Mutation Analysis of DNAJC Family for Early-Onset Parkinson's Disease in a Chinese Cohort

Background: Recently, members of the DnaJ homolog C (DNAJC) family have been identified to be associated with Parkinson's disease (PD) and other neurodegenerative disorders. However, most studies are based on European-ancestry population and no comprehensive analysis is further conducted.

Objectives: In this study, we aim to systematically explore the associations of DNAJCs by genetic analysis in a large Chinese early-onset PD (EOPD) cohort.

Methods: Rare variants were identified using whole exome sequencing in a cohort of 664 unrelated patients with EOPD. Allelic association analysis was performed with Fisher's exact test to clarify the associations at allele level. Gene-based burden analysis was conducted for both rare variants and damaging variants to illuminate the involvement of DNAJCs in EOPD at the gene level.

Results: In total, 61 rare variants were identified in the current study. At the allele level, 2 variants, p.T1109R and p.L174H, in DNAJC26 were significant after Bonferroni correction; 2 variants, p.V1271A and p.A476V, in DNAJC26; 2 variants, p.M477T and p.D1670G, in DNAJC13; 1 variant, p.L19I, in DNAJC10; and 1 variant, p.N526S, in DNAJC6 reached nominal significance. Moreover, a novel compound heterozygous mutation in DNAJC6 was identified. At the gene level, gene-based burden analysis showed a clear enrichment of rare variants in DNAJC26 in patients with EOPD, but not other DNAJCs.

Conclusions: Our work identifies novel rare variants of DNAJC26 to be associated with EOPD and enhances our understanding of the role of DNAJC family members in EOPD. © 2020 International Parkinson and Movement Disorder Society.