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 analysed runs of homozygosity (ROHs) for total length (SROH), number (NROH), average length (AvROH), and genomic inbreeding coefficient (FROH). ROHs were intersected with known PD, pallid-pyramidal syndrome, and atypical Parkinsonism gene regions and risk loci to assess pleomorphic and 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 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 prioritised 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.

The authors have declared no competing interest.

This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (NIA), National Institute of Health, Department of Health and Human Services; project number Z01 AG000535 and ZIA AG000949, as well as the National Institute of Neurological Disorders and Stroke (NINDS, program # ZIANS003154) and the National Human Genome Research Institute (NHGRI). Data used in the preparation of this article were obtained from the Global Parkinson's Genetics Program (GP2). GP2 is funded by the Aligning Science Across Parkinson's (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson's Research (https://gp2.org). For a complete list of GP2 members see https://gp2.org. Additional funding was provided by The Michael J. Fox Foundation for Parkinson's Research through grant MJFF-009421/17483. This work utilised the computational resources of the NIH STRIDES Initiative (https://cloud.nih.gov) through the Other Transaction agreement - Azure: OT2OD032100, Google Cloud Platform: OT2OD027060, Amazon Web Services: OT2OD027852. This work utilised the computational resources of the NIH HPC Biowulf cluster (https://hpc.nih.gov). K.S is funded by the Micheal J. Fox Foundation (MJFF) and Aligning Sciences Across Parkinson's Disease Global Parkinson Genetic Program (ASAP-GP2). Z-H.F. is supported by the Aligning Science Across Parkinson's (ASAP) Global Parkinson's Genetics Program (GP2) and received GP2 salary support from The Michael J. Fox Foundation for Parkinson's Research. I.M. was supported by grants from NIG (R01NS112499-01A1), the Michael J. Fox Foundation (MJFF), and Aligning Science Across Parkinson's Disease Global Parkinson's Genetics Program (ASAP-GP2). J.A.U. is funded by The Rainwater Charitable Foundation through the Tau consortium and the Center for Alzheimer's and Related Dementias. N.E.M. is supported by the NIH (1K08NS131581) and ASAP GP2; he is a member of the steering committee of the PD GENEration study and receives an honorarium from the Parkinson's Foundation. H.M. is employed by UCL. In the last 12 months he reports paid consultancy from Roche, Aprinoia, AI Therapeutics and Amylyx; lecture fees/honorarium- BMJ, Kyowa Kirin, Movement Disorders Society. Research Grants from Parkinson's UK, Cure Parkinson's Trust, PSP Association, Medical Research Council, Michael J. Fox Foundation. H.M. is a co-applicant on a patent application related to C9ORF72 - Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). A.Z is funded by the MCSBHT - Medical College of Saint Bartholomew's Hospital Trust. E.P-P. is supported by the Chilean National Agency for Investigation and Development, ANID (Fondecyt grant 1221464). C.F.H. is supported by the Chilean National Agency for Investigation and Development, ANID (Beca Doctorado Nacional 2020 Folio 21201541). E.E., A.J.H-M., P-J.K., M.O., I.J.K.S, and S.B-C. do not have any financial disclosures.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Data used in the preparation of this article were obtained from Global Parkinson's Genetics Program (GP2). GP2 is funded by the Aligning Science Across Parkinson's (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinsons Research (https://gp2.org). All GP2 data for these analyses is available through collaboration with Accelerating Medicines Partnership in Parkinson's disease and is available through application on the AMP-PD website.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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Data used in the preparation of this article were obtained from Global Parkinson's Genetics Program (GP2). GP2 is funded by the Aligning Science Across Parkinson's (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson's Research (https://gp2.org). All GP2 data for these analyses is available through collaboration with Accelerating Medicines Partnership in Parkinson's disease and is available through application on the AMP-PD website (https://amp-pd.org/register-for-amp-pd). For a complete list of GP2 members see https://gp2.org. GenoTools version 10 (https://github.com/GP2code/GenoTools) was used for quality control, imputation, and ancestry prediction. A secure workspace on the online Terra platform (https://app.tera.bio/) was created to analyse the data using GP2's release 6. Finally, all scripts used for the data analysis can be found in the public domain of GitHub (https://github.com/GP2code/ROH_genomewide/, (Markarious, 2025)).

https://amp-pd.org/register-for-amp-pd

https://github.com/GP2code/GenoTools

https://github.com/GP2code/ROH_genomewide