TY - JOUR
T1 - African ancestry GWAS of dementia in a large military cohort identifies significant risk loci
AU - Sherva, Richard
AU - Zhang, Rui
AU - Sahelijo, Nathan
AU - Jun, Gyungah
AU - Anglin, Tori
AU - Chanfreau, Catherine
AU - Cho, Kelly
AU - Fonda, Jennifer R.
AU - Gaziano, J. Michael
AU - Harrington, Kelly M.
AU - Ho, Yuk Lam
AU - Kremen, William S.
AU - Litkowski, Elizabeth
AU - Lynch, Julie
AU - Neale, Zoe
AU - Roussos, Panos
AU - Marra, David
AU - Mez, Jesse
AU - Miller, Mark W.
AU - Salat, David H.
AU - Tsuang, Debby
AU - Wolf, Erika
AU - Zeng, Qing
AU - Panizzon, Matthew S.
AU - Merritt, Victoria C.
AU - Farrer, Lindsay A.
AU - Hauger, Richard L.
AU - Logue, Mark W.
N1 - Publisher Copyright:
© 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2023/3
Y1 - 2023/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85144527881&partnerID=8YFLogxK
U2 - 10.1038/s41380-022-01890-3
DO - 10.1038/s41380-022-01890-3
M3 - Article
AN - SCOPUS:85144527881
SN - 1359-4184
VL - 28
SP - 1293
EP - 1302
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 3
ER -