GenToS: Use of orthologous gene information to prioritize signals from human GWAS

Abstract

Genome-wide association studies (GWAS) evaluate associations between genetic variants and a trait or disease of interest free of prior biological hypotheses. GWAS require stringent correction for multiple testing, with genome-wide significance typically defined as association p-value >5 10-8. This study presents a new tool that uses external information about genes to prioritizeSNP associations (GenToS). For a given list of candidate genes, Gen- ToS calculates an appropriate statistical significance threshold and then searches for traitassociated variants in summary statistics from humanGWAS. It thereby allows for identifying trait-associated genetic variants that do not meet genome-wide significance. The program additionally tests for enrichment of significant candidate gene associations in the humanGWAS data compared to the number expected by chance. As proof of principle, this report used external information from a comprehensive resource of genetically manipulated and systematically phenotyped mice. Based on selectedmurine phenotypes for which humanGWAS data for corresponding traits were publicly available, several candidate gene input lists were derived. Using GenToS for the investigation of candidate genes underlying murine skeletal phenotypes in data from a large human discoveryGWAS meta-analysis of bone mineral density resulted in the identification of significantly associated variants in 29 genes. Index variants in 28 of these loci were subsequently replicated in an independent GWAS replication step, highlighting that they are true positive associations. One signal, COL11A1, has not been discovered throughGWAS so far and represents a novel human candidate gene for altered bone mineral density. The number of observed genes that contained significant SNP associations in humanGWAS based on murine candidate gene input lists was much greater than the number expected by chance across several complex human traits (enrichment p-value as low as 10-10). GenToS can be used with any candidate gene list, any GWAS summary file, runs on a desktop computer and is freely available.