Novel loci for Alzheimer's disease identified by a genome-wide association study in Ashkenazi Jews.

Abstract

Most Alzheimer's disease (AD) loci have been discovered in individuals with European ancestry (EA). We applied principal component analysis using Gaussian mixture models and an Ashkenazi Jewish (AJ) reference genome-wide association study (GWAS) data set to identify Ashkenazi Jews ascertained in GWAS (n=42,682), whole genome sequencing (WGS, n=16,815), and whole exome sequencing (WES, n=20,504) data sets. The association of AD was tested genome wide (GW) in the GWAS and WGS data sets and exome wide (EW) in all three data sets (EW). Gene-based analyses were performed using aggregated rare variants. In addition to apolipoprotein E (APOE), GW analyses (1355 cases and 1661 controls) revealed associations with TREM2 R47H (p=9.66×10-9 ), rs541586606 near RAB3B (p=5.01×10-8 ), and rs760573036 between SPOCK3 and ANXA10 (p=6.32×10-8 ). In EW analyses (1504 cases and 2047 controls), study-wide significant association was observed with rs1003710 near SMAP2 (p=1.91×10-7 ). A significant gene-based association was identified with GIPR (p=7.34×10-7 ). Our results highlight the efficacy of founder populations for AD genetic studies.