Inferring the Molecular Mechanisms of Noncoding Alzheimer's Disease-Associated Genetic Variants.

TitleInferring the Molecular Mechanisms of Noncoding Alzheimer's Disease-Associated Genetic Variants.
Publication TypeJournal Article
Year of Publication2019
AuthorsAmlie-Wolf A, Tang M, Way J, Dombroski B, Jiang M, Vrettos N, Chou Y-F, Zhao Y, Kuzma A, Mlynarski EE, Leung YYee, Brown CD, San Wang L-, Schellenberg GD
JournalJ Alzheimers Dis
Volume72
Issue1
Pagination301-318
Date Published08/2019
ISSN1875-8908
Abstract

Most of the loci identified by genome-wide association studies (GWAS) for late-onset Alzheimer's disease (LOAD) are in strong linkage disequilibrium (LD) with nearby variants all of which could be the actual functional variants, often in non-protein-coding regions and implicating underlying gene regulatory mechanisms. We set out to characterize the causal variants, regulatory mechanisms, tissue contexts, and target genes underlying these associations. We applied our INFERNO algorithm to the top 19 non-APOE loci from the IGAP GWAS study. INFERNO annotated all LD-expanded variants at each locus with tissue-specific regulatory activity. Bayesian co-localization analysis of summary statistics and eQTL data was performed to identify tissue-specific target genes. INFERNO identified enhancer dysregulation in all 19 tag regions analyzed, significant enrichments of enhancer overlaps in the immune-related blood category, and co-localized eQTL signals overlapping enhancers from the matching tissue class in ten regions (ABCA7, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, EPHA1, FERMT2, ZCWPW1). In several cases, we identified dysregulation of long noncoding RNA (lncRNA) transcripts and applied the lncRNA target identification algorithm from INFERNO to characterize their downstream biological effects. We also validated the allele-specific effects of several variants on enhancer function using luciferase expression assays. By integrating functional genomics with GWAS signals, our analysis yielded insights into the regulatory mechanisms, tissue contexts, genes, and biological processes affected by noncoding genetic variation associated with LOAD risk.

DOI10.3233/JAD-190568
Alternate JournalJ. Alzheimers Dis.
PubMed ID31561366