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.

中文翻译：

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帕金森病患者遗传性非典型帕金森病基因中罕见的破坏性变异的负担增加

据报道，与溶酶体贮积病或线粒体途径相关的基因中罕见编码变异的负担增加与特发性帕金森病有关。在遗传性帕金森病致病基因中破坏罕见编码变异的负担增加的假设下，我们通过病例对照设计分析了罕见编码变异的负担。使用了两组全外显子组测序数据和一组临床验证的特发性帕金森病病例和对照的全基因组基因分型数据，这些数据对公众开放。序列核关联测试优化用于分析遗传性帕金森病基因组中罕见变异的负担，该基因组是通过手动管理从在线孟德尔遗传数据库构建的。遗传性帕金森病基因组由 17 个具有家族性帕金森病基因座符号前缀的基因和 75 个遗传性非典型帕金森病基因组成。我们在所有三个数据集中检测到遗传性帕金森病基因中预测的破坏性罕见编码变异的丰富负担的显着关联。对基因组亚组中罕见变异负担测试的荟萃分析揭示了遗传性非典型帕金森病基因组中罕见破坏性变异的负担与 PD 之间的关联，但在具有家族性帕金森病基因座符号前缀的亚组基因组中没有关联. 我们的结果强调了罕见的破坏性变异在遗传性非典型帕金森病的致病基因中的作用。