AbstractImportanceBiallelic PRKN mutation carriers with Parkinson’s disease (PD) typically have an earlier disease onset, slow disease progression and, often, different neuropathology compared to sporadic patients. However, the role of heterozygous PRKN variants in the risk of PD remains unclear.ObjectiveTo examine the association between heterozygous PRKN variants, including single nucleotide variants and copy number variations (CNVs), and PD status.DesignThis case-control study was conducted in Canada using data from 4 centers in Canada, France, the United States and Israel, collected between 2013 and 2020.SettingMulticenter, population matched, unrelated participants.ParticipantsPD patients were compared with healthy controls. Participants were excluded if genetic data quality was poor, PRKN variants were biallelic, or relatedness was discovered. In total, 2,807 patients and 3,627 controls were recruited for the study. Data analyses were performed from January 2019 to March 2020.ExposureInheritance of heterozygous PRKN variants.Main Outcome(s) and Measure(s)PD was diagnosed by movement disorder specialists according to the UK Brain Bank Criteria or the Movement Disorder Society criteria. Targeted next-generation sequencing with molecular inversion probes and multiplex ligation-dependent probe amplification were used to detect rare variants and CNVs. These variants were examined with optimized sequence kernel association tests after accounting for potential pathogenicity. P values of optimized sequence kernel association tests between heterozygous PRKN variants and PD were measured.ResultsDNA of all participants were sequenced, including 1,903 late onset (mean [SD], 64.02±7.81 years, 1,196 men [63%]) and 542 early onset patients (mean [SD], 43.30±6.60, 368 men [68%]). Age at onset was not available for 349 patients. Carriers of two PRKN variants were excluded from the analysis. No associations were found between heterozygous variants and risk of PD. Pathogenic and likely pathogenic heterozygous variants and CNVs were less common among PD patients (1.0%) than among controls (1.3%).Conclusion and RelevanceThis study suggests that heterozygous variants and CNVs in PRKN are not associated with PD. Molecular inversion probes allow for rapid and cost-effective detection of all types of PRKN variants, which may be useful for pre-trial screening and for clinical and basic science studies specifically targeting PRKN patients.Key PointsQuestionAre rare heterozygous PRKN single nucleotide variants and copy number variations associated with Parkinson’s disease?FindingsIn this case-controls study including 2,807 patients and 3,627 controls, we found no significant association between rare heterozygous PRKN variants and risk of Parkinson’s disease.MeaningPRKN-associated parkinsonism is an autosomal recessive Mendelian disease, and based on our data, heterozygous carriers are not likely to be at increased risk of Parkinson’s disease.
Genetics of Parkinson’s Disease: The Role of Copy Number Variations