Abstract
Isolated dystonia is a common movement disorder often caused by genetic mutations, although it is predominantly sporadic in nature. Common variants of dystonia-related genes were reported to be risk factors for idiopathic isolated dystonia. In this study, we aimed to analyse the roles of previously reported GTP cyclohydrolase (GCH1) and Torsin family 1 member A (TOR1A) polymorphisms in an Indian isolated dystonia case-control group. A total of 292 sporadic isolated dystonia patients and 316 control individuals were genotyped for single-nucleotide polymorphisms (SNPs) of GCH1 (rs3759664:G > A, rs12147422:A > G and rs10483639:C > G) and TOR1A (rs13300897:G > A, rs1801968:G > C, rs1182:G > T and rs3842225:G > Δ) using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and confirmed by direct Sanger sequencing. The statistical significance of allelic, genotypic and haplotypic associations of all of the SNPs were evaluated using the two-tailed Fisher exact test. The minor allele (A) of rs3759664 is significantly associated with isolated limb dystonia as a risk factor (p = 0.005). The minor allele (C) of rs1801968 is strongly associated with isolated dystonia (p < 0.0001) and most of its subtypes. The major allele of rs3842225 (G) may act as a significant risk factor for Writer’s cramp (p = 0.03). Four different haplogroups comprising of either rs1182 or rs3842225 or in combination with rs1801968 and rs13300897 were found to be significantly associated with isolated dystonia. No other allelic, genotypic or haplotypic association was found to be significant with isolated dystonia cohort or its endophenotype stratified groups. Our study suggests that TOR1A common variants have a significant role in isolated dystonia pathogenesis in the Indian population, whereas SNPs in the GCH1 gene may have a limited role.
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Acknowledgements
The authors are thankful to the patients, controls and their family members for participating in this study and acknowledge with thanks Dr. Ananya Ray-Soni, Tessera Therapeutics, Cambridge, MA, USA, for linguistic editing including grammar. SG was supported by the INSPIRE fellowship provided by the Department of Science & Technology, Govt. of India. SR was also supported by fellowships from the University Grant Commission (UGC), Govt. of India. We would also like to express our heartfelt sadness at the sudden demise of Prof. Shyamal Kumar Das, our clinical collaborator and one of the co-authors of this article.
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The study was supported partially by grants from the University Grant Commission [grant No. F.14–38/2007(Inno./ASIST)] and the Department of Science and Technology [(DST-PURSE) and (DST-CSI) to JR], Govt. of India.
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Giri, S., Ghosh, A., Roy, S. et al. Association of TOR1A and GCH1 Polymorphisms with Isolated Dystonia in India. J Mol Neurosci 71, 325–337 (2021). https://doi.org/10.1007/s12031-020-01653-1
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DOI: https://doi.org/10.1007/s12031-020-01653-1