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

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.

Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction

“…At 61 loci, there was a single independent lead SNP as well as a single top-scoring gene. These included six known loci, strengthening previous reports (MEIS1, PTPRD, SKOR1, NTNG1, CADM1 and RANBP17) 3,4,[10][11][12][13] . Because drug repurposing is one of the fastest options for translating GWAS findings into patient care, we mapped the top-scoring genes against the druggable genome and identified 13 potential candidates targeted by existing compounds (Table 1).…”

Genomic analysis identifies risk factors in restless legs syndrome

“…We identified 21 associations for seven genes at the transcriptome-wide significant level (Figure 2c), of which four were not identified in the previous transcriptome-wide association study (TWAS) for RLS: GLO1 (6p21), ELFN1 (7p22.3), UBASH3B (11q24.1), and CAPNS1 (19q13) 52 . Consistent with previous findings, the expression of three known RLS genes, MEIS1 , SKOR1 , and MAP2K5, were also associated with RLS 52-54 . A fine-mapping analysis using the ‘Fine mapping Of CaUsal gene Sets’ (FOCUS) software (v.0.802) 35 prioritized SKOR1 , PTPRD-AS1 , PRMT6 , STEAP2 , and GTPBP10 as putative candidate genes for RLS with posterior probabilities of 0.69, 0.13, 0.06, 0.06, and 0.02, respectively (Supplementary Table 6).…”

“…To do so, we used two transcriptomic imputation approaches, FUSION 33 and S-PrediXcan 34 , and tested the differential expression of these gene models in 13 brain tissues (Table 3). We identified 21 associations for seven genes at the transcriptome-wide significant level (Figure 2c), of which four were not identified in the previous transcriptome-wide association study (TWAS) for RLS: GLO1 (6p21), ELFN1 (7p22.3), UBASH3B (11q24.1), and CAPNS1 (19q13) 52 . Consistent with previous findings, the expression of three known RLS genes, MEIS1, SKOR1, and MAP2K5, were also associated with RLS [52][53][54] .…”

Exploration of restless legs syndrome under the new concept: A review

“…[ 3 ] To date, genome-wide association studies of RLS have identified 13 different genes in several communities in Northern Europe, These genes are represented by chromosome 6p21.2 (BTBD9), 2p14 (MEIS1), 9p24.1-p23 (PTPRD), 15q23 (MAP2K5/SKOR1), and 16q12.1 (TOX3/BC034767) mononucleotides. [ 16 , 17 ] In addition, recent studies have identified 7 additional major susceptibility loci for RLS: RLS1 at 12q12-q21, RLS2 at 14q13-q21, RLS3 at 9p24-p22, RLS4 at 2q33, RLS5 at 20p13, RLS6 at 19p13, and RLS7 at 16p12.1. [ 18 , 19 ] The pathophysiological functions of these genomic loci are yet to be defined, but their main functions appear to be related to the neural development of the limb during the embryonic period.…”