A Multi-center Genome-wide Association Study of Cervical Dystonia.
A Multi-center Genome-wide Association Study of Cervical Dystonia.
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DOI：
10.1002/mds.28732
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Jinnah HA
中科院分区：
文献类型：
--
作者：
Sun YV;Li C;Hui Q;Huang Y;Barbano R;Rodriguez R;Malaty IA;Reich S;Bambarger K;Holmes K;Jankovic J;Patel NJ;Roze E;Vidailhet M;Berman BD;LeDoux MS;Espay AJ;Agarwal P;Pirio-Richardson S;Frank SA;Ondo WG;Saunders-Pullman R;Chouinard S;Natividad S;Berardelli A;Pantelyat AY;Brashear A;Fox SH;Kasten M;Krämer UM;Neis M;Bäumer T;Loens S;Borsche M;Zittel S;Maurer A;Gelderblom M;Volkmann J;Odorfer T;Kühn AA;Borngräber F;König IR;Cruchaga C;Cotton AC;Kilic-Berkmen G;Freeman A;Factor SA;Scorr L;Bremner JD;Vaccarino V;Quyyumi AA;Klein C;Perlmutter JS;Lohmann K;Jinnah HA
孤立性肌张力障碍的几个单基因原因已被确定，但他们共同只占一小部分的情况下。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;但结论受到样本量小、遗传变异部分覆盖或重现性差的限制。使用全基因组方法在大型多中心颈部肌张力障碍队列中识别稳健的遗传变异和基因座。我们使用来自肌张力障碍联盟的颈部肌张力障碍样本进行了全基因组关联研究。Logistic和线性回归，包括年龄，性别和人口结构作为协变量，被用来评估变异和基因为基础的遗传与疾病状态和发病年龄的关联。我们还进行了一个复制研究的一个确定的全基因组的显着信号。经过质量控制后，919名颈部肌张力障碍患者与1,491名欧洲血统的对照者被纳入分析。我们发现了一个全基因组显着变异（rs 2219975，3号染色体，COL 8A 1上游，p值3.04×10 - 8）。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，这种关联没有被复制。基于基因的分析确定DEND 1A与颈部肌张力障碍显著相关（p值1.23×10−6）。一个低频变异与较低的发病年龄相关（16.4±2.9岁，p值=3.07×10−8，次要等位基因频率=0.01），位于9号染色体上的GABBR 2基因（rs 147331823）。颈部肌张力障碍的遗传基础是复杂的，可能由多个不同的小效应量的变体组成。可能需要更大的样本量来提供足够的统计功效，以解决颈部肌张力障碍的可能多基因病因。
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 multi-center 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 1,491 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). 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.
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影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
DOI：
10.1212/nxg.0000000000000069
发表时间：
2016-06
期刊：
Neurology. Genetics
影响因子：
--
作者：
LeDoux MS;Vemula SR;Xiao J;Thompson MM;Perlmutter JS;Wright LJ;Jinnah HA;Rosen AR;Hedera P;Comella CL;Weissbach A;Junker J;Jankovic J;Barbano RL;Reich SG;Rodriguez RL;Berman BD;Chouinard S;Severt L;Agarwal P;Stover NP
通讯作者：
Stover NP
影响因子：
8.6
作者：
Albanese, Alberto;Bhatia, Kailash;Bressman, Susan B.;DeLong, Mahlon R.;Fahn, Stanley;Fung, Victor S. C.;Hallett, Mark;Jankovic, Joseph;Jinnah, Hyder A.;Klein, Christine;Lang, Anthony E.;Mink, Jonathan W.;Teller, Jan K.
通讯作者：
Teller, Jan K.
影响因子：
8.6
作者：
Mok, Kin Y.;Schneider, Susanne A.;Bhatia, Kailash P.
通讯作者：
Bhatia, Kailash P.
影响因子：
81.5
作者：
Balint, Bettina;Mencacci, Niccolo E.;Bhatia, Kailash P.
通讯作者：
Bhatia, Kailash P.