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

Abstract

INTRODUCTIONMost Alzheimer's disease (AD) loci have been discovered in individuals with European ancestry (EA).METHODSWe 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.RESULTSIn 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).DISCUSSIONOur results highlight the efficacy of founder populations for AD genetic studies.

Genetics of Alzheimer’s Disease in the African American Population

“…To achieve this goal, scientists must not only simply include samples from diverse ancestral populations in large-scale genomic studies but truly partner with communities that have been historically excluded from research to ensure equitable benefit sharing [ 136 , 137 ] and assemble diverse teams to support these partnerships [ 138 ]. With this motivation, the ADSP prioritized the inclusion of diverse populations [ 139 ] and partnership with local investigators in many parts of the world, including the Caribbean, South America, Africa, Asia, and the Middle East, to enroll diverse cohorts that are sufficiently powered for genetic association studies [ 55 , 102 , 109 , 140 , 141 , 142 , 143 ]. In addition, while accurate risk prediction which takes into account SDOH and ancestry is important, and indeed this is one of the primary motivations of the priority to increase non-EUR representation in genetic studies, ancestry-specific protocols for treatment or identification of those at risk should be carefully evaluated and applied in a way that is respectful and does not limit access to care [ 16 ].…”