Whole-exome sequencing, burden testing, Mendelian randomization, and colocalization in a European cohort identified enrichment of rare variants in multiple DNAJC genes and provide convergent genetic evidence implicating DNAJC13 (and shared signals for DNAJC19) as Parkinson's disease susceptibility…

By genetically linking DNAJC family members—chaperone/co‑chaperone proteins involved in protein homeostasis and endosomal/vesicular trafficking—to PD, the study highlights mechanistic pathways (protein folding, endosome‑lysosome dysfunction) that are relevant and potentially targetable for drug…

BACKGROUND: Recent studies suggested that genetic mutations in the DNAJC family might elevate the risk of Parkinson's disease (PD). Nevertheless, the role of some DNAJC genes in PD remains controversial, and previous studies lacked downstream research. In this study, we aim to explore the relationship between DNAJC family genes and PD in a European cohort through a comprehensive method. METHODS: Rare variants were identified by whole-exome sequencing from a cohort of 403 PD patients and 182 healthy controls. Fisher's exact test was conducted to assess the allelic associations. Gene-based burden analysis was conducted to detect the enrichment effect of mutations in DNAJC genes. Mendelian randomization was performed to explore the association of gene expression levels with PD risk. Finally, colocalization analysis was used to explore the shared genetic structure of DNAJC and PD. RESULTS: In total, we identified 464 rare variants, 437 of which were significant at the allele level. At the gene level, rare variants in 7 genes (DNAJC1, DNAJC6, DNAJC10, DNAJC11, DNAJC13, DNAJC16 and DNAJC27) were enriched in PD patients. At the gene expression level, a positive causal association of DNAJC13 with PD was revealed. Colocalization analysis reinforced the genetic associations of DNAJC13 and DNAJC19 with PD risk by identifying shared variants. CONCLUSIONS: We provided convergent genetic evidence supporting DNAJC13 as a susceptibility gene for PD. We presented the first evidence that rare variants in DNAJC1, DNAJC11 and DNAJC16 were enriched in PD patients, and replicated the previously reported associations of DNAJC6, DNAJC10 and DNAJC27 with PD.