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

Anurag Verma^#^{1

2

3}, Jennifer E Huffman^#^{4

5

6}, Alex Rodriguez^#⁷, Mitchell Conery^#⁸, Molei Liu^#⁹, Yuk-Lam Ho⁴, Youngdae Kim¹⁰, David A Heise¹¹, Lindsay Guare², Vidul Ayakulangara Panickan¹², Helene Garcon⁴, Franciel Linares¹³, Lauren Costa¹⁴, Ian Goethert¹⁵, Ryan Tipton¹⁶, Jacqueline Honerlaw⁴, Laura Davies¹⁷, Stacey Whitbourne^{6

14

18}, Jeremy Cohen¹¹, Daniel C Posner⁴, Rahul Sangar¹⁴, Michael Murray¹⁴, Xuan Wang^{12

19}, Daniel R Dochtermann²⁰, Poornima Devineni²⁰, Yunling Shi²⁰, Tarak Nath Nandi⁷, Themistocles L Assimes²¹, Charles A Brunette^{6

22}, Robert J Carroll²³, Royce Clifford^{24

25}, Scott Duvall^{26

27}, Joel Gelernter^{28

29}, Adriana Hung³⁰, Sudha K Iyengar³¹, Jacob Joseph^{32

33}, Rachel Kember^{34

35}, Henry Kranzler^{34

35}, Colleen M Kripke², Daniel Levey^{28

36}, Shiuh-Wen Luoh^{37

38}, Victoria C Merritt²⁴, Cassie Overstreet²⁸, Joseph D Deak^{39

40}, Struan F A Grant^{41

42

43

44}, Renato Polimanti³⁹, Panos Roussos⁴⁵, Gabrielle Shakt^{1

46}, Yan V Sun⁴⁷, Noah Tsao^{1

46}, Sanan Venkatesh⁴⁵, Georgios Voloudakis⁴⁵, Amy Justice^{36

48

49}, Edmon Begoli⁵⁰, Rachel Ramoni⁵¹, Georgia Tourassi⁵², Saiju Pyarajan²⁰, Philip Tsao^{21

53}, Christopher J O'Donnell⁵⁴, Sumitra Muralidhar⁵¹, Jennifer Moser⁵¹, Juan P Casas⁴, Alexander G Bick⁵⁵, Wei Zhou^{56

57

58}, Tianxi Cai^#¹², Benjamin F Voight^#^{1

8

44

59}, Kelly Cho^#^{6

14

18}, J Michael Gaziano^#^{6

14

18}, Ravi K Madduri^#⁷, Scott Damrauer^#^{1

44

46

60}, Katherine P Liao^#^{4

6

12

61

62}

Affiliations

¹ Corporal Michael Crescenz VA Medical Center, Philadelphia, PA 19104, USA.
² Department of Medicine, Division of Translational Medicine and Human Genetics, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA.
³ Institute for Biomedical Informatics, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁴ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA 02130, USA.
⁵ Palo Alto Veterans Institute for Research (PAVIR), Palo Alto Health Care System, Palo Alto, CA 94304, USA.
⁶ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁷ Data Science and Learning, Argonne National Laboratory, Lemont, IL 60439, USA.
⁸ Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁹ Department of Biostatistics, Columbia University's Mailman School of Public Health, New York, NY 10032, USA.
¹⁰ Mathematics and Computer Science Division, Argonne National Laboratory, Lemont, IL 60439, USA.
¹¹ National Security Sciences Directorate, Cyber Resilience and Intelligence Division, Oak Ridge National Laboratory, Dept of Energy, Oak Ridge, TN 37831, USA.
¹² Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
¹³ R&D Systems Engineering, Information Technology Services Directorate, Oak Ridge National Laboratory, Dept of Energy, Oak Ridge, TN 37831, USA.
¹⁴ MVP Boston Coordinating Center, VA Boston Healthcare System, Boston, MA 02111, USA.
¹⁵ Data Management and Engineering, Information Technology Services Division, Oak Ridge National Laboratory, Dept of Energy, Oak Ridge, TN 37831, USA.
¹⁶ Knowledge Discovery Infrastructure, Information Technology Services Division, Oak Ridge National Laboratory, Dept of Energy, Oak Ridge, TN 37831, USA.
¹⁷ Computing and Computational Sciences Dir PMO, PMO, Oak Ridge National Laboratory, Dept of Energy, Oak Ridge, TN 37831, USA.
¹⁸ Department of Medicine, Division of Aging, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹⁹ Department of Population Health Sciences, University of Utah, Salt Lake City, UT 84112, USA.
²⁰ VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA 02130, USA.
²¹ Medicine, Cardiology, VA Palo Alto Healthcare System, Palo Alto, CA 94304, USA.
²² Research Service, VA Boston Healthcare System, Boston, MA 02130, USA.
²³ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37211, USA.
²⁴ Research Department, VA San Diego Healthcare System, San Diego, CA 92161, USA.
²⁵ Department of Otolaryngology, UCSD San Diego, La Jolla, CA 92093, USA.
²⁶ VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT 84148, USA.
²⁷ Internal Medicine, Epidemiology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
²⁸ Psychiatry, Human Genetics, Yale University, New Haven, CT, 06520, USA.
²⁹ VA Connecticut Healthcare System West Haven, West Haven, CT, 06516, USA.
³⁰ Medicine, Nephrology & Hypertension, VA Tennessee Valley Healthcare System & Vanderbilt University, Nashville, TN 37232, USA.
³¹ Departments of Population and Quantitative Health Sciences, Genetics and Genome Sciences, and Ophthalmology and Visual Sciences and the Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
³² Medicine, Cardiology Section, VA Providence Healthcare System, Providence, RI 02908, USA.
³³ Department of Medicine, Brown University, Providence, RI, 02908, USA.
³⁴ Mental Illness Research, Education and Clinical Center, Corporal Michael Crescenz VA Medical Center, Philadelphia, PA 19104, USA.
³⁵ Department of Psychiatry, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA.
³⁶ Medicine, VA Connecticut Healthcare System West Haven, West Haven, CT 06516, USA.
³⁷ VA Portland Health Care System, Portland, OR 97239, USA.
³⁸ Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
³⁹ Psychiatry, Yale University, New Haven, CT 06520, USA.
⁴⁰ Psychiatry, VA Connecticut Healthcare System West Haven, West Haven, CT 06516, USA.
⁴¹ Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴² Department of Pediatrics, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁴³ Divisions of Human Genetics and Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴⁴ Department of Genetics, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁴⁵ Psychiatry, Mental Illness Research, Education and Clinical Center, James J. Peters VA Medical Center; Icahn School of Medicine at Mount Sinai, Bronx, NY 10468, USA.
⁴⁶ Department of Surgery, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁴⁷ Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA 30322, USA.
⁴⁸ Internal Medicine, General Medicine, Yale University, New Haven, CT 06520, USA.
⁴⁹ Health Policy, Yale School of Public Health, New Haven, CT 06520, USA.
⁵⁰ Oak Ridge National Laboratory, Dept of Energy, Oak Ridge, TN, 37831, USA.
⁵¹ Office of Research and Development, Department of Veterans Affairs, Washington, DC, 20420, USA.
⁵² National Center for Computational Sciences, Oak Ridge National Laboratory, Dept of Energy, Oak Ridge, TN, 37831, USA.
⁵³ Department of Medicine, Stanford University, Palo Alto, CA, 94304, USA.
⁵⁴ Medicine, Cardiology, VA Boston Healthcare System, Boston, MA 02130, USA.
⁵⁵ Department of Medicine, Division of Genetic Medicine, Vanderbilt University, Nashville, TN, 37325, USA.
⁵⁶ Department of Medicine, Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵⁷ Stanley Center for Psychiatric Research, Cambridge, MA 02142, USA.
⁵⁸ Program in Medical and Population Genetics, Cambridge, MA 02142, USA.
⁵⁹ Institute of Translational Medicine and Therapeutics, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁶⁰ Cardiovascular Institute, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁶¹ Medicine, Rheumatology, VA Boston Healthcare System, Boston, MA 02130, USA.
⁶² Department of Medicine, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA 02115, USA.

^# Contributed equally.

PMID: 39024449
DOI: 10.1126/science.adj1182

Free article

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

Anurag Verma et al. Science. 2024.

Free article

. 2024 Jul 19;385(6706):eadj1182.

doi: 10.1126/science.adj1182. Epub 2024 Jul 19.

Authors

Affiliations

¹ Corporal Michael Crescenz VA Medical Center, Philadelphia, PA 19104, USA.
² Department of Medicine, Division of Translational Medicine and Human Genetics, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA.
³ Institute for Biomedical Informatics, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁴ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA 02130, USA.
⁵ Palo Alto Veterans Institute for Research (PAVIR), Palo Alto Health Care System, Palo Alto, CA 94304, USA.
⁶ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁷ Data Science and Learning, Argonne National Laboratory, Lemont, IL 60439, USA.
⁸ Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁹ Department of Biostatistics, Columbia University's Mailman School of Public Health, New York, NY 10032, USA.
¹⁰ Mathematics and Computer Science Division, Argonne National Laboratory, Lemont, IL 60439, USA.
¹¹ National Security Sciences Directorate, Cyber Resilience and Intelligence Division, Oak Ridge National Laboratory, Dept of Energy, Oak Ridge, TN 37831, USA.
¹² Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
¹³ R&D Systems Engineering, Information Technology Services Directorate, Oak Ridge National Laboratory, Dept of Energy, Oak Ridge, TN 37831, USA.
¹⁴ MVP Boston Coordinating Center, VA Boston Healthcare System, Boston, MA 02111, USA.
¹⁵ Data Management and Engineering, Information Technology Services Division, Oak Ridge National Laboratory, Dept of Energy, Oak Ridge, TN 37831, USA.
¹⁶ Knowledge Discovery Infrastructure, Information Technology Services Division, Oak Ridge National Laboratory, Dept of Energy, Oak Ridge, TN 37831, USA.
¹⁷ Computing and Computational Sciences Dir PMO, PMO, Oak Ridge National Laboratory, Dept of Energy, Oak Ridge, TN 37831, USA.
¹⁸ Department of Medicine, Division of Aging, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹⁹ Department of Population Health Sciences, University of Utah, Salt Lake City, UT 84112, USA.
²⁰ VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA 02130, USA.
²¹ Medicine, Cardiology, VA Palo Alto Healthcare System, Palo Alto, CA 94304, USA.
²² Research Service, VA Boston Healthcare System, Boston, MA 02130, USA.
²³ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37211, USA.
²⁴ Research Department, VA San Diego Healthcare System, San Diego, CA 92161, USA.
²⁵ Department of Otolaryngology, UCSD San Diego, La Jolla, CA 92093, USA.
²⁶ VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT 84148, USA.
²⁷ Internal Medicine, Epidemiology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
²⁸ Psychiatry, Human Genetics, Yale University, New Haven, CT, 06520, USA.
²⁹ VA Connecticut Healthcare System West Haven, West Haven, CT, 06516, USA.
³⁰ Medicine, Nephrology & Hypertension, VA Tennessee Valley Healthcare System & Vanderbilt University, Nashville, TN 37232, USA.
³¹ Departments of Population and Quantitative Health Sciences, Genetics and Genome Sciences, and Ophthalmology and Visual Sciences and the Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
³² Medicine, Cardiology Section, VA Providence Healthcare System, Providence, RI 02908, USA.
³³ Department of Medicine, Brown University, Providence, RI, 02908, USA.
³⁴ Mental Illness Research, Education and Clinical Center, Corporal Michael Crescenz VA Medical Center, Philadelphia, PA 19104, USA.
³⁵ Department of Psychiatry, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA.
³⁶ Medicine, VA Connecticut Healthcare System West Haven, West Haven, CT 06516, USA.
³⁷ VA Portland Health Care System, Portland, OR 97239, USA.
³⁸ Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.
³⁹ Psychiatry, Yale University, New Haven, CT 06520, USA.
⁴⁰ Psychiatry, VA Connecticut Healthcare System West Haven, West Haven, CT 06516, USA.
⁴¹ Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴² Department of Pediatrics, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁴³ Divisions of Human Genetics and Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
⁴⁴ Department of Genetics, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁴⁵ Psychiatry, Mental Illness Research, Education and Clinical Center, James J. Peters VA Medical Center; Icahn School of Medicine at Mount Sinai, Bronx, NY 10468, USA.
⁴⁶ Department of Surgery, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁴⁷ Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA 30322, USA.
⁴⁸ Internal Medicine, General Medicine, Yale University, New Haven, CT 06520, USA.
⁴⁹ Health Policy, Yale School of Public Health, New Haven, CT 06520, USA.
⁵⁰ Oak Ridge National Laboratory, Dept of Energy, Oak Ridge, TN, 37831, USA.
⁵¹ Office of Research and Development, Department of Veterans Affairs, Washington, DC, 20420, USA.
⁵² National Center for Computational Sciences, Oak Ridge National Laboratory, Dept of Energy, Oak Ridge, TN, 37831, USA.
⁵³ Department of Medicine, Stanford University, Palo Alto, CA, 94304, USA.
⁵⁴ Medicine, Cardiology, VA Boston Healthcare System, Boston, MA 02130, USA.
⁵⁵ Department of Medicine, Division of Genetic Medicine, Vanderbilt University, Nashville, TN, 37325, USA.
⁵⁶ Department of Medicine, Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵⁷ Stanley Center for Psychiatric Research, Cambridge, MA 02142, USA.
⁵⁸ Program in Medical and Population Genetics, Cambridge, MA 02142, USA.
⁵⁹ Institute of Translational Medicine and Therapeutics, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁶⁰ Cardiovascular Institute, University of Pennsylvania - Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁶¹ Medicine, Rheumatology, VA Boston Healthcare System, Boston, MA 02130, USA.
⁶² Department of Medicine, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA 02115, USA.

^# Contributed equally.

PMID: 39024449
DOI: 10.1126/science.adj1182

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.

PubMed Disclaimer

Update of

Diversity and Scale: Genetic Architecture of 2,068 Traits in the VA Million Veteran Program.
Verma A, Huffman JE, Rodriguez A, Conery M, Liu M, Ho YL, Kim Y, Heise DA, Guare L, Panickan VA, Garcon H, Linares F, Costa L, Goethert I, Tipton R, Honerlaw J, Davies L, Whitbourne S, Cohen J, Posner DC, Sangar R, Murray M, Wang X, Dochtermann DR, Devineni P, Shi Y, Nandi TN, Assimes TL, Brunette CA, Carroll RJ, Clifford R, Duvall S, Gelernter J, Hung A, Iyengar SK, Joseph J, Kember R, Kranzler H, Levey D, Luoh SW, Merritt VC, Overstreet C, Deak JD, Grant SFA, Polimanti R, Roussos P, Sun YV, Venkatesh S, Voloudakis G, Justice A, Begoli E, Ramoni R, Tourassi G, Pyarajan S, Tsao PS, O'Donnell CJ, Muralidhar S, Moser J, Casas JP, Bick AG, Zhou W, Cai T, Voight BF, Cho K, Gaziano MJ, Madduri RK, Damrauer SM, Liao KP. Verma A, et al. medRxiv [Preprint]. 2023 Jun 29:2023.06.28.23291975. doi: 10.1101/2023.06.28.23291975. medRxiv. 2023. Update in: Science. 2024 Jul 19;385(6706):eadj1182. doi: 10.1126/science.adj1182. PMID: 37425708 Free PMC article. Updated. Preprint.

Comment in

Genomic diversity improves disease discovery for all.
Williamson A, Fatumo S. Williamson A, et al. Science. 2024 Jul 19;385(6706):255-256. doi: 10.1126/science.adq7784. Epub 2024 Jul 18. Science. 2024. PMID: 39024460

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

Affiliations

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

Authors

Affiliations

Abstract

Update of

Comment in

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources