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Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology Publisher Pubmed



Suzuki K1, 2, 3 ; Hatzikotoulas K4 ; Southam L4 ; Taylor HJ5, 6, 7 ; Yin X8, 9 ; Lorenz KM10, 11, 12 ; Mandla R13, 14 ; Huertachagoya A13 ; Melloni GEM15 ; Kanoni S16 ; Rayner NW4 ; Bocher O4 ; Arruda AL4, 17, 18 ; Sonehara K3, 19, 20, 21 Show All Authors
Authors
  1. Suzuki K1, 2, 3
  2. Hatzikotoulas K4
  3. Southam L4
  4. Taylor HJ5, 6, 7
  5. Yin X8, 9
  6. Lorenz KM10, 11, 12
  7. Mandla R13, 14
  8. Huertachagoya A13
  9. Melloni GEM15
  10. Kanoni S16
  11. Rayner NW4
  12. Bocher O4
  13. Arruda AL4, 17, 18
  14. Sonehara K3, 19, 20, 21
  15. Namba S3
  16. Lee SSK22
  17. Preuss MH22
  18. Petty LE23
  19. Schroeder P13, 14
  20. Vanderwerff B9
  21. Kals M24
  22. Bragg F25, 26
  23. Lin K25
  24. Guo X27
  25. Zhang W28, 29
  26. Yao J27
  27. Kim YJ30
  28. Graff M31
  29. Takeuchi F32
  30. Nano J33
  31. Lamri A34, 35
  32. Nakatochi M36
  33. Moon S30
  34. Scott RA37
  35. Cook JP38
  36. Lee JJ39
  37. Pan I40
  38. Taliun D9
  39. Parra EJ41
  40. Chai JF42
  41. Bielak LF43
  42. Tabara Y44
  43. Hai Y27
  44. Thorleifsson G45
  45. Grarup N46
  46. Sofer T47, 48, 49
  47. Wuttke M50
  48. Sarnowski C51
  49. Gieger C33, 52, 53
  50. Nousome D54
  51. Trompet S55, 56
  52. Kwak SH57
  53. Long J58
  54. Sun M59
  55. Tong L60
  56. Chen WM61
  57. Nongmaithem SS62
  58. Noordam R56
  59. Lim VJY42
  60. Tam CHT63, 64
  61. Joo YY65
  62. Chen CH68
  63. Raffield LM69
  64. Prins BP70
  65. Nicolas A71
  66. Yanek LR72
  67. Chen G73
  68. Brody JA74
  69. Kabagambe E58, 75
  70. An P76
  71. Xiang AH77
  72. Choi HS78
  73. Cade BE48, 79
  74. Tan J27
  75. Broadaway KA69
  76. Williamson A37, 80
  77. Kamali Z81, 82
  78. Cui J83
  79. Thangam M84
  80. Adair LS85
  81. Adeyemo A73
  82. Aguilarsalinas CA86
  83. Ahluwalia TS87, 88
  84. Anand SS34, 35, 89
  85. Bertoni A90
  86. Borkjensen J46
  87. Brandslund I91, 92
  88. Buchanan TA93
  89. Burant CF94
  90. Butterworth AS6, 95, 96, 97
  91. Canouil M98, 99
  92. Chan JCN63, 64, 100, 101
  93. Chang LC68
  94. Chee ML102
  95. Chen J103, 104
  96. Chen SH105
  97. Chen YT68
  98. Chen Z25, 26
  99. Chuang LM106, 107
  100. Cushman M108
  101. Danesh J6, 70, 95, 96, 97
  102. Das SK109
  103. De Silva HJ110
  104. Dedoussis G111
  105. Dimitrov L112
  106. Doumatey AP73
  107. Du S85, 113
  108. Duan Q69
  109. Eckardt KU114, 115
  110. Emery LS116
  111. Evans DS117
  112. Evans MK118
  113. Fischer K24, 119
  114. Floyd JS74
  115. Ford I120
  116. Franco OH121
  117. Frayling TM122
  118. Freedman BI123
  119. Genter P124
  120. Gerstein HC34, 35, 89
  121. Giedraitis V125
  122. Gonzalezvillalpando C126
  123. Gonzalezvillalpando ME126
  124. Gordonlarsen P85, 113
  125. Gross M127
  126. Guare LA128
  127. Hackinger S70
  128. Hakaste L129, 130
  129. Han S30
  130. Hattersley AT131
  131. Herder C52, 132, 133
  132. Horikoshi M134
  133. Howard AG113, 135
  134. Hsueh W136
  135. Huang M40, 137
  136. Huang W138
  137. Hung YJ139, 140
  138. Hwang MY30
  139. Hwu CM141, 142
  140. Ichihara S143
  141. Ikram MA121
  142. Ingelsson M125
  143. Islam MT144
  144. Isono M32
  145. Jang HM30
  146. Jasmine F60
  147. Jiang G63, 64
  148. Jonas JB145
  149. Jorgensen T146, 147, 148
  150. Kamanu FK15
  151. Kandeel FR149
  152. Kasturiratne A150
  153. Katsuya T151, 152
  154. Kaur V14
  155. Kawaguchi T44
  156. Keaton JM5, 58, 112
  157. Kho AN153, 154
  158. Khor CC155
  159. Kibriya MG60
  160. Kim DH156
  161. Kronenberg F157
  162. Kuusisto J158
  163. Lall K24
  164. Lange LA159
  165. Lee KM160, 161
  166. Lee MS162, 163
  167. Lee NR164
  168. Leong A165, 166
  169. Li L167, 168
  170. Li Y69
  171. Ligao R169
  172. Ligthart S121
  173. Lindgren CM170, 171, 172
  174. Linneberg A146, 173
  175. Liu CT174
  176. Liu J155, 175
  177. Locke AE176, 177, 300
  178. Louie T116
  179. Luan J37
  180. Luk AO63, 64
  181. Luo X178
  182. Lv J167, 168
  183. Lynch JA160, 161
  184. Lyssenko V179, 180
  185. Maeda S134, 181, 182
  186. Mamakou V183
  187. Mansuri SR62, 184
  188. Matsuda K185
  189. Meitinger T186, 187, 188
  190. Melander O84
  191. Metspalu A24
  192. Mo H5
  193. Morris AD189
  194. Moura FA15
  195. Nadler JL190
  196. Nalls MA71, 191, 192
  197. Nayak U61
  198. Ntalla I16
  199. Okada Y3, 19, 20, 21, 193, 194
  200. Orozco L195
  201. Patel SR196
  202. Patil S9
  203. Pei P168
  204. Pereira MA197
  205. Peters A33, 52, 188, 198
  206. Pirie FJ199
  207. Polikowsky HG23
  208. Porneala B166
  209. Prasad G200, 201
  210. Rasmussentorvik LJ67
  211. Reiner AP202
  212. Roden M52, 132, 133
  213. Rohde R31
  214. Roll K27
  215. Sabanayagam C102, 203, 204
  216. Sandow K27
  217. Sankareswaran A62, 184
  218. Sattar N205
  219. Schonherr S157
  220. Shahriar M60
  221. Shen B118
  222. Shi J138
  223. Shin DM30
  224. Shojima N2
  225. Smith JA43, 206
  226. So WY63, 101
  227. Stancakova A158
  228. Steinthorsdottir V45
  229. Stilp AM116
  230. Strauch K207, 208, 209
  231. Taylor KD27
  232. Thorand B33, 52
  233. Thorsteinsdottir U45, 210
  234. Tomlinson B63, 211
  235. Tran TC5
  236. Tsai FJ212
  237. Tuomilehto J213, 214, 215, 216
  238. Tusieluna T217, 218
  239. Udler MS13, 14, 165
  240. Valladaressalgado A219
  241. Van Dam RM42, 175
  242. Van Klinken JB220, 221, 222
  243. Varma R223
  244. Wacherrodarte N224
  245. Wheeler E37
  246. Wickremasinghe AR150
  247. Van Dijk KW220, 221, 225
  248. Witte DR226, 227
  249. Yajnik CS228
  250. Yamamoto K229
  251. Yamamoto K229
  252. Yoon K30
  253. Yu C167, 168
  254. Yuan JM231, 232
  255. Yusuf S34, 35, 89
  256. Zawistowski M9
  257. Zhang L102
  258. Zheng W58
  259. Kanona S16
  260. Van Heel DA286
  261. Raffel LJ233
  262. Igase M234
  263. Ipp E124
  264. Redline S48, 79, 235
  265. Cho YS78
  266. Lind L236
  267. Province MA76
  268. Fornage M237
  269. Hanis CL238
  270. Ingelsson E239, 240
  271. Zonderman AB118
  272. Psaty BM74, 241, 242
  273. Wang YX243
  274. Rotimi CN73
  275. Becker DM72
  276. Matsuda F44
  277. Liu Y90, 244
  278. Yokota M245
  279. Kardia SLR43
  280. Peyser PA43
  281. Pankow JS197
  282. Engert JC246, 247
  283. Bonnefond A98, 99, 248
  284. Froguel P98, 99, 248
  285. Wilson JG249
  286. Sheu WHH140, 142, 250
  287. Wu JY68
  288. Hayes MG251, 252, 253
  289. Ma RCW63, 64, 100, 101
  290. Wong TY102, 203, 204
  291. Mookkanamori DO169
  292. Tuomi T84, 129, 130, 254
  293. Chandak GR62, 255
  294. Collins FS5
  295. Bharadwaj D256
  296. Pare G35, 257
  297. Sale MM61
  298. Ahsan H60
  299. Motala AA199
  300. Shu XO58
  301. Park KS57, 258
  302. Jukema JW55, 259
  303. Cruz M219
  304. Chen YDI27
  305. Rich SS260
  306. Mckeancowdin R54
  307. Grallert H33, 52, 261
  308. Cheng CY102, 203, 204
  309. Ghanbari M121
  310. Tai ES42, 175, 262
  311. Dupuis J174, 263
  312. Kato N32
  313. Laakso M158
  314. Kottgen A50
  315. Koh WP264, 265
  316. Bowden DW112, 266, 267
  317. Palmer CNA268
  318. Kooner JS29, 269, 270, 271
  319. Kooperberg C202
  320. Liu S40, 137, 272
  321. North KE31
  322. Saleheen D273, 274, 275
  323. Hansen T46
  324. Pedersen O46
  325. Wareham NJ37
  326. Lee J30
  327. Kim BJ30
  328. Millwood IY25, 26
  329. Walters RG25, 26
  330. Stefansson K45, 210
  331. Ahlqvist E84
  332. Goodarzi MO83
  333. Mohlke KL69
  334. Langenberg C37, 276, 277
  335. Haiman CA278
  336. Loos RJF22, 46, 279
  337. Florez JC13, 14, 165
  338. Rader DJ12, 280, 281, 282
  339. Ritchie MD12, 283, 284
  340. Zollner S9, 285
  341. Magi R24
  342. Marston NA15
  343. Ruff CT15
  344. Finer S287
  345. Denny JC5, 288
  346. Yamauchi T2
  347. Kadowaki T2, 289
  348. Chambers JC28, 29, 269, 290
  349. Ng MCY112, 267, 291
  350. Sim X42
  351. Below JE23
  352. Tsao PS239, 292, 293
  353. Chang KM10, 294
  354. Mccarthy MI170, 295, 296, 301
  355. Meigs JB13, 165, 166
  356. Mahajan A170, 295, 301
  357. Spracklen CN297
  358. Mercader JM13, 14, 79
  359. Boehnke M9
  360. Rotter JI27
  361. Vujkovic M10, 294, 298
  362. Voight BF10, 11, 12, 281
  363. Morris AP1, 4, 24
  364. Zeggini E4, 299

Source: Nature Published:2024


Abstract

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. © The Author(s) 2024.
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