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Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program

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Verma, Anurag, Huffman, Jennifer E., Rodriguez, Alex, Conery, Mitchell, Liu, Molei, Ho, Yuk-Lam, Kim, Youngdae, Heise, David A. +63 more·2024·Science
DOI 10.1126/science.adj1182PMC PMC12857194

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Abstract

One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third ( n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.

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  • 220 (84%) of the 261 lead variants had at least one pleiotropic association across 2,068 traits.

    “A total of 220 (84%) lead variants had at least one pleiotropic association (Supplementary Table 13), among which 208 were multi-ancestry lead variants, 8 were European genetic ancestry lead variants and 3 were male sex-stratified lead variants.”

    From Genomic and transcriptomic analyses of aortic stenosis enhance therapeutic target discovery and disease prediction (2026) · cites this paper as [20]

    The Results section, “Cross-trait genetic architecture identifies pleiotropic genes” (page unavailable), reports pleiotropy for genes, not the claimed proportion of lead variants. Searches for 220, 261, 84%, and the ancestry breakdown found no passage in our copy establishing that 220 of 261 lead variants had a pleiotropic association. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Verma, A., Huffman, J. E., Rodriguez, A., Conery, M., Liu, M., Ho, Y.-L., Kim, Y., Heise, D. A., Guare, L., Panickan, V. A., Garcon, H., Linares, F., Costa, L., Goethert, I., Tipton, R., Honerlaw, J., Davies, L., Whitbourne, S., Cohen, J., Posner, D. C., Sangar, R., Murray, M., Wang, X., Dochtermann, D. R., Devineni, P., Shi, Y., Nandi, T. N., Assimes, T. L., Brunette, C. A., Carroll, R. J., Clifford, R., Duvall, S., Gelernter, J., Hung, A., Iyengar, S. K., Joseph, J., Kember, R., Kranzler, H., Kripke, C. M., Levey, D., Luoh, S.-W., Merritt, V. C., Overstreet, C., Deak, J. D., Grant, S. F. A., Polimanti, R., Roussos, P., Shakt, G., Sun, Y. V., Tsao, N., Venkatesh, S., Voloudakis, G., Justice, A., Begoli, E., Ramoni, R., Tourassi, G., Pyarajan, S., Tsao, P., O'Donnell, C. J., Muralidhar, S., Moser, J., Casas, J. P., Bick, A. G., Zhou, W., Cai, T., Voight, B. F., Cho, K., Gaziano, J. M., Madduri, R. K., Damrauer, S., & Liao, K. P.
Affiliations
  • Philadelphia VA Medical Center (US)
  • Harvard University (US)
  • Argonne National Laboratory (US)
  • University of Pennsylvania (US)
  • Columbia University (US)
  • VA Boston Healthcare System (US)
  • Oak Ridge National Laboratory (US)
  • Brigham and Women's Hospital (US)
  • VA Palo Alto Health Care System (US)
  • Vanderbilt University Medical Center (US)
  • University of California San Diego (US)
  • University of Utah (US)
  • Yale University (US)
  • Vanderbilt University (US)
  • Case Western Reserve University (US)
  • Brown University (US)
  • Oregon Health & Science University (US)
  • VA San Diego Healthcare System (US)
  • Children's Hospital of Philadelphia (US)
  • James J. Peters VA Medical Center (US)
  • Emory University (US)
  • United States Department of Veterans Affairs (US)
  • Medicine, Cardiology, VA Boston Healthcare System, Boston, MA 02130, USA.
  • Massachusetts General Hospital (US)
Corresponding author
  • Verma, Anurag
  • Huffman, Jennifer E.
  • Rodriguez, Alex
  • Conery, Mitchell
  • Liu, Molei
  • Cai, Tianxi
  • Voight, Benjamin F.
  • Cho, Kelly
  • Gaziano, J. Michael
  • Madduri, Ravi K.
  • Damrauer, Scott
  • Liao, Katherine P.
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2024-07-19
Volume
385
Issue
6706
Pages
eadj1182-eadj1182
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.adj1182
PMC
PMC12857194
OpenAlex
W4400770247
Cited by
463
References
14
Citations by year
2026: 230 · 2025: 202 · 2024: 29 · 2023: 2
FWCI
122.35
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science (publishedVersion)
  • medRxiv (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (acceptedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
Funders
  • U.S. Department of Energy (AC05-00OR22725, DE--AC05--00OR22725, DE-AC05?, Contract No. DE-AC05-00OR22725, Contract DE-AC05-00OR22725, No. DE-AC05-00OR22725, 00OR22725)
  • U.S. Department of Veterans Affairs (I01-CX001737, IK2-CX001780, DE-AC05-00OR22725, I01-BX004821, UL1TR002548, I01CX001849, BX004189, I01 BX004189, I01CX001849-01, I01 BX005831, MVP000, P30 EY025585, I01 BX003364)
  • Battelle (DE-AC05- 00OR22725, DE-AC05)
  • AstraZeneca
  • GlaxoSmithKline
  • Office of Research and Development (MVP#000)
  • Alnylam Pharmaceuticals
  • Celgene
  • University of Utah
  • American Society of Clinical Psychopharmacology
  • Parexel
  • UT-Battelle (DE-AC05, DEAC05-00OR22725, AC05-00OR22725)
  • Novo Nordisk
  • Astellas Pharma
  • H. Lundbeck A/S
  • National Institutes of Health (DE-AC05-00OR22725, UL1TR002548, EY011373, EY025585)
  • Office of Science (DEAC05- 00OR22725, No. DE-AC05-00OR22725, AC05-00OR22725)
  • Clinical and Translational Science Collaborative of Cleveland, School of Medicine, Case Western Reserve University (UL1TR002548)
  • National Institute on Alcohol Abuse and Alcoholism (T32AA028259)
  • National Institute on Aging (R01AG065582, R01AG067025)
  • National Institute of Mental Health (K08MH122911)
  • National Human Genome Research Institute (K99HG012222, R00HG012222)
  • National Eye Institute (P30EY011373, P30EY025585)
  • National Institute of General Medical Sciences (R01GM138597, DE-AC05-00OR22725)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK126194, UM1DK126194)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR072577)
  • U.S. National Library of Medicine (R01LM010685)
  • National Center for Advancing Translational Sciences
  • Janssen Pharmaceuticals
  • Oak Ridge National Laboratory (AC05-00OR22725, Contract No. DE-AC05-00OR22725, DE-AC05-00OR22725)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Race, Genetics, and Society
Keywords
Million Veteran Program, genetic architecture, genome-wide association study, genetic susceptibility loci, fine mapping, non-European populations, underrepresented groups, health disparities, veterans, causal variants

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