Translating Alzheimer's disease-associated polymorphisms into functional candidates: a survey of IGAP genes and SNPs

Abstract

The International Genomics of Alzheimer's Project (IGAP) is a consortium for characterizing the genetic landscape of Alzheimer's disease (AD). The identified and/or confirmed 19 single-nucleotide polymorphisms (SNPs) associated with AD are located on non-coding DNA regions, and their functional impacts on AD are as yet poorly understood. We evaluated the roles of the IGAP SNPs by integrating data from many resources, based on whether the IGAP SNP was (1) a proxy for a coding SNP or (2) associated with altered mRNA transcript levels. For (1), we confirmed that 12 AD-associated coding common SNPs and five nonsynonymous rare variants are in linkage disequilibrium with the IGAP SNPs. For (2), the IGAP SNPs in CELF1 and MS4A6A were associated with expression of their neighboring genes, MYBPC3 and MS4A6A, respectively, in blood. The IGAP SNP in DSG2 was an expression quantitative trait loci (eQTL) for DLGAP1 and NETO1 in the human frontal cortex. The IGAP SNPs in ABCA7, CD2AP, and CD33 each acted as eQTL for AD-associated genes in brain. Our approach for identifying proxies and examining eQTL highlighted potentially impactful, novel gene regulatory phenomena pertinent to the AD phenotype.

Keywords: ADGC; ADSP; GWAS; Neuroinflammation; WES.