Genome-Wide Assessment Reveals Ancestral Differences in Homozygosity Patterns Potentially Linked to Parkinson's Disease Etiology

Background: Recessive genetic variation and extended runs of homozygosity (ROHs) may contribute to the unexplained heritability of Parkinson's disease (PD), particularly in diverse and understudied populations. Objective: We conducted the first large-scale, multi-ancestral investigation of PD to examine the impact of genome-wide homozygosity on disease risk and age at onset (AAO). Using genotyping, imputed, and whole-genome sequencing data from 36,127 PD cases and 19,475 controls across nine ancestral populations from the Global Parkinson's Genetics Program, we aimed to identify novel regions of homozygosity contributing to PD heritability. Methods: We analyzed ROHs for total length (SROH), number (NROH), average length (AVROH), and genomic inbreeding coefficient (FROH). ROHs were intersected with known PD, pallido-pyramidal syndrome, and atypical parkinsonism gene regions and risk loci to assess pleomorphic or pleiotropic contributions. Homozygosity mapping identified ROH overlaps in families, consanguineous individuals, and early-onset PD (EOPD) cases. Results: Significant differences in SROH, AVROH, NROH, and FROH were observed between case status across ancestries, persisting after excluding known PD-associated recessive genes. Our analysis revealed distinct patterns of ROH enrichment associated with AAO, suggesting recessive genetic modifiers of PD. Homozygosity mapping was used to prioritize 52 variants either segregating in families or present in individuals with consanguinity. In total, 1,559 ROHs in consanguineous individuals and EOPD overlapped known PD gene regions and risk loci. Conclusions: ROH regions contribute to PD heritability across ancestries, partly reflecting recessive genetic architecture. Larger and more diverse whole-genome sequencing studies are needed to identify rare recessive variants influencing PD risk.