摘要

Abstract Background Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterised by the degeneration of motor neurons, which are responsible for voluntary movement. There remains limited understanding of disease aetiology, with median survival of ALS of three years and no effective treatment. Identifying genes that contribute to ALS susceptibility is an important step towards understanding aetiology. The vast majority of published human genetic studies, including for ALS, have used samples of European ancestry. The importance of trans-ethnic studies in human genetic studies is widely recognised, yet a dearth of studies of non-European ancestries remains. Here, we report analyses of novel whole-exome sequencing (WES) data from Chinese ALS and control individuals. Methods WES data were generated for 610 ALS cases and 460 controls drawn from Chinese populations. We assessed evidence for an excess of rare damaging mutations at the gene level and the gene set level, considering only singleton variants filtered to have allele frequency less than 5 × 10–5 in reference databases. To meta-analyse our results with a published study of European ancestry, we used a Cochran–Mantel–Haenszel test to compare gene-level variant counts in cases vs controls. Results No gene passed the genome-wide significance threshold with ALS in Chinese samples alone. Combining rare variant counts in Chinese with those from the largest WES study of European ancestry resulted in three genes surpassing genome-wide significance: TBK1 (p = 8.3 × 10–12), SOD1 (p = 8.9 × 10–9) and NEK1 (p = 1.1 × 10–9). In the Chinese data alone, SOD1 and NEK1 were nominally significantly associated with ALS (p = 0.04 and p = 7 × 10–3, respectively) and the case/control frequencies of rare coding variants in these genes were similar in Chinese and Europeans (SOD1: 1.5%/0.2% vs 0.9%/0.1%, NEK1 1.8%/0.4% vs 1.9%/0.8%). This was also true for TBK1 (1.2%/0.2% vs 1.4%/0.4%), but the association with ALS in Chinese was not significant (p = 0.14). Conclusions While SOD1 is already recognised as an ALS-associated gene in Chinese, we provide novel evidence for association of NEK1 with ALS in Chinese, reporting variants in these genes not previously found in Europeans.

译文

摘要背景肌萎缩性侧索硬化症 (ALS) 是一种进行性神经系统疾病,其特征是负责自主运动的运动神经元的退化。对疾病病因的理解仍然有限,肌萎缩侧索硬化症的中位生存期为三年,没有有效的治疗方法。识别导致肌萎缩侧索硬化症易感性的基因是理解病因的重要一步。绝大多数已发表的人类基因研究,包括肌萎缩侧索硬化症,都使用了欧洲血统的样本。跨种族研究在人类基因研究中的重要性得到了广泛认可,然而对非欧洲祖先的研究仍然缺乏。在这里,我们报告了来自中国 ALS 和对照个体的新的全基因组测序 (WES) 数据的分析。方法生成来自中国人群的 610 例 ALS 病例和 460 例对照的 WES 数据。我们在基因水平和基因集水平上评估了过量罕见破坏性突变的证据,仅考虑参考数据库中筛选的单胎变异的等位基因频率小于 5 ¼ × 10-5。为了用已发表的欧洲血统研究对我们的结果进行荟萃分析,我们使用了 Cochran-Mantel-Haenszel 检验来比较病例和对照组的基因水平变异计数。结果仅在中国样本中,没有基因通过 ALS 的全基因组显著性阈值。将中国人的罕见变异计数与欧洲祖先最大的 WES 研究相结合,产生了三个超过全基因组意义的基因: TBK1 (p   =  8。 3 × 10-月),SOD1 (p   8 =。 9 × 10-9) 和 NEK1 (p = 1。 1 × 10-9)。仅在中国数据中,SOD1 和 NEK1 名义上与 ALS 显著相关 (p =  0。分别为 04 和 p   = 1.5% × 10-3),这些基因中罕见编码变体的病例/控制频率在中国和欧洲相似 (SOD1: 0.2%/0.9% vs 0.1%/, NEK1 1.8%/0.4% vs 1.9%/0.8%)。TBK1 也是如此 (1.2%/0.2% vs 1.4%/0.4%),但汉语中与肌萎缩侧索硬化症的关联并不显著 (p =)。结论虽然 SOD1 在中国人中已经被认为是肌萎缩侧索硬化症相关基因,但我们为 NEK1 与肌萎缩侧索硬化症的关联提供了新的证据,报告了这些基因的变异,这些基因以前在欧洲人中没有发现。

Amyotrophic lateral sclerosis

儿科 瘫痪性疾病 疾病
概述  :  

肌萎缩侧索硬化(ALS)是一种进展性瘫痪性疾病,以脑和脊髓运动神经元的退行性变为特点。它以局部无力隐匿起病,但无情地扩展累及大多数肌肉,包括膈肌。通常在3到5年内出现呼吸肌麻痹而死亡。流行病学特点在欧洲和美国,每10万人每年有1-2个新发ALS患者,每10万人的总患病人数约为3-5。这些统计数据在全球相对一致,尽管在少数地区ALS更常见。ALS的发病率和患病率随年龄增长。在美国和欧洲,终生累积患ALS的风险约为1/400,单在美国,预计现在活着的人将有80万死于ALS。约10%的ALS患者是

amyotrophic 英 /eimaiə'trɔfik/  美 /eimaiə'trɔfik/

释    义   adj. 肌萎缩的

例    句   For around a decade, scientists have been trying to regrow nerve cells lost in neurodegenerativediseases such as Parkinson's, Alzheimer's and amyotrophic lateral sclerosis (ALS) from stem cells.大约十年间,科学家们一直尝试利用干细胞使神经退变性疾病中的神经细胞再生,例如帕金森病,阿尔茨默病和肌萎缩侧索硬化。

 

lateral 英 /ˈlætərəl/  美 /ˈlætərəl/

释    义   n. 侧部;[语] 边音     

adj. 侧面的,横向的     

vt. 横向传球

例    句   At this point you must alternate lateral and radial truing . Be patient. 在这点上你必须交替的从侧面和纵向进行调整。

 

sclerosis 英 /skləˈrəʊsɪs/ 美 /skləˈroʊsɪs/

释    义   n. [病理] 硬化,[医] 硬化症;细胞壁硬化

例    句   Tuberous sclerosis can lead to the formation of fibroids or tumors in the pancreas, bone, and liver.结节性硬化症可以导致患者的胰腺、骨骼和肝脏发生纤维瘤或其他肿瘤。

请扫描右侧二维码,免费查看词汇专业知识背景