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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

2020; Nature Portfolio; Volume: 52; Issue: 7 Linguagem: Inglês

10.1038/s41588-020-0637-y

1546-1718

Marijana Vujković, Jacob M. Keaton, Julie A. Lynch, Donald R. Miller, Jin Zhou, Catherine Tcheandjieu, Jennifer E. Huffman, Themistocles L. Assimes, Kimberly Lorenz, Xiang Zhu, Austin T. Hilliard, Renae Judy, Jie Huang, Kyung Min Lee, Derek Klarin, Saiju Pyarajan, John Danesh, Olle Melander, Asif Rasheed, Nadeem Hayat Mallick, Shahid Hameed, Irshad Hussain Qureshi, Muhammad Afzal, Uzma Malik, Anjum Jalal, Shahid Abbas, Xin Sheng, Long Gao, Klaus H. Kaestner, Katalin Suszták, Yan V. Sun, Scott L. DuVall, Kelly Cho, Jennifer S. Lee, J. Michael Gaziano, Lawrence S. Phillips, James B. Meigs, Peter D. Reaven, Peter W.F. Wilson, Todd L. Edwards, Daniel J. Rader, Scott M. Damrauer, Christopher J. O’Donnell, Philip S. Tsao, Mark A. Atkinson, Al C. Powers, Ali Naji, Klaus H. Kaestner, Gonçalo R. Abecasis, Aris Baras, Michael Cantor, Giovanni Coppola, Aris N. Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan R. Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Evan K. Maxwell, William Salerno, Jeffrey Staples, Ashish Yadav, Marcus B. Jones, Lyndon J. Mitnaul, Samuel M. Aguayo, Sunil K. Ahuja, Zuhair K. Ballas, Sujata Bhushan, Edward J. Boyko, David Cohen, John Concato, Joseph I. Constans, Louis J. Dell’Italia, Joseph Fayad, Ronald Fernando, Hermes Flórez, Melinda A. Gaddy, Saib Gappy, Gretchen Gibson, Michael Godschalk, Jennifer A. Greco, Samir Gupta, Salvador Gutierrez, Kimberly Hammer, Mark B. Hamner, John B. Harley, Adriana M. Hung, Mostaqul Huq, Robin A. Hurley, Pran Iruvanti, Douglas Ivins, Frank J. Jacono, Darshana Jhala, Laurence S. Kaminsky, Scott Kinlay, Jon B. Klein, Suthat Liangpunsakul, Jack Lichy, Stephen Mastorides, Roy O. Mathew, Kristin Mattocks, Rachel McArdle, Paul N. Meyer, Laurence J. Meyer, Jonathan P. Moorman, Timothy R. Morgan, Maureen Murdoch, Xuan‐Mai T. Nguyen, Olaoluwa Okusaga, Krisann K. Oursler, Nora Ratcliffe, Michael Rauchman, R. Brooks Robey, George Ross, Richard J. Servatius, Satish Sharma, Scott E. Sherman, Elif Sonel, Peruvemba Sriram, Todd Stapley, Rob Striker, Neeraj Tandon, Gerardo Villareal, Agnes Wallbom, John M. Wells, Jeff Whittle, Mary A. Whooley, Junzhe Xu, Shing‐Shing Yeh, Michaela Aslan, Jessica V. Brewer, Mary T. Brophy, Todd Connor, Dean P. Argyres, Nhan Do, Elizabeth R. Hauser, Donald E. Humphries, Luis E. Selva, Shahpoor Shayan, Brady Stephens, Stacey B. Whitbourne, Hongyu Zhao, Jennifer Moser, Jean C. Beckham, Jim Breeling, Jonathan Romero, Grant D. Huang, Rachel Ramoni, Saiju Pyarajan, Yan V. Sun, Kelly Cho, Peter W.F. Wilson, Christopher J. O’Donnell, Philip S. Tsao, Kyong–Mi Chang, J. Michael Gaziano, Sumitra Muralidhar, Kyong–Mi Chang, Benjamin F. Voight, Danish Saleheen,

Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

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. 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.