] Below, Jennifer E. [26] Tsao, Philip S. [151] [193] [194] [212] [213] Chang, Kyong-Mi [12] [13] McCarthy, Mark [28] [155] [214] [215] [216] Meigs, James 0000-0002-2439-2657 [14] [15] [16] [17] [19] Mahajan, Anubha 0000-0001-5585-3420 [28] [155] [215] [216] Spracklen, C. N. 0000-0003-3590-7182 [217] [218] Mercader, Josep 0000-0001-8494-3660 [14] [15] [16] [17] [19] Boehnke, M. 0000-0002-6442-7754 [10] [11] Rotter, Jerome I. [31] [32] [33] Vujkovic, Marijana [12] [13] Voight, Benjamin F 0000-0002-6205-9994 (Corresponding author) [12] [13] Morris, A. P. 0000-0002-9169-118X (Corresponding author) [3] [4] [5] [27] Zeggini, E. (Corresponding author) [4] [5] [23] VA Million Veteran Program AMED GRIFIN Diabet Initiative BioBank Japan Project Penn Med BioBank Regeneron Genetics Ctr Genes & Hlth Res Team eMERGE Consortium Int Consortium Blood Pressure Meta Anal Glucose & Insulin

Affiliations

  1. [1] Osaka Univ, Dept Clin Gene Therapy, Grad Sch Med, Osaka, Japan
    2. [NORA names: Japan; Asia, East; OECD];
  2. [2] Univ Tokyo, Dept Diabet & Metab Dis, Grad Sch Med, Tokyo, Japan
    3. [NORA names: Japan; Asia, East; OECD];
  3. [3] Univ Manchester, Div Musculoskeletal & Dermatol Sci, Ctr Genet & Genom Versus Arthrit, Ctr Musculoskeletal Res, Manchester, Lancs, England
    4. [NORA names: United Kingdom; Europe, Non-EU; OECD];
  4. [4] German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany
    5. [NORA names: Germany; Europe, EU; OECD];
  5. [5] German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany
    6. [NORA names: Germany; Europe, EU; OECD];

Abstract

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes(1,2) and molecular mechanisms that are often specific to cell type(3,4). 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 x 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 scores(5) 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.

Data Provider: Clarivate

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