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.

不安腿综合征（RLS）是一种常见的神经系统疾病，在中欧和北美的患病率为5-15％。尽管全基因组关联研究（GWAS）已经确定了RLS的一些常见风险区域，但致病基因尚未得到充分阐明。我们从GWAS的最新荟萃分析中，对15,126例RLS病例和95,725例对照进行了转录组范围的关联研究，以及GTEx v7和CMC背外侧前额叶皮层组织组的基因表达权重。我们在转录组范围内的显着水平上鉴定出13个关联（在8个独立基因座中），其中6个与先前的GWAS不相关：SKAP1，SLC36A1，CCDC57，FN3KRP，NCOA6 /TRPC4AP。精细映射方法优先考虑CMTR1，RP1-153P14.5，PRPF6和PPP3R1，据我们所知，后者是第一个直接与多巴胺能途径有关的RLS相关基因。总体而言，我们的研究结果突出了将基因表达数据与GWAS集成在一起的功能，以便为功能性后续研究确定可能的致病基因。