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Cited by 741Genetic Associations and EpidemiologyGenetic Mapping and Diversity in Plants and AnimalsDiabetes and associated disorders

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

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Vujkovic, Marijana, Keaton, Jacob M., Lynch, Julie A., Miller, Donald R., Zhou, Jin, Tcheandjieu, Catherine, Huffman, Jennifer E., Assimes, Themistocles L. +176 more·2020·Nature Genetics
DOI 10.1038/s41588-020-0637-yPMC PMC7343592

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Abstract

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.

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  • JAKMIP1 is associated with type 2 diabetes and medications used to treat it.

    “associated with type 2 diabetes and medications used to treat it82–84.”

    From Genetic determinants of plasma protein levels in the Estonian population (2024) · cites this paper as [84]

    The Results section on gene–drug relationships discusses type 2 diabetes loci and drug interactions, but does not identify JAKMIP1. Searches for JAKMIP1 and its proposed association with diabetes medications found no passage in our copy addressing that gene. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

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Authors
Vujkovic, M., Keaton, J. M., Lynch, J. A., Miller, D. R., Zhou, J., Tcheandjieu, C., Huffman, J. E., Assimes, T. L., Lorenz, K., Zhu, X., Hilliard, A. T., Judy, R. L., Huang, J., Lee, K. M., Klarin, D., Pyarajan, S., Danesh, J., Melander, O., Rasheed, A., Mallick, N. H., Hameed, S., Qureshi, I. H., Afzal, M. N., Malik, U., Jalal, A., Abbas, S., Sheng, X., Gao, L., Kaestner, K. H., Susztak, K., Sun, Y. V., DuVall, S. L., Cho, K., Lee, J. S., Gaziano, J. M., Phillips, L. S., Meigs, J. B., Reaven, P. D., Wilson, P. W., Edwards, T. L., Rader, D. J., Damrauer, S. M., O’Donnell, C. J., Tsao, P. S., The HPAP Consortium, Atkinson, M. A., Powers, A. C., Naji, A., Kaestner, K. H., Regeneron Genetics Center, Abecasis, G. R., Baras, A., Cantor, M. N., Coppola, G., Economides, A. N., Lotta, L. A., Overton, J. D., Reid, J. G., Shuldiner, A. R., Beechert, C., Forsythe, C., Fuller, E. D., Gu, Z., Lattari, M., Lopez, A. E., Schleicher, T. D., Padilla, M. S., Toledo, K., Widom, L., Wolf, S. E., Pradhan, M., Manoochehri, K., Ulloa, R. H., Bai, X., Balasubramanian, S., Barnard, L., Blumenfeld, A. L., Eom, G., Habegger, L., Hawes, A., Khalid, S., Maxwell, E. K., Salerno, W. J., Staples, J. C., Yadav, A., Jones, M. B., Mitnaul, L. J., Program, V. M. V., Aguayo, S. M., Ahuja, S. K., Ballas, Z. K., Bhushan, S., Boyko, E. J., Cohen, D. M., Concato, J., Constans, J. I., Dellitalia, L. J., Fayad, J. M., Fernando, R. S., Florez, H. J., Gaddy, M. A., Gappy, S. S., Gibson, G., Godschalk, M., Greco, J. A., Gupta, S., Gutierrez, S., Hammer, K. D., Hamner, M. B., Harley, J. B., Hung, A. M., Huq, M., Hurley, R. A., Iruvanti, P. R., Ivins, D. J., Jacono, F. J., Jhala, D. N., Kaminsky, L. S., Kinlay, S., Klein, J. B., Liangpunsakul, S., Lichy, J. H., Mastorides, S. M., Mathew, R. O., Mattocks, K. M., McArdle, R., Meyer, P. N., Meyer, L. J., Moorman, J. P., Morgan, T. R., Murdoch, M., Nguyen, X.-M. T., Okusaga, O. O., Oursler, K.-A. K., Ratcliffe, N. R., Rauchman, M. I., Robey, R. B., Ross, G. W., Servatius, R. J., Sharma, S. C., Sherman, S. E., Sonel, E., Sriram, P., Stapley, T., Striker, R. T., Tandon, N., Villareal, G., Wallbom, A. S., Wells, J. M., Whittle, J. C., Whooley, M. A., Xu, J., Yeh, S.-S., Aslan, M., Brewer, J. V., Brophy, M. T., Connor, T., Argyres, D. P., Do, N. V., Hauser, E. R., Humphries, D. E., Selva, L. E., Shayan, S., Stephens, B., Whitbourne, S. B., Zhao, H., Moser, J., Beckham, J. C., Breeling, J. L., Romero, J. P. C., Huang, G. D., Ramoni, R. B., Pyarajan, S., Sun, Y. V., Cho, K., Wilson, P. W., O’Donnell, C. J., Tsao, P. S., Chang, K.-M., Gaziano, J. M., Muralidhar, S., Chang, K.-M., Voight, B. F., & Saleheen, D.
Affiliations
  • VA Tennessee Valley Healthcare System (US)
  • University of Massachusetts Lowell (US)
  • University of Arizona (US)
  • VA Palo Alto Health Care System (US)
  • VA Boston Healthcare System (US)
  • Philadelphia VA Medical Center (US)
  • Peking University (CN)
  • VA Salt Lake City Healthcare System (US)
  • Broad Institute (US)
  • University of Cambridge (GB)
  • Lund University (SE)
  • Center for Non-Communicable Diseases (PK)
  • Punjab Institute of Cardiology (PK)
  • King Edward Medical University (PK)
  • University of Pennsylvania (US)
  • University of Utah (US)
  • Emory University (US)
  • Nashville VA Medical Center (US)
  • University of Florida Health (US)
  • Regeneron (United States) (US)
  • Phoenix VA Health Care System (US)
  • Iowa City VA Health Care System (US)
  • VA North Texas Health Care System (US)
  • VA Puget Sound Health Care System (US)
  • Portland VA Medical Center (US)
  • VA Connecticut Healthcare System (US)
  • Birmingham VA Medical Center (US)
  • VA Southern Nevada Healthcare System (US)
  • VA Loma Linda Healthcare System (US)
  • VA Eastern Kansas Health Care System (US)
  • John D. Dingell VA Medical Center (US)
  • Hunter Holmes McGuire VA Medical Center (US)
  • VA San Diego Healthcare System (US)
  • Edward Hines, Jr. VA Hospital (US)
  • Ralph H. Johnson VA Medical Center (US)
  • W. G. (Bill) Hefner VA Medical Center (US)
  • Hampton VA Medical Center (US)
  • VA Northeast Ohio Healthcare System (US)
  • New York/New Jersey VA Health Care Network (US)
  • Richard L. Roudebush VA Medical Center (US)
  • James A. Haley Veterans' Hospital (US)
  • Columbia VA Health Care System (US)
  • Bay Pines VA Healthcare System (US)
  • James H. Quillen VA Medical Center (US)
  • Minneapolis VA Health Care System (US)
  • Michael E. DeBakey VA Medical Center (US)
  • Manchester VA Medical Center (US)
  • White River Junction VA Medical Center (US)
  • VA Pacific Islands Health Care System (US)
  • Providence VA Medical Center (US)
  • VA NY Harbor Healthcare System (US)
  • North Florida/South Georgia Veterans Health System (US)
  • William S. Middleton Memorial Veterans Hospital (US)
  • Overton Brooks VA Medical Center (US)
  • New Mexico VA Health Care System (US)
  • Edith Nourse Rogers Memorial Veterans Hospital (US)
  • VA Western New York Healthcare System (US)
  • Raymond G. Murphy VA Medical Center (US)
  • Durham VA Medical Center (US)
  • Harvard University (US)
  • South Texas Veterans Health Care System (US)
  • Columbia University Irving Medical Center (US)
Corresponding author
  • Voight, Benjamin F.
  • Saleheen, Danish
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2020-06-15
Volume
52
Issue
7
Pages
680-691
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-020-0637-y
PMC
PMC7343592
OpenAlex
W3035152464
Cited by
741
References
13
Citations by year
2026: 94 · 2025: 111 · 2024: 147 · 2023: 129 · 2022: 150 · 2021: 94 · 2020: 16
FWCI
14.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • medRxiv (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01-CX001737, IK2-CX001780, I01-BX004821, I01 CX001025, I01-BX003362, MVP000, U01 DK098246)
  • Office of Research and Development (MVP#000, I01-CX001025)
  • University of Pennsylvania
  • Regeneron Pharmaceuticals
  • University of Pennsylvania Health System
  • National Institutes of Health (5t32hl007734-30, 1uc4dk112217-01, HL0-07734, DK101478, T32-HL007734)
  • National Heart, Lung, and Blood Institute (T-32HL007734, HL007734)
  • National Human Genome Research Institute (HG010067, R01HG010067)
  • National Institute of Allergy and Infectious Diseases (R03AI133172)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK101478, UC4-DK-112217, R01DK087635, U01 DK091958, R56DK101478, R21DK099716, R01DK101478, U34DK091958, U01DK098246, UM1DK078616, P30DK111024, P30DK123704)
  • National Institute of Environmental Health Sciences (P30ES006694)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
type 2 diabetes, genetic susceptibility, genetic susceptibility loci, vascular outcomes, diabetic retinopathy, chronic kidney disease, peripheral arterial disease, diabetic neuropathy, coronary artery disease, polygenic risk score, transcriptome-wide association study, drug-gene interactions, Million Veteran Program
MeSH terms
Black or African American, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Europe, Female, Humans, Hypoglycemic Agents, Male, Risk Assessment, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Chromosomes, Human, X, Diabetes Complications, Genetic Association Studies

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