Genome-wide assessment identifies novel runs of homozygosity linked to Parkinson's disease etiology across diverse ancestral populations

Abstract

Objective: We conducted the first large-scale, multi-ancestral investigation of Parkinson's disease (PD) to examine the impact of genome-wide homozygosity on disease risk and age at onset. Using genotyping, imputed, and whole-genome sequencing (WGS) data from 16,599 PD cases and 13,585 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 runs of homozygosity (ROHs) for total length (S_ROH), number (N_ROH), average length (AV_ROH), and genomic inbreeding coefficient (F_ROH). 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 S_ROH, AV_ROH, N_ROH, and F_ROH were observed between cases and controls across multiple ancestral groups, persisting after excluding known PD-associated recessive genes. Our analysis revealed distinct patterns of ROH enrichment associated with age at onset, suggesting recessive genetic modifiers of PD across diverse ancestral backgrounds. Homozygosity mapping identified 672 case-exclusive ROH pools, 21 prioritized variants, and 1,300 ROHs enriched in cases. Finally, 167 ROHs in consanguineous individuals and EOPD overlapped known PD and risk loci.

Interpretation: Our findings suggest that ROH regions contribute to PD heritability in a global context, with a portion attributed to recessive allelic architecture. We developed an open-science framework for unbiased homozygosity mapping. Future studies should use larger, diverse cohorts and WGS data to uncover rare recessive variants linked to PD susceptibility.

Figure 1:

Overview of runs of homozygosity trends observed in different populations. N_ROH = total number of runs of homozygosity, S_ROH = total length of runs of homozygosity.

Figure 2:

Workflow and rationale summary. AAC = African Admixed, AFR = African, AJ = Ashkenazi Jewish, AMR = American Admixed, AVROH = average runs of homozygosity length, CAS = Central Asian, EAS = East Asian, EOPD = early-onset Parkinson’s disease, EUR = European, F= inbreeding coefficient, FROH = run of homozygosity based estimates for the inbreeding coefficient, KB = kilobase, LOPD = late-onset Parkinson’s disease, MB = megabase, MDE = Middle-Eastern, NROH, number of runs of homozygosity, ROH = runs of homozygosity, SAS = South Asian, SNPs = single nucleotide polymorphisms, SROH = total length of runs of homozygosity, - = excluding.