Analysis of HeterozygousPRKNVariants and Copy-Number Variations in Parkinson's Disease

BACKGROUND BiallelicPRKNmutation carriers with Parkinson's disease (PD) typically have an earlier disease onset, slow disease progression, and, often, different neuropathology compared to sporadic PD patients. However, the role of heterozygousPRKNvariants in the risk of PD is controversial. OBJECTIVES Our aim was to examine the association between heterozygousPRKNvariants, including single-nucleotide variants and copy-number variations (CNVs), and PD. METHODS We fully sequencedPRKNin 2809 PD patients and 3629 healthy controls, including 1965 late-onset (63.97 +/- 7.79 years, 63% men) and 553 early-onset PD patients (43.33 +/- 6.59 years, 68% men).PRKNwas sequenced using targeted next-generation sequencing with molecular inversion probes. CNVs were identified using a combination of multiplex ligation-dependent probe amplification and ExomeDepth. To examine whether rare heterozygous single-nucleotide variants and CNVs inPRKNare associated with PD risk and onset, we used optimized sequence kernel association tests and regression models. RESULTS We did not find any associations between all types ofPRKNvariants and risk of PD. Pathogenic and likely-pathogenic heterozygous single-nucleotide variants and CNVs were less common among PD patients (1.52%) than among controls (1.8%, false discovery rate-correctedP= 0.55). No associations with age at onset and in stratified analyses were found. CONCLUSIONS Heterozygous single-nucleotide variants and CNVs inPRKNare not associated with PD. Molecular inversion probes allow for rapid and cost-effective detection of all types ofPRKNvariants, which may be useful for pretrial screening and for clinical and basic science studies targeting specificallyPRKNpatients. (c) 2020 International Parkinson and Movement Disorder Society

Automated summary

The study found no association between heterozygous single-nucleotide variants and CNVs in PRKN and the risk of PD. Pathogenic and likely-pathogenic variants were less common among PD patients than controls, with no associations found with age at onset.