Novel Loci for Alzheimer Disease Identified by Genome Wide Association Study in Ashkenazi Jews

Abstract Background Previous studies identified associations of Alzheimer’s disease (AD) risk primarily in outbred European ancestry (EA) populations. We focused on Ashkenazi Jews (AJs) who descended from a founder population in eastern Europe. Method We discriminated AJs in the multiethnic Alzheimer’s Disease Genetic Consortium (ADGC) TOPMed imputed GWAS dataset (n = 53,502) and whole genome sequencing (WGS, n = 16,815) and whole exome sequencing (WES, n = 20,504) datasets assembled by the Alzheimer’s Disease Sequencing Project using a reference GWAS dataset including persons with four AJ grandparents (n = 3,435). Principal component (PC) analysis was performed for each AD dataset combined with the AJ reference data, and a Gaussian mixture model was applied for population clustering. GWA analyses were performed by combining AJs discriminated from the ADGC and WGS subjects (G1) using genome‐wide data and from all three datasets using variants called from exome capture (G2). Separate analyses of individual common (MAF≥1%) and rare (MAF<1%) variants and gene‐based analyses including rare variants were performed using models adjusting for age, sex, and PCs. Result Totals of 2,956, 738 and 1,062 unique AJs were identified in the ADGC, WGS and WES datasets, respectively. After filtering duplicate and closely related individuals, the sample sizes were 1,355 cases and 1,661 controls for G1 and 1,504 cases and 2,047 controls for G2 analyses. Excluding the APOE region, G1 analyses revealed a genome‐wide significant (GWS) association (P<5.0×10 −8 ) with the TREM2 R47H missense mutation (P = 9.66×10 −9 ) and suggestive associations with rs541586606 near RAB3B (P = 5.01×10 −8 ), rs545690149 near ZNF890P , (P = 5.77×10 −8 ) and rs1225737296 near ANXA10 (P = 6.32×10 −8 ). In G2 analyses, we obtained GWS associations with GBA intronic SNP rs3115534 (P = 3.20×10 −13 ) and TREM2 R47H (P = 2.64×10 −10 ), and suggestive associations with rs1003710 in SMAP2 (P = 1.91×10 −7 ) and rs200698976 in ZNF890P (P = 3.49×10 −7 ). No GWS rare variant associations were identified. Significant gene‐based association was identified with GIPR (7.34×10 −7 ). Conclusion Among the novel findings, GBA was previously associated with Parkinson disease and Lewy body dementia (LBD). Remarkably, rs3115534 is located 35 bp from, but not in linkage disequilibrium with, N370S that is associated with LBD in AJs. Moreover, rs3115534 (MAF = 0.027 AJ controls) is rare in EAs (MAF = 0.0015). Our results highlight the efficacy of GWAS in founder populations.