Transcriptome-wide association study for restless legs syndrome identifies new susceptibility genes
Fulya Akçimen, Faezeh Sarayloo, Calwing Liao, Jay P. Ross, Rachel De Barros Oliveira, Patrick A. Dion, Guy A. Rouleau
Abstract
Restless legs syndrome (RLS) is a common neurological condition, with a prevalence of 5-15% in Central Europe and North America. Although genome-wide association studies (GWAS) have identified some common risk regions for RLS, the causal genes have yet to be fully elucidated. We conducted a transcriptome-wide association study involving 15,126 RLS cases and 95,725 controls, from the most recent meta-analysis of GWAS, and gene expression weights of GTEx v7 and the CMC dorsolateral prefrontal cortex tissue panels. We identified 13 associations (in 8 independent loci) at the transcriptome-wide significant level, of which 6 were not implicated in the previous GWAS: SKAP1, SLC36A1, CCDC57, FN3KRP, NCOA6/TRPC4AP. A fine-mapping approach prioritized CMTR1, RP1-153P14.5, PRPF6, and PPP3R1 - to our knowledge, the latter of which is the first RLS-associated gene directly implicated in dopaminergic pathways. Overall, our findings highlight the power of integrating gene expression data with GWAS to prioritize putative causal genes for functional follow-up studies.