A Multi‐center Genome‐wide Association Study of Cervical Dystonia

Abstract

Background Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome‐wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility. Objective To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome‐wide approach. Methods We performed a genome‐wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant‐ and gene‐based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome‐wide significant signal. Results After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome‐wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P‐value 3.04 × 10−8). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene‐based analysis identified DENND1A to be significantly associated with cervical dystonia (P‐value 1.23 × 10−6). One low‐frequency variant was associated with lower age‐at‐onset (16.4 ± 2.9 years, P‐value = 3.07 × 10−8, minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823). Conclusion The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi‐genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society

Paroxysmal limb dystonias associated with GABBR2 pathogenic variant: A case-based literature review

“…To date, no functional studies have been carried out to explain the possible pathogenesis of dystonic posturing. Recently, Sun et al have found a GABBR2 variant associated with cervical dystonia using next-generation sequencing [20]. The authors conclude that future studies will be needed to confirm this finding and the disease association of the GABBR2 gene with (paroxysmal) dystonic posturing.…”

Isolated Cervical Dystonia: Diagnosis and Classification

“…Genetic testing is usually unrevealing in iCD, particularly when onset is in adulthood. Genetic iCD has been associated with different dystonia genes that account for only a small proportion of the familial cases 69 . Genes causing iCD (familial and sporadic) currently include GNAL , THAP1 , ANO3 , and less commonly other genes, with a significant degree of phenotypic heterogeneity and intrafamilial variability 70‐73 …”

Association Between Dystonia-Related Genetic Loci and Parkinson's Disease in Eastern China

“…In addition, new association studies have been performed. For example, SNPs in COL8A1, DENND1A, and GABBR2 were found to be associated with cervical dystonia in a multicenter GWAS (5). These loci have not been replicated in case-control studies.…”

“…The cause of PD is still not clear, but genetic and environmental factors have been shown to work together in its risk (3). Among these genetic factors, increasing SNP loci were found to be related to the onset of PD in genome-wide association studies (GWASs) (4)(5)(6). Dystonia is a neurological condition characterized by involuntary movements or postures due to persistent or intermittent muscle contractions (7).…”