Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis

被引：491

作者：

Vujkovic, Marijana ^{[1
,2
]}

Keaton, Jacob M. ^{[3
,4
,5
,6
]}

Lynch, Julie A. ^{[7
,8
]}

Miller, Donald R. ^{[9
,10
]}

Zhou, Jin ^{[11
,12
]}

Tcheandjieu, Catherine ^{[13
,14
,15
]}

Huffman, Jennifer E. ^{[16
]}

Assimes, Themistocles L. ^{[13
,14
]}

Lorenz, Kimberly ^{[1
,17
,18
]}

Zhu, Xiang ^{[13
,19
]}

Hilliard, Austin T. ^{[13
,14
]}

Judy, Renae L. ^{[1
,20
]}

Huang, Jie ^{[16
,21
]}

Lee, Kyung M. ^{[7
]}

Klarin, Derek ^{[16
,22
,23
,24
]}

Pyarajan, Saiju ^{[16
,25
,26
]}

Danesh, John ^{[27
]}

Melander, Olle ^{[28
]}

Rasheed, Asif ^{[29
]}

Mallick, Nadeem H. ^{[30
]}

Hameed, Shahid ^{[30
]}

Qureshi, Irshad H. ^{[31
,32
]}

Afzal, Muhammad Naeem ^{[31
,32
]}

Malik, Uzma ^{[31
,32
]}

Jalal, Anjum ^{[33
]}

Abbas, Shahid ^{[33
]}

Sheng, Xin ^{[2
]}

Gao, Long ^{[17
]}

Kaestner, Klaus H. ^{[17
]}

Susztak, Katalin ^{[2
]}

Sun, Yan V. ^{[34
,35
]}

DuVall, Scott L. ^{[7
,36
]}

Cho, Kelly ^{[16
,25
]}

Lee, Jennifer S. ^{[13
,14
]}

Gaziano, J. Michael ^{[16
,25
]}

Phillips, Lawrence S. ^{[34
,37
]}

Meigs, James B. ^{[23
,26
,38
]}

Reaven, Peter D. ^{[11
,39
]}

Wilson, Peter W. ^{[34
,40
]}

Edwards, Todd L. ^{[4
,41
]}

Rader, Daniel J. ^{[2
,17
]}

Damrauer, Scott M. ^{[1
,20
]}

O'Donnell, Christopher J. ^{[16
,25
,26
]}

Tsao, Philip S. ^{[13
,14
]}

Chang, Kyong-Mi ^{[1
,2
,42
]}

Voight, Benjamin F. ^{[1
,17
,18
]}

Saleheen, Danish ^{[29
,43
,44
]}

机构：

[1] Corporal Michael J Crescenz VA Med Ctr, Philadelphia, PA 19104 USA

[2] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA

[3] Tennessee Valley Healthcare Syst, Biomed Lab Res & Dev, Nashville, TN USA

[4] Vanderbilt Univ, Med Ctr, Vanderbilt Genet Inst, Nashville, TN USA

[5] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA

[6] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN USA

[7] VA Salt Lake City Hlth Care Syst, VA Informat & Comp Infrastruct, Salt Lake City, UT USA

[8] Univ Massachusetts, Coll Nursing & Hlth Sci, Lowell, MA USA

[9] Edith Nourse Rogers Mem VA Hosp, Bedford, MA USA

[10] Univ Massachusetts, Ctr Populat Hlth, Lowell, MA USA

[11] Phoenix VA Hlth Care Syst, Phoenix, AZ USA

[12] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ USA

[13] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA

[14] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA

[15] Stanford Univ, Dept Pediat Cardiol, Sch Med, Stanford, CA 94305 USA

[16] VA Boston Healthcare Syst, Boston, MA USA

[17] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA

[18] Univ Penn, Dept Syst Pharmacol & Translat Therapeut, Perelman Sch Med, Philadelphia, PA 19104 USA

[19] Stanford Univ, Dept Stat, Stanford, CA 94305 USA

[20] Univ Penn, Dept Surg, Perelman Sch Med, Philadelphia, PA 19104 USA

[21] Peking Univ, Sch Publ Hlth, Dept Global Hlth, Beijing, Peoples R China

[22] Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA

[23] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA

[24] Univ Florida, Sch Med, Div Vasc Surg & Endovasc Therapy, Gainesville, FL USA

[25] Brigham Womens Hosp, Dept Med, Boston, MA USA

[26] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[27] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England

[28] Lund Univ, Dept Clin Sci Malmo, Malmo, Sweden

[29] Ctr Noncommunicable Dis, Karachi, Sindh, Pakistan

[30] Punjab Inst Cardiol, Lahore, Punjab, Pakistan

[31] King Edward Med Univ, Dept Med, Lahore, Punjab, Pakistan

[32] Mayo Hosp, Lahore, Punjab, Pakistan

[33] Faisalabad Inst Cardiol, Dept Cardiol, Faisalabad, Punjab, Pakistan

[34] Atlanta VA Med Ctr, Decatur, GA USA

[35] Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA

[36] Univ Utah, Sch Med, Dept Internal Med, Salt Lake City, UT USA

[37] Emory Univ, Sch Med, Div Endocrinol, Atlanta, GA USA

[38] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA

[39] Univ Arizona, Coll Med, Phoenix, AZ USA

[40] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA

[41] Nashville VA Med Ctr, Nashville, TN USA

[42] South Texas Vet Hlth Care Syst, San Antonio, TX USA

[43] Columbia Univ, Dept Med, Irving Med Ctr, New York, NY 10027 USA

[44] Columbia Univ, Dept Cardiol, Irving Med Ctr, New York, NY 10027 USA

来源：

NATURE GENETICS | 2020年 / 52卷 / 07期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

GENOME-WIDE; GENE-EXPRESSION; ASSOCIATION; CELL; DISEASE; HEALTH; HERITABILITY; ENRICHMENT; MUTATIONS; DATABASE;

D O I：

10.1038/s41588-020-0637-y

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Genome-wide association meta-analyses among 1.4 million individuals identify 318 new risk loci for type 2 diabetes and provide insight into the contribution of these risk variants to diabetes-related vascular outcomes. We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score (PRS) was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD) and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP-T2D interactions at 13 variants, including coronary heart disease (CHD), CKD, PAD and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.

引用

页码：680 / +

页数：21

共 62 条

[1] Integration of ATAC-seq and RNA-seq identifies human alpha cell and beta cell signature genes [J].

Ackermann, Amanda M. ;

Wang, Zhiping ;

Schug, Jonathan ;

Naji, Ali ;

Kaestner, Klaus H. .

MOLECULAR METABOLISM, 2016, 5 (03) :233-244

[2] A global reference for human genetic variation [J].

Altshuler, David M. ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Donnelly, Peter ;

Eichler, Evan E. ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Green, Eric D. ;

Hurles, Matthew E. ;

Knoppers, Bartha M. ;

Korbel, Jan O. ;

Lander, Eric S. ;

Lee, Charles ;

Lehrach, Hans ;

Mardis, Elaine R. ;

Marth, Gabor T. ;

McVean, Gil A. ;

Nickerson, Deborah A. ;

Wang, Jun ;

Wilson, Richard K. ;

Boerwinkle, Eric ;

Doddapaneni, Harsha ;

Han, Yi ;

Korchina, Viktoriya ;

Kovar, Christie ;

Lee, Sandra ;

Muzny, Donna ;

Reid, Jeffrey G. ;

Zhu, Yiming ;

Chang, Yuqi ;

Feng, Qiang ;

Fang, Xiaodong ;

Guo, Xiaosen ;

Jian, Min ;

Jiang, Hui ;

Jin, Xin ;

Lan, Tianming ;

Li, Guoqing ;

Li, Jingxiang ;

Li, Yingrui ;

Liu, Shengmao ;

Liu, Xiao ;

Lu, Yao ;

Ma, Xuedi ;

Tang, Meifang ;

Wang, Bo .

NATURE, 2015, 526 (7571) :68-+

[3] Integrating common and rare genetic variation in diverse human populations [J].

Altshuler, David M. ;

Gibbs, Richard A. ;

Peltonen, Leena ;

Dermitzakis, Emmanouil ;

Schaffner, Stephen F. ;

Yu, Fuli ;

Bonnen, Penelope E. ;

de Bakker, Paul I. W. ;

Deloukas, Panos ;

Gabriel, Stacey B. ;

Gwilliam, Rhian ;

Hunt, Sarah ;

Inouye, Michael ;

Jia, Xiaoming ;

Palotie, Aarno ;

Parkin, Melissa ;

Whittaker, Pamela ;

Chang, Kyle ;

Hawes, Alicia ;

Lewis, Lora R. ;

Ren, Yanru ;

Wheeler, David ;

Muzny, Donna Marie ;

Barnes, Chris ;

Darvishi, Katayoon ;

Hurles, Matthew ;

Korn, Joshua M. ;

Kristiansson, Kati ;

Lee, Charles ;

McCarroll, Steven A. ;

Nemesh, James ;

Keinan, Alon ;

Montgomery, Stephen B. ;

Pollack, Samuela ;

Price, Alkes L. ;

Soranzo, Nicole ;

Gonzaga-Jauregui, Claudia ;

Anttila, Verneri ;

Brodeur, Wendy ;

Daly, Mark J. ;

Leslie, Stephen ;

McVean, Gil ;

Moutsianas, Loukas ;

Nguyen, Huy ;

Zhang, Qingrun ;

Ghori, Mohammed J. R. ;

McGinnis, Ralph ;

McLaren, William ;

Takeuchi, Fumihiko ;

Grossman, Sharon R. .

NATURE, 2010, 467 (7311) :52-58

[4] An atlas of active enhancers across human cell types and tissues [J].

Andersson, Robin ;

Gebhard, Claudia ;

Miguel-Escalada, Irene ;

Hoof, Ilka ;

Bornholdt, Jette ;

Boyd, Mette ;

Chen, Yun ;

Zhao, Xiaobei ;

Schmidl, Christian ;

Suzuki, Takahiro ;

Ntini, Evgenia ;

Arner, Erik ;

Valen, Eivind ;

Li, Kang ;

Schwarzfischer, Lucia ;

Glatz, Dagmar ;

Raithel, Johanna ;

Lilje, Berit ;

Rapin, Nicolas ;

Bagger, Frederik Otzen ;

Jorgensen, Mette ;

Andersen, Peter Refsing ;

Bertin, Nicolas ;

Rackham, Owen ;

Burroughs, A. Maxwell ;

Baillie, J. Kenneth ;

Ishizu, Yuri ;

Shimizu, Yuri ;

Furuhata, Erina ;

Maeda, Shiori ;

Negishi, Yutaka ;

Mungall, Christopher J. ;

Meehan, Terrence F. ;

Lassmann, Timo ;

Itoh, Masayoshi ;

Kawaji, Hideya ;

Kondo, Naoto ;

Kawai, Jun ;

Lennartsson, Andreas ;

Daub, Carsten O. ;

Heutink, Peter ;

Hume, David A. ;

Jensen, Torben Heick ;

Suzuki, Harukazu ;

Hayashizaki, Yoshihide ;

Mueller, Ferenc ;

Forrest, Alistair R. R. ;

Carninci, Piero ;

Rehli, Michael ;

Sandelin, Albin .

NATURE, 2014, 507 (7493) :455-+

[5]

[Anonymous], 2018, DIABETES CARE, V41, pS1, DOI [10.2337/dc18-SINT01, 10.2337/dc18-Sint01]

[6] DESIGN AND FEASIBILITY [J].

BERGLUND, G ;

ELMSTAHL, S ;

JANZON, L ;

LARSSON, SA .

JOURNAL OF INTERNAL MEDICINE, 1993, 233 (01) :45-51

[7]

BONASGUARCH S, 2018, NAT COMMUN, V9

[8] An atlas of genetic correlations across human diseases and traits [J].

Bulik-Sullivan, Brendan ;

Finucane, Hilary K. ;

Anttila, Verneri ;

Gusev, Alexander ;

Day, Felix R. ;

Loh, Po-Ru ;

Duncan, Laramie ;

Perry, John R. B. ;

Patterson, Nick ;

Robinson, Elise B. ;

Daly, Mark J. ;

Price, Alkes L. ;

Neale, Benjamin M. .

NATURE GENETICS, 2015, 47 (11) :1236-+

[9] LD Score regression distinguishes confounding from polygenicity in genome-wide association studies [J].

Bulik-Sullivan, Brendan K. ;

Loh, Po-Ru ;

Finucane, Hilary K. ;

Ripke, Stephan ;

Yang, Jian ;

Patterson, Nick ;

Daly, Mark J. ;

Price, Alkes L. ;

Neale, Benjamin M. .

NATURE GENETICS, 2015, 47 (03) :291-+

[10] Expanding the phenotype of reciprocal 1q21.1 deletions and duplications: a case series [J].

Buse, Martina ;

Cuttaia, Helenia C. ;

Palazzo, Daniela ;

Mazara, Marcella V. ;

Lauricella, Salvatrice A. ;

Malacarne, Michela ;

Pierluigi, Mauro ;

Cavani, Simona ;

Piccione, Maria .

ITALIAN JOURNAL OF PEDIATRICS, 2017, 43

← 1 2 3 4 5 6 7 →