Analysis of rare variants of autosomal‐dominant genes in a Chinese population with sporadic Parkinson’s disease

• Published in: Molecular genetics & genomic medicine 2020-10, Vol.8 (10), p.e1449-n/a
• Main Authors: Zheng, Ran, Jin, Chong‐Yao, Chen, Ying, Ruan, Yang, Gao, Ting, Lin, Zhi‐Hao, Dong, Jia‐Xian, Yan, Ya‐Ping, Tian, Jun, Pu, Jia‐Li, Zhang, Bao‐Rong
• Format: Article
• Language: English
• Subjects: Age; Amino acids; Autosomal dominant inheritance; autosomal‐dominant genes; Confidence intervals; Consortia; Disease; Etiology; Genes; gene‐based analysis; Genomes; Kinases; LRRK2 protein; Males; Movement disorders; Mutation; Neurodegenerative diseases; Original; Parkinson's disease; Protein gene product 9.5; Proteins; rare variants; sporadic
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.1449

Background To date, several studies have suggested that genes involved in monogenic forms of Parkinson's disease (PD) contribute to unrelated sporadic cases, but there is limited evidence in the Chinese population. Methods We performed a systematic analysis of 12 autosomal‐dominant PD (AD‐PD) genes (SNCA, LRRK2, GIGYF2, VPS35, EIF4G1, DNAJC13, CHCHD2, HTRA2, NR4A2, RIC3, TMEM230, and UCHL1) using panel sequencing and database filtration in a case‐control study of a cohort of 391 Chinese sporadic PD patients and unrelated controls. We evaluated the association between candidate variants and sporadic PD using gene‐based analysis. Results Overall, 18 rare variants were discovered in 18.8% (36/191) of the index patients. In addition to previously reported pathogenic mutations (LRRK2 p.Arg1441His and p.Ala419Val), another four unknown variants were found in LRRK2, which also contribute to PD risk (p = 0.002; odds ratio (OR) = 7.83, 95% confidence intervals (CI) = 1.76–34.93). The cumulative frequency of undetermined rare variants was significantly higher in PD patients (14.1%) than in controls (3.5%) (p = 0.0002; OR=4.54, 95% CI = 1.93‐10.69). Conclusion Our results confirm the strong impact of LRRK2 on the risk of sporadic PD, and also provide considerable evidence of the existence of additional undetermined rare variants in AD‐PD genes that contribute to the genetic etiology of sporadic PD in a Chinese cohort. Our results confirm the strong impact of LRRK2 on the risk of sporadic PD, and also provide considerable evidence of the existence of additional undetermined rare variants in AD‐PD genes that contribute to the genetic etiology of sporadic PD in a Chinese cohort.