P3‐016: Overlap of gwas loci and expression quantitative trait loci (eQTL) in Alzheimer's disease

A meta-analysis of genome-wide association studies (GWAS) with 25,580 cases and 48,466 controls was performed by the International Genomics of Alzheimer's Project (IGAP) consortium that reported over twenty susceptibility loci significantly associated with a risk for developing late-onset Alzheimer's disease (LOAD), out of which 11 were novel. Several of the GWAS identified variants are non-coding; primarily involved in transcriptional regulatory mechanisms and are enriched with expression quantitative trait loci (eQTL) in a tissue-specific manner. Here, we investigate the correlation between identified LOAD susceptibility variants with gene expression eQTLs, using publicly available datasets. We looked for overlap of our known GWAS association signals with eQTL signals. Using the IGAP GWAS data, we selected genome-wide significant variants located in ABCA7, BIN1, CD2AP, CD33, CASS4, CELF2, CLU, CR1, EPHA1, FERMT2, HLA-DRB5/DRB1, INPP5D, MEF2C, MS4A6A, NME8, PICALM, PTK2B, SLC24A4, SORL1, and ZCWPW1. The APOE locus was excluded from this analysis due to poor coverage by the GWAS platform. eQTL datasets were downloaded from Braineac (http://www.braineac.org), a database consisting of transcript-level and exon-specific expression data from 10 human brain regions from 134 neuropathologically-normal brains from individuals of European descent. We inputted our SNPs of interest into Braineac and extracted its corresponding p-values, which represent the association with gene expression levels, using the MatrixEQTL package in R. The LocusZoom tool was used to generate the LD plots for suggestive and significant eQTLs overlapped with GWAS results. Most of the GWAS identified variants were not significantly associated with gene expression except SNP rs6656401 was found to be a significant gene and exon-level cis-eQTL for CR1 (P = 6.5e-0.7 for ID t2377332 and P=3.7e-07 for ID 2377395) in the white matter (WHMT) region. Also, rs9331896 is a significant exon-level cis-eQTL for CLU (P = 6.0e-07 in average-all for expression ID 3129085). The motivation for our study was to use publically available eQTL data to further investigate the known AD risk loci. This highlights novel avenues and risk genes prioritization for follow-up functional studies to better understand the underlying mechanism associated with disease aetiology at the identified risk loci.