Analysis of heterozygous PRKN variants and copy number variations in Parkinson's disease

BackgroundBiallelic PRKN mutation carriers with Parkinsons disease (PD) typically have an earlier disease onset, slow disease progression and, often, different neuropathology compared to sporadic PD patients. However, the role of heterozygous PRKN variants in the risk of PD is controversial. ObjectivesWe aimed to examine the association between heterozygous PRKN variants, including single nucleotide variants and copy-number variations, and PD. MethodsWe fully sequenced PRKN in 2,809 PD patients and 3,629 healthy controls, including 1,965 late onset (63.97{+/-}7.79 years, 63% men) and 553 early onset PD patients (43.33{+/-}6.59 years, 68% men). PRKN was sequenced using targeted next-generation sequencing with molecular inversion probes. Copy-number variations were identified using a combination of multiplex ligation-dependent probe amplification and ExomeDepth. To examine whether rare heterozygous single nucleotide variants and copy-number variations in PRKN are associated with PD risk and onset, we used optimized sequence kernel association tests and regression models. ResultsWe did not find any associations between all types of PRKN variants and risk of PD. Pathogenic and likely-pathogenic heterozygous single nucleotide variants and copy-number variations were less common among PD patients (1.52%) than among controls (1.8%, false discovery rate-corrected p=0.55). No associations with age at onset and in stratified analyses were found. ConclusionsHeterozygous single nucleotide variants and copy-number variations in PRKN are not associated with Parkinsons disease. 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.