DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases.
DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases.
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DOI：
10.1002/ana.24656
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发表时间：
2016-06
影响因子：
11.2
通讯作者：
Jones L
中科院分区：
文献类型：
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作者：
Bettencourt C;Hensman-Moss D;Flower M;Wiethoff S;Brice A;Goizet C;Stevanin G;Koutsis G;Karadima G;Panas M;Yescas-Gómez P;García-Velázquez LE;Alonso-Vilatela ME;Lima M;Raposo M;Traynor B;Sweeney M;Wood N;Giunti P;SPATAX Network;Durr A;Holmans P;Houlden H;Tabrizi SJ;Jones L
多聚谷氨酰胺疾病包括亨廷顿病（HD）和多发性脊髓小脑共济失调（SCA），是最常见的遗传性神经退行性疾病之一。它们是由不同基因中编码谷氨酰胺的CAG束扩张引起的。较长的CAG重复序列与较早的发病年龄相关，但这并不能解释所有的差异，并且在这些疾病中存在额外的遗传修饰因子。最近的一项HD全基因组关联研究（GWAS）发现发病年龄与DNA修复途径中的遗传变异之间存在关联，因此我们测试了DNA修复基因变异的修饰效应是否在多聚谷氨酰胺疾病中具有更广泛的影响。我们组建了一个由1，462名患有HD和多聚谷氨酰胺SCA的受试者组成的独立队列，并对从HD研究中最显著的命中中选择的单核苷酸多态性（SNP）进行基因分型。在对DNA修复基因进行分组分析时，我们发现在对所有多聚谷氨酰胺疾病进行分组时，与发病年龄的相关性最显著（HD+ SCA; p = 1.43 × 10-5）。在个体SNP分析中，我们发现FAN 1中的rs3512与HD+ SCA（p = 1.52 × 10-5）和所有SCA（p = 2.22 × 10-4）以及PMS 2中的rs 1805323与HD+ SCA（p = 3.14 × 10-5）具有显著相关性，所有这些与HD GWAS中的方向相同。我们发现，DNA修复基因显着修改HD和SCA发病时的年龄，这表明一个共同的致病机制，可以通过观察到的重复序列的体细胞扩增，可以通过基因操作疾病模型中的DNA修复来调节。这为多种疾病提供了新的治疗机会。《神经病学年鉴》2016;79：983-990
The polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome‐wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases. We assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single‐nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study. In the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10–5). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10–5) and all SCAs (p = 2.22 × 10–4) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10–5), all in the same direction as in the HD GWAS. We show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016;79:983–990