Transcriptome-wide association study for restless legs syndrome identifies new susceptibility genes

Fulya Akçimen,Rachel De Barros Oliveira,Patrick A Dion,Calwing Liao,Faezeh Sarayloo,Guy A Rouleau,Jay P Ross

doi:10.1038/s42003-020-1105-z

Fulya Akçimen, Rachel De Barros Oliveira + Show 5 more

Open Access

https://doi.org/10.1038/s42003-020-1105-z

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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.

Highlights

Restless legs syndrome (RLS) is a common neurological condition, with a prevalence of 5–15% in Central Europe and North America
As a complementary to the previous genome-wide association studies (GWAS), this study aimed to identify novel genes associated with RLS that are not well explained by individual SNP tagging
This study identified 13 associations at the transcriptome-wide significant level, of which six were not implicated in the previous GWAS

Summary

Introduction

Restless legs syndrome (RLS) is a common neurological condition, with a prevalence of 5–15% in Central Europe and North America. Genome-wide association studies (GWAS) have identified some common risk regions for RLS, the causal genes have yet to be fully elucidated. The latest genome-wide association studies (GWAS) meta-analysis identified a total of 19 RLS risk loci that explained 60% of the estimated SNP-based heritability of 19.6% 4. Using the summary statistics of the most recent RLS-GWAS cohort of European ancestry, various post-GWAS approaches including gene annotation, pathway and gene-set enrichment analyses were applied to prioritize genes in associated loci and identify related biological mechanisms. Unlike the previous methods that often associate loci with the nearest gene or focus on individual significant SNP and eQTL associations, transcriptome-wide association studies (TWASs) focus on whole expression and trait associations rather than only top eQTL associations[5]. Through leveraging available transcriptomic imputation approaches, FUSION5 and S-PrediXcan[6], we sought to integrate eQTL analyses with summarylevel GWAS data to determine more detailed information on, and discover novel genes, underlying the pathology of RLS

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