Journal article
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
Nature genetics, Vol.52(7), pp.680-691
07/01/2020
DOI: 10.1038/s41588-020-0637-y
PMCID: PMC7343592
PMID: 32541925
Abstract
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.
Details
- Title: Subtitle
- 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
- Creators
- Marijana Vujkovic - University of PennsylvaniaJacob M. Keaton - Tennessee Valley Healthcare Syst, Biomed Lab Res & Dev, Nashville, TN USAJulie A. Lynch - VA Salt Lake City Hlth Care Syst, VA Informat & Comp Infrastruct, Salt Lake City, UT USADonald R. Miller - Edith Nourse Rogers Memorial Veterans HospitalJin Zhou - Phoenix VA Health Care SystemCatherine Tcheandjieu - VA Palo Alto Hlth Care Syst, Palo Alto, CA USAJennifer E. Huffman - VA Boston Healthcare Syst, Boston, MA USAThemistocles L. Assimes - VA Palo Alto Hlth Care Syst, Palo Alto, CA USAKimberly Lorenz - University of PennsylvaniaXiang Zhu - VA Palo Alto Hlth Care Syst, Palo Alto, CA USAAustin T. Hilliard - VA Palo Alto Hlth Care Syst, Palo Alto, CA USARenae L. Judy - University of PennsylvaniaJie Huang - VA Boston Healthcare Syst, Boston, MA USAKyung M. Lee - VA Salt Lake City Hlth Care Syst, VA Informat & Comp Infrastruct, Salt Lake City, UT USADerek Klarin - VA Boston Healthcare Syst, Boston, MA USASaiju Pyarajan - VA Boston Healthcare Syst, Boston, MA USAJohn Danesh - University of CambridgeOlle Melander - Lund UniversityAsif Rasheed - Ctr Noncommunicable Dis, Karachi, Sindh, PakistanNadeem H. Mallick - Punjab Inst Cardiol, Lahore, Punjab, PakistanShahid Hameed - Punjab Inst Cardiol, Lahore, Punjab, PakistanIrshad H. Qureshi - Mayo HospitalMuhammad Naeem Afzal - Mayo HospitalUzma Malik - Mayo HospitalAnjum Jalal - Faisalabad Inst Cardiol, Dept Cardiol, Faisalabad, Punjab, PakistanShahid Abbas - Faisalabad Inst Cardiol, Dept Cardiol, Faisalabad, Punjab, PakistanXin Sheng - University of PennsylvaniaLong Gao - University of PennsylvaniaKlaus H. Kaestner - University of PennsylvaniaKatalin Susztak - University of PennsylvaniaYan V. Sun - Emory UniversityScott L. DuVall - VA Salt Lake City Hlth Care Syst, VA Informat & Comp Infrastruct, Salt Lake City, UT USAKelly Cho - VA Boston Healthcare Syst, Boston, MA USAJennifer S. Lee - VA Palo Alto Hlth Care Syst, Palo Alto, CA USAJ. Michael Gaziano - VA Boston Healthcare Syst, Boston, MA USALawrence S. Phillips - Emory UniversityJames B. Meigs - Broad InstitutePeter D. Reaven - Phoenix VA Health Care SystemPeter W. Wilson - Emory UniversityTodd L. Edwards - Vanderbilt UniversityDaniel J. Rader - University of PennsylvaniaScott M. Damrauer - University of PennsylvaniaChristopher J. O'Donnell - VA Boston Healthcare Syst, Boston, MA USAPhilip S. Tsao - VA Palo Alto Hlth Care Syst, Palo Alto, CA USAKyong-Mi Chang - Philadelphia VA Medical CenterBenjamin F. Voight - Philadelphia VA Medical CenterDanish Saleheen - Ctr Noncommunicable Dis, Karachi, Sindh, PakistanRegeneron Genetics Center
- Contributors
- Zuhair K Ballas (Contributor) - University of Iowa, Immunology
- Resource Type
- Journal article
- Publication Details
- Nature genetics, Vol.52(7), pp.680-691
- DOI
- 10.1038/s41588-020-0637-y
- PMID
- 32541925
- PMCID
- PMC7343592
- NLM abbreviation
- Nat Genet
- ISSN
- 1061-4036
- eISSN
- 1546-1718
- Publisher
- Springer Nature
- Number of pages
- 21
- Grant note
- I01-BX003362; I01-CX001025; I01CX001737 / VA award IK2-CX001780 / Veterans Administration; US Department of Veterans Affairs UC4-DK-112217; R01 DK087635; R21DK099716; U01 DK091958; U01 DK098246; P30DK111024; R03AI133172 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA VA Cooperative Studies Program PHILLI12A0 / Cystic Fibrosis Foundation award HG010067 / NIH National Human Genome Research Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) T32 HL007734 / National Heart, Lung, and Blood Institute of the NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) Linda Pechenik Montague Investigator award DK101478 / National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) MVP000 / MVP, Office of Research and Development, Veterans Health Administration 130457 / VA Informatics and Computing Infrastructure (VINCI) VA HSR RES
- Language
- English
- Date published
- 07/01/2020
- Academic Unit
- Immunology; Internal Medicine
- Record Identifier
- 9984359946802771
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