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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

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Introduction: Cervical dystonia is the most common of the adult-onset focal dystonias. Most cases are idiopathic. The current view is that cervical dystonia may be caused by some combination of genetic and environmental factors. Genetic contributions have been studied extensively, but there are few studies of other factors. We conducted an exploratory metabolomics analysis of cervical dystonia to identify potentially abnormal metabolites or altered biological pathways. Methods: Plasma samples from 100 cases with idiopathic cervical dystonia and 100 controls were compared using liquid chromatography coupled with mass spectrometry-based metabolomics. Results: A total of 7346 metabolic features remained after quality control, and up to 289 demonstrated significant differences between cases and controls, depending on statistical criteria chosen. Pathway analysis revealed 9 biological processes to be significantly associated at p < 0.05, 5 pathways were related to carbohydrate metabolism, 3 pathways were related to lipid metabolism. Conclusion: This is the first large scale metabolomics study for any type of dystonia. The results may provide potential novel insights into the biology of cervical dystonia.