Functional Characterisation of a GWAS Risk Locus Identifies GPX3 as a Lead Candidate Gene in ALS

Amyotrophic lateral sclerosis (ALS) is a complex late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies have identified eleven risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Current association analysis data alone cannot determine the most plausible risk gene in this locus. Here, we undertake a comprehensive suite of studies to provide objective evidence to support or reject the relevance of these two genes. We use bioinformatic integration of genetic association data with omics reference data sets, in-vitro and in-vivo approaches to narrow down the likely candidate. TNIP1 and GPX3 are implicated in-silico (rs10463311 is an eQTL for these two genes). In-vivo expression analyses in ALS cases identify that GPX3 expression decreases with increased disability and rate of progression. Validation in-vivo, indicate GPX3 loss-of-function causes motor deficits in zebrafish embryos. Taken together, these results support GPX3 as being the ALS risk gene in this locus which has implications for understanding disease mechanisms and targeted therapeutic approaches.