Diversity and Scale: Genetic Architecture of 2,068 Traits in the VA Million Veteran Program.

Genome-wide association studies (GWAS) have underrepresented individuals from non-European populations, impeding progress in characterizing the genetic architecture and consequences of health and disease traits. To address this, we present a population-stratified phenome-wide GWAS followed by a multi-population meta-analysis for 2,068 traits derived from electronic health records of 635,969 participants in the Million Veteran Program (MVP), a longitudinal cohort study of diverse U.S. Veterans genetically similar to the respective African (121,177), Admixed American (59,048), East Asian (6,702), and European (449,042) superpopulations defined by the 1000 Genomes Project. We identified 38,270 independent variants associating with one or more traits at experiment-wide P < 4.6 × 10 - 11 significance; fine-mapping 6,318 signals identified from 613 traits to single-variant resolution. Among these, a third (2,069) of the associations were found only among participants genetically similar to non-European reference populations, demonstrating the importance of expanding diversity in genetic studies. Our work provides a comprehensive atlas of phenome-wide genetic associations for future studies dissecting the architecture of complex traits in diverse populations.
Competing Interests: Competing interests CJD and JPC are employed full-time by the Novartis Institute of Biomedical Interest (their major contributions to this project were while employed at VA Boston Healthcare System). H.K. is a member of advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals; Enthion Pharmaceuticals; and Clearmind Medicine; a consultant to Sobrera Pharmaceuticals; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative; which was supported in the last three years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, Otsuka, and Pear Therapeutics; and holder of U.S. patent 10,900,082 titled: “Genotype-guided dosing of opioid agonists,” issued 26 January 2021. JG and RP are paid for their editorial work in the journal Complex Psychiatry. RP reports a research grant from Alkermes. SD reports grants from Alnylam Pharmaceuticals, Inc, grants from Astellas Pharma, Inc; grants from AstraZeneca Pharmaceuticals LP; grants from Biodesix, grants from Celgene Corporation; grants from Cerner Enviza; grants from GlaxoSmithKline PLC, grants from Janssen Pharmaceuticals, Inc.; grants from Kantar Health; grants from Myriad Genetic Laboratories, Inc.; grants from Novartis International AG; grants from Parexel International Corporation through the University of Utah or Western Institute for Veteran Research outside the submitted work. SMD receives research support from RenalytixAI and Novo Nordisk, outside the scope of the current research, and is named as a co-inventor on a Government-owned US Patent application related to the use of genetic risk prediction for venous thromboembolic disease and for the use of PDE3B inhibition for preventing cardiovascular disease, both filed by the US Department of Veterans Affairs in accordance with Federal regulatory requirements.