PUBLICATION

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

Authors
Jiang, Y.J., Fann, C.S., Fuh, J.L., Chung, M.Y., Huang, H.Y., Chu, K.C., Wang, Y.F., Hsu, C.L., Kao, L.S., Chen, S.P., Wang, S.J.
ID
ZDB-PUB-220331-6
Date
2022
Source
The journal of headache and pain   23: 39 (Journal)
Registered Authors
Chu, Kuo-Chang, Jiang, Yun-Jin
Keywords
Genome-wide association study, Migraine, Restless legs syndrome, VSTM2L and CCDC141, Zebrafish
MeSH Terms
  • Humans
  • Zebrafish/genetics
  • Genome-Wide Association Study
  • Animals
  • Restless Legs Syndrome*/complications
  • Restless Legs Syndrome*/genetics
(all 6)
PubMed
35350973 Full text @ J Headache Pain
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.
Genes / Markers
Figures
Figure Gallery (4 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
AB + CRISPR1-ccdc141controlDay 4
AB + CRISPR1-ccdc141controlDay 5
AB + CRISPR1-vstm2lbcontrolDay 4
AB + CRISPR1-vstm2lbcontrolDay 5
AB + CRISPR2-ccdc141controlDay 4
AB + CRISPR2-ccdc141controlDay 5
AB + CRISPR2-vstm2lbcontrolDay 4
AB + CRISPR2-vstm2lbcontrolDay 5
AB + MO1-ccdc141controlProtruding-mouth
AB + MO1-ccdc141controlDay 4
1 - 10 of 18
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
zf3535
    		Small Deletion
    zf3536
      		Small Deletion
      zf3537
        		Insertion
        zf3538
          		Small Deletion
          zf3539
            		Small Deletion
            1 - 5 of 5
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            Human Disease / Model
            No data available
            Sequence Targeting Reagents
            Target Reagent Reagent Type
            ccdc141CRISPR1-ccdc141CRISPR
            ccdc141CRISPR2-ccdc141CRISPR
            ccdc141MO1-ccdc141MRPHLNO
            ccdc141MO2-ccdc141MRPHLNO
            ccdc141MO3-ccdc141MRPHLNO
            vstm2lbCRISPR2-vstm2lbCRISPR
            vstm2lbCRISPR1-vstm2lbCRISPR
            vstm2lbMO1-vstm2lbMRPHLNO
            vstm2lbMO2-vstm2lbMRPHLNO
            vstm2lbMO3-vstm2lbMRPHLNO
            1 - 10 of 10
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            Fish
            Fish
            AB
            AB + CRISPR1-ccdc141
            AB + CRISPR1-vstm2lb
            AB + CRISPR2-ccdc141
            AB + CRISPR2-vstm2lb
            AB + MO1-ccdc141
            AB + MO2-vstm2lb
            1 - 7 of 7
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            Antibodies
            No data available
            Orthology
            No data available
            Engineered Foreign Genes
            No data available
            Mapping
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            Citation
            Jiang, Y.J., Fann, C.S., Fuh, J.L., Chung, M.Y., Huang, H.Y., Chu, K.C., Wang, Y.F., Hsu, C.L., Kao, L.S., Chen, S.P., Wang, S.J. (2022) Genome-wide analysis identified novel susceptible genes of restless legs syndrome in migraineurs. The journal of headache and pain. 23:39.