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African ancestry GWAS of dementia in a large military cohort identifies significant risk loci

Molecular Psychiatry volume 28, pages 1293–1302 (2023)Cite this article

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Abstract

While genome wide association studies (GWASs) of Alzheimer’s Disease (AD) in European (EUR) ancestry cohorts have identified approximately 83 potentially independent AD risk loci, progress in non-European populations has lagged. In this study, data from the Million Veteran Program (MVP), a biobank which includes genetic data from more than 650,000 US Veteran participants, was used to examine dementia genetics in an African descent (AFR) cohort. A GWAS of Alzheimer’s disease and related dementias (ADRD), an expanded AD phenotype including dementias such as vascular and non-specific dementia that included 4012 cases and 18,435 controls age 60+ in AFR MVP participants was performed. A proxy dementia GWAS based on survey-reported parental AD or dementia (n = 4385 maternal cases, 2256 paternal cases, and 45,970 controls) was also performed. These two GWASs were meta-analyzed, and then subsequently compared and meta-analyzed with the results from a previous AFR AD GWAS from the Alzheimer’s Disease Genetics Consortium (ADGC). A meta-analysis of common variants across the MVP ADRD and proxy GWASs yielded GWAS significant associations in the region of APOE (p = 2.48 × 10−101), in ROBO1 (rs11919682, p = 1.63 × 10−8), and RNA RP11-340A13.2 (rs148433063, p = 8.56 × 10−9). The MVP/ADGC meta-analysis yielded additional significant SNPs near known AD risk genes TREM2 (rs73427293, p = 2.95 × 10−9), CD2AP (rs7738720, p = 1.14 × 10−9), and ABCA7 (rs73505251, p = 3.26 × 10−10), although the peak variants observed in these genes differed from those previously reported in EUR and AFR cohorts. Of the genes in or near suggestive or genome-wide significant associated variants, nine (CDA, SH2D5, DCBLD1, EML6, GOPC, ABCA7, ROS1, TMCO4, and TREM2) were differentially expressed in the brains of AD cases and controls. This represents the largest AFR GWAS of AD and dementia, finding non-APOE GWAS-significant common SNPs associated with dementia. Increasing representation of AFR participants is an important priority in genetic studies and may lead to increased insight into AD pathophysiology and reduce health disparities.

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Fig. 1: Manhattan and quantile-quantile plots for the meta-analysis of the Alzheimer’s disease and related dementias and proxy dementia genome-wide association studies in Million Veterans Program African Americans.
Fig. 2: Manhattan and quantile-quantile plots for the meta-analysis of the Alzheimer’s disease and related dementias and proxy dementia genome-wide association studies in Million Veterans Program African Americans and the Alzheimer’s disease genome-wide association study in Alzheimer’s Disease Genetics Consortium African Americans.

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Data availability

The data underlying this publication is accessible to researchers with MVP data access. MVP is currently only accessible to researchers an approved funded MVP project, either through a VA Merit Award or a career development award. See https://www.research.va.gov/funding/Guidance-MVP-Data-Access-Merit-Award.pdf and for details. Summary statistics of the ADRD and proxy GWASs will be made publicly available on dbGAP.

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Author contributions

Conceptualization: MWL, RS, LAF, VM, MSP, RLH. Formal Analysis: RZ, RS, NS Data Curation: RS, RZ. Data interpretation: RS, RZ, LAF, MWL. Methodology: All authors. Funding Acquisition: MWL, Visualization: MWL, Writing – Original draft: RS, MWL, LAF Writing- editing and approval of the manuscript: All authors. Resources: JMG.

Funding

This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by VA BLR&D grant 1 I01 BX004192 (MVP015). ZN was supported by National Institute of Mental Health award T32MH019836. JRF was supported by VA CSR&D grant 1IK2CX002192-01A2. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the US government.

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Authors and Affiliations

  1. National Center for PTSD, Behavioral Sciences Division, VA Boston Healthcare System, Boston, MA, USA

    Richard Sherva, Rui Zhang, Zoe Neale, Mark W. Miller, Erika Wolf & Mark W. Logue

  2. Boston University Chobanian & Avedisian School of Medicine, Biomedical Genetics, Boston, MA, USA

    Richard Sherva, Nathan Sahelijo, Gyungah Jun, Jesse Mez, Lindsay A. Farrer & Mark W. Logue

  3. VA Informatics and Computing Infrastructure (VINCI), Salt Lake City, UT, USA

    Tori Anglin, Catherine Chanfreau & Julie Lynch

  4. Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA

    Kelly Cho, J. Michael Gaziano, Kelly M. Harrington, Yuk-Lam Ho & David Marra

  5. Division of Aging, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Kelly Cho & J. Michael Gaziano

  6. Department of Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, 02118, USA

    Jennifer R. Fonda, Kelly M. Harrington, Zoe Neale, David Marra, Mark W. Miller, Erika Wolf & Mark W. Logue

  7. Translational Research Center for TBI and Stress Disorders (TRACTS) and Geriatric Research, Educational and Clinical Center (GRECC), VA Boston Healthcare System, Boston, MA, USA

    Jennifer R. Fonda

  8. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    Jennifer R. Fonda

  9. Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, CA, USA

    William S. Kremen, Matthew S. Panizzon, Victoria C. Merritt & Richard L. Hauger

  10. Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla, CA, USA

    William S. Kremen, Matthew S. Panizzon & Richard L. Hauger

  11. Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Elizabeth Litkowski

  12. VA Eastern Colorado Healthcare System, Aurora, CO, USA

    Elizabeth Litkowski

  13. Center for Disease Neurogenomics, Departments of Psychiatry and Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Panos Roussos

  14. Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA

    Panos Roussos

  15. Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, New York, NY, USA

    Panos Roussos

  16. Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA

    Jesse Mez & Lindsay A. Farrer

  17. Boston University Alzheimer’s Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA

    Jesse Mez & Lindsay A. Farrer

  18. Neuroimaging Research for Veterans Center, VA Boston Healthcare System, Boston, MA, USA

    David H. Salat

  19. Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA

    Debby Tsuang

  20. VA Washington DC Healthcare System, Washington, DC, USA

    Qing Zeng

  21. Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, San Diego, CA, USA

    Matthew S. Panizzon & Victoria C. Merritt

  22. VA San Diego Healthcare System, 3350 La Jolla Village Dr, San Diego, CA, USA

    Victoria C. Merritt & Richard L. Hauger

  23. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

    Lindsay A. Farrer & Mark W. Logue

  24. Department of Ophthalmology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA

    Lindsay A. Farrer

  25. Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA

    Lindsay A. Farrer

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Sherva, R., Zhang, R., Sahelijo, N. et al. African ancestry GWAS of dementia in a large military cohort identifies significant risk loci. Mol Psychiatry 28, 1293–1302 (2023). https://doi.org/10.1038/s41380-022-01890-3

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