African ancestry GWAS of dementia in a large military cohort identifies significant risk loci
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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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The MVP cohort used in this study was assembled for an African-ancestry dementia genome-wide association study described by Sherva et al.
“The MVP cohort used herein was assembled for an African-ancestry dementia genome-wide association study described by Sherva et al. 17”
From Association of African Ancestry–Specific <i>APOE</i> Missense Variant R145C With Risk of Alzheimer Disease (2023) · cites this paper as [17]
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1 retracted
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“Neither the ABCA7 frameshift deletion reported in Cukier et al. [34] (rs142076058), nor the insertion/deletion polymorphism in the gene reported by Logue et al. (rs567222111) [16] were nominally significant in the combined MVP sample (p > 0.05).”
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Self-citationArtificial intelligence for dementia genetics and omics
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- Authors
- Sherva, R., Zhang, R., Sahelijo, N., Jun, G., Anglin, T., Chanfreau, C., Cho, K., Fonda, J. R., Gaziano, J. M., Harrington, K. M., Ho, Y.-L., Kremen, W. S., Litkowski, E., Lynch, J., Neale, Z., Roussos, P., Marra, D., Mez, J., Miller, M. W., Salat, D. H., Tsuang, D., Wolf, E., Zeng, Q., Panizzon, M. S., Merritt, V. C., Farrer, L. A., Hauger, R. L., & Logue, M. W.
- Affiliations
- Boston University (US)
- VA Boston Healthcare System (US)
- Brigham and Women's Hospital (US)
- University of California San Diego (US)
- VA Eastern Colorado Health Care System (US)
- Nathan Kline Institute for Psychiatric Research (US)
- VA Puget Sound Health Care System (US)
- Washington DC VA Medical Center (US)
- Corresponding author
- Logue, Mark W.
- ORCID
- Sherva, Richard
- Zhang, Rui
- Sahelijo, Nathan
- Jun, Gyungah
- Anglin, Tori
- Chanfreau, Catherine
- Cho, Kelly
- Fonda, Jennifer R.
- Gaziano, J. Michael
- Harrington, Kelly M.
- Ho, Yuk-Lam
- Kremen, William S.
- Litkowski, Elizabeth
- Lynch, Julie
- Neale, Zoe
- Roussos, Panos
- Marra, David
- Mez, Jesse
- Miller, Mark W.
- Salat, David H.
- Tsuang, Debby
- Wolf, Erika
- Zeng, Qing
- Panizzon, Matthew S.
- Merritt, Victoria C.
- Farrer, Lindsay A.
- Hauger, Richard L.
- Logue, Mark W.
- Venue
- Molecular Psychiatry
- Published
- 2022-12-22
- Volume
- 28
- Issue
- 3
- Pages
- 1293-1302
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC10066923
- OpenAlex
- W4312128743
- Cited by
- 68
- References
- 11
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 20 · 2023: 14 · 2022: 1
- FWCI
- 2.32
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Molecular Psychiatry (publishedVersion)
- medRxiv (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX004192, IK2 CX002192, I01 CX001727)
- Office of Research and Development
- National Institute on Aging (R01AG064955, U01AG032984, R01AG050595, R01AG076838)
- National Institute of Mental Health (T32MH019836)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, dementia, African ancestry, Alzheimer's disease and related dementias, genetic susceptibility loci, apolipoprotein E, ROBO1, TREM2, CD2AP, ABCA7, Million Veteran Program, military veterans, genetic variants, non-European populations, vascular dementia, gene-environment interaction
- MeSH terms
- Aged, Alzheimer Disease, Black or African American, Dementia, Genotype, Humans, Middle Aged, Military Personnel, Polymorphism, Genetic, United States, Genetic Predisposition to Disease, Gene Expression Profiling, Databases, Genetic, Genome-Wide Association Study
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