Abstract
Genome-wide association studies (GWAS) have primarily identified trait-associated loci in the non-coding genome. Colocalization analyses of SNP associations from GWAS with expression quantitative trait loci (eQTL) evidence enable the generation of hypotheses about responsible mechanism, genes and tissues of origin to guide functional characterization. Here, we present a web-based colocalization browsing and testing tool named LocusFocus (https://locusfocus.research.sickkids.ca). LocusFocus formally tests colocalization using our established Simple Sum method to identify the most relevant genes and tissues for a particular GWAS locus in the presence of high linkage disequilibrium and/or allelic heterogeneity. We demonstrate the utility of LocusFocus, following up on a genome-wide significant locus from a GWAS of meconium ileus (an intestinal obstruction in cystic fibrosis). Using LocusFocus for colocalization analysis with eQTL data suggests variation in ATP12A gene expression in the pancreas rather than intestine is responsible for the GWAS locus. LocusFocus has no operating system dependencies and may be installed in a local web server. LocusFocus is available under the MIT license, with full documentation and source code accessible on GitHub at https://github.com/naim-panjwani/LocusFocus.
Highlights
The majority of disease-associated variants identified by genome-wide association studies (GWAS) lie in non-protein-coding regions of the genome [1]
Genome-wide association studies (GWAS) summary statistics for meconium ileus (MI) at the chr13q12.12 locus, near ATP12A, were uploaded into LocusFocus
In the event that the cystic fibrosis (CF) lung GWAS was confounded, we tested colocalization at the CF MI GWAS locus with expression quantitative trait loci (eQTL) in lung from GTEx and eQTLs from RNAseq of human nasal epithelia (HNE) harvested from individuals with CF as described in [17] and imputed using a hybrid reference sequence using the 1000 Genomes and 101 individuals with CF as described in [18]
Summary
The majority of disease-associated variants identified by genome-wide association studies (GWAS) lie in non-protein-coding regions of the genome [1]. We have made eQTL summary statistics from GTEx (v7 and v8) available for selection within our web server to test colocalization with GTEx tissues and genes using the SS method.
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