Objective: Under a hypothesis that a burden of damaging rare coding variants is increased in causative genes for hereditary parkinsonism, we analyzed burdens of rare coding variants with a case-control design.

Background: 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.

Method: 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 public, were used. The sequence kernel association test–optimal was used to analyze variant burden in the hereditary parkinsonism gene set. A hereditary parkinsonism gene set consisting of 92 causative genes related to hereditary disorders accompanying parkinsonism regardless of a locus symbol prefix for familial Parkinson’s disease was constructed from the Online Mendelian Inheritance in Man database.

Results: We detected a significant association of enriched burdens of predicted damaging rare coding variants in hereditary parkinsonism genes in all three datasets. The significant associations remained after multiple testing correction in two datasets with larger sample sizes. In secondary analyses using a subset of genes without a locus symbol prefix for familial Parkinson’s disease, the associations of burden remained significant in two datasets.

Conclusion: Our results highlight the roles of damaging rare coding variants in causative genes for Mendelian disorders accompanying parkinsonism. We propose that causative genes for atypical hereditary parkinsonian disorders should be further explored to understand Parkinson’s disease-related genetic networks.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/enriched-burden-of-rare-coding-variants-in-hereditary-parkinsonism-genes-in-parkinsons-disease/