The burden of rare damaging variants in hereditary atypical parkinsonism genes is increased in patients with Parkinson’s disease

Increased burdens of rare coding variants in genes related to lysosomal storage disease or mitochondrial pathways were reported to be associated with idiopathic Parkinson’s disease. Under a hypothesis that the burden of damaging rare coding variants is increased in causative genes for hereditary parkinsonism, we analyzed the burdens of rare coding variants with a case-control design. Two cohorts of whole-exome sequencing data and a cohort of genome-wide genotyping data of clinically validated idiopathic Parkinson’s disease cases and controls, which were open to the public, were used. The sequence kernel association test–optimal was used to analyze the burden of rare variants in the hereditary parkinsonism gene set, which was constructed from the Online Mendelian Inheritance in Man database through manual curation. The hereditary parkinsonism gene set consisted of 17 genes with a locus symbol prefix for familial Parkinson’s disease and 75 hereditary atypical parkinsonism genes. We detected a significant association of enriched burdens of predicted damaging rare coding variants in hereditary parkinsonism genes in all three datasets. Meta-analyses of the rare variant burden test in a subgroup of gene sets revealed an association between burdens of rare damaging variants with PD in a hereditary atypical parkinsonism gene set, but not in a subgroup gene set with a locus symbol prefix for familial Parkinson’s disease. Our results highlight the roles of rare damaging variants in causative genes for hereditary atypical parkinsonian disorders. We propose that Mendelian genes associated with hereditary disorders accompanying parkinsonism are involved in Parkinson’s disease-related genetic networks. •Manual curation of OMIM identified 92 Mendelian genes for hereditary parkinsonism.•Hereditary parkinsonism genes consist of 17 PARK genes and 75 non-PARK genes.•The burden of rare damaging variants in PARK and non-PARK genes was increased in Parkinson’s disease.•A meta-analysis revealed the enrichment of rare damaging variants in non-PARK genes in Parkinson’s disease.