Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, Georgia, USA.
Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, Georgia, USA.
Mov Disord. 2021 Dec;36(12):2795-2801. doi: 10.1002/mds.28732. Epub 2021 Jul 28.
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.
To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach.
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.
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 ). 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 ). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10 , minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823).
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.
已经确定了几种孤立性肌张力障碍的单基因病因，但它们总共只占病例的一小部分。两项全基因组关联研究报告了一些潜在的肌张力障碍风险位点；但由于样本量小、遗传变异部分覆盖或可重复性差，结论受到限制。
使用全基因组方法在大型多中心颈肌张力障碍队列中识别稳健的遗传变异和位点。
我们使用肌张力障碍联盟的颈肌张力障碍样本进行了全基因组关联研究。使用逻辑和线性回归，包括年龄、性别和人口结构作为协变量，评估了变体和基因与疾病状态和发病年龄的遗传关联。我们还对一个确定的全基因组显著信号进行了复制研究。
经过质量控制，919 例颈肌张力障碍患者与 1491 例欧洲血统对照者纳入分析。我们确定了一个全基因组显著的变异（rs2219975，染色体 3，COL8A1 上游，P 值 3.04×10）。在 473 例颈肌张力障碍病例和 481 例对照的新基因分型样本中未发现该关联的复制。基于基因的分析表明 DENND1A 与颈肌张力障碍显著相关（P 值 1.23×10）。一个低频变异与发病年龄较低相关（16.4±2.9 岁，P 值=3.07×10，次要等位基因频率=0.01），位于 9 号染色体 GABBR2 基因内（rs147331823）。
颈肌张力障碍的遗传基础很复杂，可能由多个不同的小效应大小的变体组成。可能需要更大的样本量来提供足够的统计能力来解决颈肌张力障碍的多基因病因。© 2021 国际帕金森病和运动障碍学会。
