Objective: We aim to identify genetic variants of cervical dystonia (CD) in a large cohort of patients using a genome-wide association study (GWAS) approach.

Background: Collectively dystonias constitute the third most common movement disorder, after Parkinson’s disease and essential tremor. A poor understanding of disease risk and mechanism limits clinical diagnosis and mechanism-based treatments. Several genes for isolated dystonias have been identified, but they collectively account for only a small proportion of all cases. Several GWAS have reported a few plausible loci for dystonias. However, they were limited by small sample sizes, lack of coverage of genetic variants, and poor reproducibility.

Methods: We conducted a GWAS with comprehensive coverage of the genomic variation using CD samples from the Dystonia Coalition biorepository, a large international cohort. Genomic DNA samples were genotyped using the Illumina Multi-ethnic Global Array with 1.7 million directly measured common and rare variants. Logistic and linear regressions were employed to assess the genetic associations with the disease status of CD and age-at-onset, respectively.

Results: After standard quality control procedures, we had 921 CD patients and 1,492 controls of European ancestry for a GWAS. We identified six genome-wide significant (p-value < 5×10-8) common (MAF>5%) SNPs associated with CD adjusted for age, sex and population structure. These CD-associated loci include two coding regions of FAM205A and TRIM27, as well as intergenic regions on chromosome 1, 4, 16 and 18. Gene-based analysis identified DENND1A and GATA4 to be significantly associated with CD. In a GWAS of age-at-onset among 918 cervical dystonia patients, we did not identify any genome-wide significant loci. However, the most significant SNP rs631854 (p-value of 2.2×10-6), located within the TENM4 gene, was associated with a mean increase of 27 years age of onset. This gene is of interest because it has been linked to tremor, which co-occurs in about half of patients with dystonia, and encodes a transmembrane protein that is expressed primarily in neurons.

Conclusions: We identified common variants significantly associated with CD in the largest GWAS for any type of dystonia. Although further replication is warranted, GWAS of large, well-characterized samples may reveal novel genes and mechanisms of dystonias.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genome-wide-association-study-identifies-common-genetic-variants-associated-with-cervical-dystonia/