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Open Access 01-12-2022 | Migraine | Research article

Genome-wide analysis identified novel susceptible genes of restless legs syndrome in migraineurs

Authors: Yun-Jin Jiang, Cathy Shen-Jang Fann, Jong-Ling Fuh, Ming-Yi Chung, Hui-Ying Huang, Kuo-Chang Chu, Yen-Feng Wang, Chia-Lin Hsu, Lung-Sen Kao, Shih-Pin Chen, Shuu-Jiun Wang

Published in: The Journal of Headache and Pain | Issue 1/2022

Abstract

Background

Restless legs syndrome is a highly prevalent comorbidity of migraine; however, its genetic contributions remain unclear.

Objectives

To identify the genetic variants of restless legs syndrome in migraineurs and to investigate their potential pathogenic roles.

Methods

We conducted a two-stage genome-wide association study (GWAS) to identify susceptible genes for restless legs syndrome in 1,647 patients with migraine, including 264 with and 1,383 without restless legs syndrome, and also validated the association of lead variants in normal controls unaffected with restless legs syndrome (n = 1,053). We used morpholino translational knockdown (morphants), CRISPR/dCas9 transcriptional knockdown, transient CRISPR/Cas9 knockout (crispants) and gene rescue in one-cell stage embryos of zebrafish to study the function of the identified genes.

Results

We identified two novel susceptibility loci rs6021854 (in VSTM2L) and rs79823654 (in CCDC141) to be associated with restless legs syndrome in migraineurs, which remained significant when compared to normal controls. Two different morpholinos targeting vstm2l and ccdc141 in zebrafish demonstrated behavioural and cytochemical phenotypes relevant to restless legs syndrome, including hyperkinetic movements of pectoral fins and decreased number in dopaminergic amacrine cells. These phenotypes could be partially reversed with gene rescue, suggesting the specificity of translational knockdown. Transcriptional CRISPR/dCas9 knockdown and transient CRISPR/Cas9 knockout of vstm2l and ccdc141 replicated the findings observed in translationally knocked-down morphants.

Conclusions

Our GWAS and functional analysis suggest VSTM2L and CCDC141 are highly relevant to the pathogenesis of restless legs syndrome in migraineurs.

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Title: Genome-wide analysis identified novel susceptible genes of restless legs syndrome in migraineurs
Authors: Yun-Jin Jiang
Cathy Shen-Jang Fann
Jong-Ling Fuh
Ming-Yi Chung
Hui-Ying Huang
Kuo-Chang Chu
Yen-Feng Wang
Chia-Lin Hsu
Lung-Sen Kao
Shih-Pin Chen
Shuu-Jiun Wang
Publication date: 01-12-2022
Publisher: Springer Milan
Keywords: Migraine
Restless Legs Syndrome
Published in: The Journal of Headache and Pain / Issue 1/2022
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI: https://doi.org/10.1186/s10194-022-01409-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Genome-wide analysis identified novel susceptible genes of restless legs syndrome in migraineurs

Abstract

Background

Objectives

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Objectives

Methods

Results

Conclusions

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