GWAS on short tandem repeats identifies novel genetic mechanisms in Alzheimer's disease

Abstract

Genome-wide association studies (GWASs) are typically based on the analysis of single nucleotide polymorphisms (SNPs) and often exclude more complex genetic variants, such as short tandem repeats (STRs). Here, we report the results of GWAS analyses systematically assessing the role of STRs, both imputed and directly genotyped by whole genome sequencing (WGS), on risk for Alzheimers disease (AD) in a large collection of [~]330,000 individuals (3,287 AD cases; 47,048 AD-by-proxy cases, 283,111 controls) from the UK biobank. Using imputed (or WGS-derived) STR genotype data, we identified 14 (WGS: one) independent loci showing evidence for genome-wide significant association with AD risk. While most identified loci had already been highlighted by SNP-based GWAS, we detected new STR-based signals near the genes SNX32 (chr. 11q13) and WBS1 (chr. 17q11). In addition, we delineated several other loci where STRs (and not SNPs) either represent the lead signal (ABCA7) or make substantial contributions to the SNP-driven associations (HLA-DRB1, MINDY/ADAM10, and APOE). Heritability analyses estimated that STRs account for at least 3% of the total phenotypic variance of AD in this dataset. Aligning our top STRs with DNA methylation and transcriptome profiles from human brain samples suggests that several STRs may unfold their effects by impacting gene expression. Future work needs to confirm our results and delineate the likely considerable role that STRs play in the genetic makeup of AD.