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International EU-RLS-GENE Consortium (Schormair, B.) ; Zhao, C. ; Salminen, A.V. ; International EU-RLS-GENE Consortium (Oexle, K.) ; International EU-RLS-GENE Consortium (Winkelmann, J.) ; International EU-RLS-GENE Consortium (Oertel, W.H.) ; International EU-RLS-GENE Consortium (Gieger, C.) ; International EU-RLS-GENE Consortium (Peters, A.)

Reassessment of candidate gene studies for idiopathic restless legs syndrome in a large GWAS dataset of European ancestry.

Sleep 45:zsac098 (2022)

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Open Access Green as soon as Postprint is submitted to ZB.

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STUDY OBJECTIVES: Several candidate gene studies have been published for idiopathic restless legs syndrome (RLS) in populations of European ancestry, but the reported associations have not been confirmed in independent samples. Our aim was to reassess these findings in a large case-control dataset in order to evaluate their validity. METHODS: We screened PubMed for RLS candidate gene studies. We used the genome-wide association study (GWAS) dataset of the International-EU-RLS-GENE-Consortium as our replication sample, which provided genome-wide single variant association data based on at most 17,220 individuals of European ancestry. We performed additional gene-based tests using the software MAGMA and assessed the power of our study using the genpwr R package. RESULTS: We identified 14 studies conducted in European samples which assessed 45 variants in 27 genes of which five variants had been reported as significantly associated. None of these individual variants were replicated in our GWAS-based reassessment (nominal p > 0.05) and gene-based tests for the respective five genes ADH1B, GABRR3, HMOX1, MAOA, and VDR, were also non-significant (nominal p > 0.05). Our replication dataset was well-powered to detect the reported effects, even when adjusting for effect size overestimation due to winner's curse. Power estimates were close to 100% for all variants. CONCLUSION: In summary, none of the significant single variant associations from candidate gene studies were confirmed in our GWAS dataset. Therefore, these associations were likely false-positive. Our observations emphasize the need for large sample sizes and stringent significance thresholds in future association studies for RLS.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Genetic Association Studies ; Genome-wide Association Study ; Restless Legs Syndrome ; Movement Disorders

ISSN (print) / ISBN 0161-8105

e-ISSN 1550-9109

Journal Sleep

Quellenangaben Volume: 45, Issue: 8, Article Number: zsac098

Publisher American Academy of Sleep Medicine and the Sleep Research Society

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Neurogenomics (ING)
Institute of Epidemiology II (EPI2)