LocusFocus: Web-based colocalization for the annotation and functional follow-up of GWAS

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 Locus-Focus (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.

Association between genes regulating neural pathways for quantitative traits of speech and language disorders

“…We primarily focused on loci with priority scores >5, and for loci with priority scores equal to 5, we examined loci with compelling evidence in the communication disorders literature and/or our own methylation data. These loci were then examined using colocalization analysis in LocusFocus 88 , as described below, which facilitates the exploration of a GWAS signal and the degree of colocalization with eQTLs in relevant tissue.…”

“…We used LocusFocus version 1.4.9 88 to explore our GWAS signals in their degree of colocalization with expression quantitative trait loci (eQTL) for genes within ±200 kb of the lead SNP in the relevant GTEx tissues. The aim of this method is to annotate GWAS-derived associations to the most probable gene(s) and tissue(s) that may be driving that signal.…”

Genetic evidence supports the development of SLC26A9 targeting therapies for the treatment of lung disease

“…All spirometry measures were inverse rank normal transformed prior to association analysis using the RNOmni R package’s (v0.7.1) rankNorm function (59). Association statistics from each phenotype were then used for colocalization analysis with the CF GWAS summary statistics using LocusFocus (v1.4.8; (60)).…”

Loss-of-Function Variants in the SYNPO2L Gene Are Associated With Atrial Fibrillation

“…In order to further explore the genes responsible for the identified genome-wide associated risk locus, we performed a colocalization analysis. Using the LocusFocus tool ( 9 ), we tested whether the GWAS signals are colocalized with eQTL signals, and therefore are likely to share a causal variant. The LocusFocus tool utilizes the Simple Sum colocalization method based on a frequentist framework.…”