Objective: The aim of this study was to identify potential genetic modifiers of age at onset in PRKN-associated Parkinson’s disease (PD) through a genome-wide association study (GWAS). We also aimed to investigate whether polygenic risk scores (PRS) derived from sporadic PD GWAS demonstrate predictive utility in PRKN-PD.

Background: We previously demonstrated, in a genotype-phenotype correlation study of PRKN– PD, that although variant-specific factors correlate with age at onset, individuals carrying the same homozygous variant show wide phenotypic variability, for example, age at onset ranging from 10 to 49 years among those with homozygous exon 3 deletions.¹ This variability suggests the presence of additional genomic modifiers influencing disease phenotype.

Method: A total of 192 DNA samples from PRKN-PD patients were genotyped using the Illumina Infinium OmniExpress microarray; 152 samples passed quality control (PLINK v1.9). Genome-wide association testing for age at onset, as a continuous quantitative trait, was performed using REGENIE v4.1, with sex and the first ten principal components included as covariates. PRS were calculated using the Michigan Imputation Server 2 pipeline for ten published PD PRS (PGS000056, PGS000123, PGS000211, PGS000750, PGS000777, PGS000902, PGS000903, PGS001353, PGS001774, PGS003763).

Results: The majority of the cohort was of European ancestry (85%). Eight variants reached a suggestive significance threshold (P < 1×10⁻⁵), three of which clustered on chromosome 12 (~73.3 Mb); collapsing variants within ±500 kb windows to a single lead SNP per locus yielded six independent loci. Functional annotation using SnpEff classified all lead variants as non-coding. None of the ten PD PRS showed statistically significant associations with age at onset in sex-adjusted linear regression models.

Conclusion: Although the sample size was insufficient to achieve genome-wide significance, this preliminary GWAS suggests that dysregulation of gene expression control and RNA modification processes may contribute to phenotypic variation in PRKN-PD. The lack of predictive utility for any PD PRS in PRKN-PD further points to fundamental differences in the genetic architecture underlying phenotypic variation between sporadic PD and PRKN-PD, consistent with the distinct mitochondria-driven pathogenic mechanism of the latter.

References: 1.Menon PJ, Sambin S, Criniere-Boizet B, et al. Genotype-phenotype correlation in PRKN-associated Parkinson’s disease. NPJ Parkinsons Dis. 2024;10(1):72. Published 2024 Mar 29.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-genome-wide-search-for-common-variants-modifying-age-at-onset-in-prkn-associated-parkinsons-disease/