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. 2014 Feb;29(2):245-51.
doi: 10.1002/mds.25732. Epub 2013 Nov 13.

Genomewide association study in cervical dystonia demonstrates possible association with sodium leak channel

Kin Y Mok  1 , Susanne A Schneider, Daniah Trabzuni, Maria Stamelou, Mark Edwards, Dalia Kasperaviciute, Stuart Pickering-Brown, Monty Silverdale, John Hardy, Kailash P Bhatia
Affiliations

Genomewide association study in cervical dystonia demonstrates possible association with sodium leak channel

Kin Y Mok et al. Mov Disord. 2014 Feb.

Abstract

Dystonia is a common movement disorder. A number of monogenic causes have been identified. However, the majority of dystonia cases are not explained by single gene defects. Cervical dystonia is one of the commonest forms without genetic causes identified. This pilot study aimed to identify large effect-size risk loci in cervical dystonia. A genomewide association study (GWAS) was performed. British resident cervical dystonia patients of European descent were genotyped using the Illumina-610-Quad. Comparison was made with controls of European descent from the Wellcome Trust Case Control Consortium using logistic regression algorithm from PLINK. SNPs not genotyped by the array were imputed with 1000 Genomes Project data using the MaCH algorithm and minimac. Postimputation analysis was done with the mach2dat algorithm using a logistic regression model. After quality control measures, 212 cases were compared with 5173 controls. No single SNP passed the genomewide significant level of 5 × 10(-8) in the analysis of genotyped SNP in PLINK. Postimputation, there were 5 clusters of SNPs that had P value <5 × 10(-6) , and the best cluster of SNPs was found near exon 1 of NALCN, (sodium leak channel) with P = 9.76 × 10(-7) . Several potential regions were found in the GWAS and imputation analysis. The lowest P value was found in NALCN. Dysfunction of this ion channel is a plausible cause for dystonia. Further replication in another cohort is needed to confirm this finding. We make this data publicly available to encourage further analyses of this disorder.

Keywords: GWAS; NALCN; cervical dystonia; imputation; sodium leaking channel.

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Figures

Figure 1
Figure 1
(A) Manhattan plot of GWAS. (B) Manhattan plot of imputed result. The SNPs with P < 0.001 in the best 2 regions were labeled in pink, showing clustering of SNPs around the regions. GWAS, genomewide association study; SNP, single-nucleotide polymorphism. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Figure 2
Figure 2
(A) Local association plot with LD of NALCN region (Locus Zoom). There is a cluster of imputed SNPs with P value suggesting possible association. Red arrow is the best GWAS hit (rs1338041) in this region. (B) Local association plot with LD at Chr 11. Tightly linked imputed SNPs suggest possible association of cervical dystonia with an uncommon haplotype in the region that was not well tagged by common SNPs in GWAS. LD, linkage disequilibrium; GWAS, genomewide association study; Chr, chromosome; SNP, single-nucleotide polymorphism. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
See this image and copyright information in PMC

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