TY - JOUR T1 - Role of genetics in amyotrophic lateral sclerosis: a large cohort study in Chinese mainland population JF - Journal of Medical Genetics JO - J Med Genet SP - 840 LP - 849 DO - 10.1136/jmedgenet-2021-107965 VL - 59 IS - 9 AU - Yong-Ping Chen AU - Shi-Hui Yu AU - Qian-Qian Wei AU - Bei Cao AU - Xiao-Jing Gu AU - Xue-Ping Chen AU - Wei Song AU - Bi Zhao AU - Ying Wu AU - Ming-Ming Sun AU - Fei-Fei Liu AU - Yan-Bing Hou AU - Ru-Wei Ou AU - Ling-Yu Zhang AU - Kun-Cheng Liu AU - Jun-Yu Lin AU - Xin-Ran Xu AU - Chun-Yu Li AU - Jing Yang AU - Zheng Jiang AU - Jiao Liu AU - Yang-Fan Cheng AU - Yi Xiao AU - Ke Chen AU - Fei Feng AU - Ying-Ying Cai AU - Shi-Rong Li AU - Tao Hu AU - Xiao-Qin Yuan AU - Xiao-Yan Guo AU - Hui Liu AU - Qing Han AU - Qing-Qing Zhou AU - Na Shao AU - Jian-Peng Li AU - Ping-Lei Pan AU - Sha Ma AU - Hui-Fang Shang Y1 - 2022/09/01 UR - http://jmg.bmj.com/content/59/9/840.abstract N2 - Background A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers.Methods A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed.Findings 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition.Conclusions Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.All data relevant to the study are included in the article or uploaded as supplementary information. ER -