Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Department of Rheumatology and Immunology, Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Neurobiol Aging. 2021 May;101:299.e1-299.e6. doi: 10.1016/j.neurobiolaging.2020.11.005. Epub 2020 Nov 7.
Members of the transmembrane (TMEM) protein family have been identified to be associated with Parkinson's disease (PD) and other neurodegenerative disorders. However, most studies were based on the European-ancestry population and were still awaiting replications. Here, we aimed to systematically evaluate the associations of TMEMs with PD in a large Chinese early-onset PD (EOPD, age at onset <50 years) cohort. We identified rare variants (minor allele frequency <0.01) in 743 unrelated EOPD patients using whole-exome sequencing and evaluated the association between variants and EOPD at allele and gene levels. Totally 45 rare variants were identified in 6 TMEM protein family members. At allele level, p.176 K>E in TMEM175 and p.33P>R in TMEM163 were significantly associated with PD. Gene-based burden analysis showed a clear enrichment of TMEM163 variants in EOPD. Our work identifies 2 novel rare variants and TMEM163 as potential risk factors for PD provide a better understanding of the genetic involvement of TMEM protein family members in EOPD and broadens the current mutation spectrum of PD.
跨膜（TMEM）蛋白家族的成员已被确定与帕金森病（PD）和其他神经退行性疾病有关。然而，大多数研究都是基于欧洲血统人群，仍有待复制。在这里，我们旨在通过对一个大型中国早发性帕金森病（EOPD，发病年龄<50 岁）队列进行系统评估，来评估 TMEM 与 PD 的相关性。我们使用全外显子组测序在 743 名无亲缘关系的 EOPD 患者中鉴定了罕见变异（次要等位基因频率<0.01），并在等位基因和基因水平上评估了变异与 EOPD 之间的关联。在 6 个 TMEM 蛋白家族成员中发现了 45 个罕见变异。在等位基因水平上，TMEM175 的 p.176K>E 和 TMEM163 的 p.33P>R 与 PD 显著相关。基于基因的负担分析显示，EOPD 中 TMEM163 变体明显富集。我们的工作确定了 2 个新的罕见变异和 TMEM163 作为 PD 的潜在危险因素，为 TMEM 蛋白家族成员在 EOPD 中的遗传参与提供了更好的理解，并拓宽了目前 PD 的突变谱。
