Genome‐wide profiling of the noncoding regulatory mechanisms in Alzheimer’s disease

Abstract

AbstractBackgroundGenome‐wide association studies (GWAS) have identified genetic variants associated with Alzheimer’s Disease (AD), but the majority are noncoding and may affect transcriptional regulatory elements such as enhancers. While prior post‐GWAS analyses focused on analyzing only top GWAS signals, this study focuses on a systematic genome‐wide analysis of all significant GWAS signals aimed at identifying a more complete set of causal variants given a complex linkage disequilibrium (LD) genome structures and the regulatory mechanisms, and tissues/cell types.MethodTo perform genome‐wide analysis of GWAS summary statistics (NIAGADS NG00036) from the IGAP study [Lambert et al., 2013], we adopted INFERNO (http://inferno.lisanwanglab.org), a recent method for post‐GWAS analysis of non‐coding variants. INFERNO integrates GWAS data with hundreds of publicly available functional genomics datasets (e.g., ENCODE, FANTOM5, GTEx, HOMER) across 485 tissues and cell types to facilitate identification of the regulatory mechanisms and tissue/cell types affected by noncoding genetic variants.ResultsGenome‐wide INFERNO analysis identified 168 distinct loci by pruning all genome‐wide significant (p‐value < 5e‐8) GWAS variants using LD structure, a significant increase compared to original top‐SNP analysis (19 loci). Across these 168 distinct loci, INFERNO identified 1,358 candidate potentially causal variants in LD. Around 6% of these variants were localized in coding exons, 67% overlapped enhancers in at least one tissue and 57% overlapped transcription factor binding sites. Co‐localization analysis of GWAS and eQTL data (GTEx_v6p) identified tissue‐specific effects of 53 variants on 43 genes across 16 INFERNO tissue categories, with 12 variants affecting expression of 16 genes in the blood (RP11‐1036E20.9, ZNF223, ZNF285B, RP11‐286H15.1, FAM115D, EPHA1‐AS1, TAS2R60, TAS2R62P, PTK2B) and brain (CR1, ABCA7, POLR2E, EML2, PPM1N, RP11‐385F7.1, FAM115C). These INFERNO‐identified genes include both novel and genes previously implicated in AD. E.g. EPHA1‐AS1 activity was confirmed by luciferase reporter assay [Amlie‐Wolf et al., 2019]. Additionally, our analysis found that PTK2B gene, an early marker of Tau pathology [Dourlen et al., 2016], is regulated by rs28834970 that also disrupts binding motif of HLF(bZIP) in blood.ConclusionGenome‐wide INFERNO analysis confirmed experimentally validated and discovered additional plausible biological mechanisms related to AD. These can help to inform the development of better AD therapeutic targets.