Genetic Analysis of HSP40/DNAJ Family Genes in Parkinson's Disease: a Large Case-Control Study.

Molecular chaperones were reported to play an important role in PD pathogenesis. Recent studies revealed the association of several HSP40/DNAJ family genes with PD, but no genetic analysis of all the DNAJ family genes in PD has been conducted. To systematically analyze the genetic impact of all the DNAJ family genes in PD, we performed genetic analysis for these genes in a large case-control study. We analyzed the rare variants in 49 DNAJ family genes from 3879 PD patients and 2931 healthy controls by whole-exome sequencing and whole-genome sequencing. All rare missense variants and the subgroups of rare damaging missense (Dmis) and loss-of-function (LoF) variants were gathered to test the accumulated association of these variants in each gene with PD. In total, 1617 rare nonsynonymous variants of DNAJ family genes with minor allele frequency less than 1% were identified in our cohort. We identified 82 rare missense variants for DNAJC26 in sporadic early-onset PD (sEOPD) or familial PD (FPD), and 17 Dmis and one LoF variant were detected among them. Gene-based burden analysis showed that the rare Dmis variants alone or Dmis plus LoF variants together of DNAJC26 were significantly enriched in PD patients. We also found suggestive associations of DNAJB2 and DNAJC18 with PD in sEOPD or FPD and DNAJC2, DNAJC10, DNAJC22, DNAJC24, DNAJC27, DNAJC28, and DNAJC29 with PD in sporadic late-onset PD. In conclusion, rare missense variants of DNAJC26 were significantly enriched in FPD or sEOPD. Moreover, DNAJB2, DNAJC2, DNAJC10, DNAJC18, DNAJC22, DNAJC24, DNAJC27, DNAJC28, and DNAJC29 were suggestively associated with PD.