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

Sheng, Xin, Voight, Benjamin F., Meigs, James B., Lorenz, Kimberly, Tsao, Philip S., Kaestner, Klaus H., DuVall, Scott L., Tcheandjieu, Catherine, Assimes, Themistocles L., Qureshi, Irshad H., Zhu, Xiang, Sun, Yan V., Miller, Donald R., Rasheed, Asif, Lynch, Julie A., Susztak, Katalin, Danesh, John, Gao, Long, Damrauer, Scott M., Chang, Kyong-Mi, Jalal, Anjum, Melander, Olle, Lee, Jennifer S., Cho, Kelly, Hameed, Shahid, Wilson, Peter W., Vujkovic, Marijana, Huang, Jie, Saleheen, Danish, Reaven, Peter D., Rader, Daniel J., Afzal, Muhammad Naeem, Judy, Renae L., Pyarajan, Saiju, Klarin, Derek, Gaziano, J. Michael, Lee, Kyung M., Malik, Uzma, Huffman, Jennifer E., Abbas, Shahid, Mallick, Nadeem H., Keaton, Jacob M., Zhou, Jin, Hilliard, Austin T., Phillips, Lawrence S., O’Donnell, Christopher J., Edwards, Todd L.

2020

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/205/2138 / 631/208/457 / 692/699/2743/137 / African Americans / Agriculture / Animal Genetics and Genomics / Asian people / Association analysis / Basic Medicine / Biobanks / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cardiovascular disease / Cardiovascular diseases / Chromosomes, Human, X / Clinical Medicine / Coronary artery disease / Diabetes / Diabetes Complications - genetics / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - complications / Diabetes Mellitus, Type 2 - drug therapy / Diabetes Mellitus, Type 2 - ethnology / Diabetes Mellitus, Type 2 - genetics / Diabetic Angiopathies - genetics / Diabetic neuropathy / Drug development / Endocrinology and Diabetes / Endokrinologi och diabetes / Etiology / Europe / Female / Gene expression / Gene Function / Genetic analysis / Genetic Association Studies / Genetic Predisposition to Disease / Genomes / Heart diseases / Hispanic people / Human Genetics / Humans / Hypoglycemic Agents - therapeutic use / Kidney diseases / Klinisk medicin / Male / Medical and Health Sciences / Medical Genetics and Genomics (including Gene Therapy) / Medicin och hälsovetenskap / Medicinsk genetik och genomik (Här ingår: Genterapi) / Medicinska och farmaceutiska grundvetenskaper / Meta-analysis / Metabolism / Polymorphism, Single Nucleotide / Retinopathy / Risk / Risk Assessment / Single-nucleotide polymorphism / Studies / Target recognition / Therapeutic applications / Vascular diseases / X chromosomes