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Ayellet Segre, Andrew Hamel, John Rouhana, Anthony P Khawaja, Mark James Simcoe, Christopher J Hammond, Pirro G Hysi, GTEx consortium, Janey L Wiggs; Integrative analysis of GWAS and eQTLs proposes new genetic associations and causal genes for Primary Open Angle Glaucoma. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4252. doi: https://doi.org/.
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Genome-wide association studies (GWAS) have led to the discovery of 30 genomic loci with common variants associated with Primary Open Angle Glaucoma (POAG) risk, explaining ~5% of POAG heritability. The majority of these associations lie in noncoding regions, suggesting that genetic regulation of gene expression plays a primary role in disease risk. It is also difficult to decipher the causal genes in these often, multi-genic regions. To address these challenges, we tested whether expression quantitative trait loci (eQTLs) or splicing QTLs (sQTLs) in human tissues could be used to prioritize causal genes in association regions and detect new genetic associations with POAG.
We developed a statistical method (eQTLEnrich.v2) that tests whether different types of QTLs are enriched for genetic associations (genome-wide significant and subthreshold) with a given complex disease or trait compared to expectation, correcting for confounding factors, e.g., MAF, distance to TSS, and linkage disequilibrium. If enrichment is found, a second step is applied to test if target genes of QTLs with top ranked GWAS p-values (e.g. P<0.05) are enriched in signaling or metabolic pathways, gene ontologies, or mouse phenotype ontologies (eGeneEnrich.v2). We applied this method to the NEIGHBORHOOD POAG GWAS meta-analysis and the UK Biobank GWAS of intraocular pressure (IOP), using eQTLs and sQTLs from 49 tissues in the Genotype-Tissue Expression (GTEx) project.
We found significant enrichment of POAG and IOP associations amongst eQTLs in relevant tissues (P<5E-04, adjusted fold-enrichment=1.1-1.4), e.g., artery and nerve, proposing hundreds of new genetic associations with regulatory effects on POAG risk. The target genes of the top ranked eQTLs (GWAS p<0.05) were enriched in several biological pathways, pointing to putative causal genes underlying the associations. Replication of the new associations will be tested in a large, independent POAG GWAS (UK Biobank). Enrichment amongst sQTLs and the relative contribution of eQTLs and sQTLs to POAG heritability will also be presented.
This work demonstrates that variation in transcriptional regulation substantially contributes to POAG risk and IOP, and proposes new causal genes for glaucoma. Future eQTL studies in ocular tissues will help refine the pathogenic processes and tissues implicated by genetics of POAG.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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