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. 2026 Mar 11.
doi: 10.1002/mds.70182. Online ahead of print.

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

Kathryn Step  1   2 , Carlos F Hernández  3 , Marzieh Khani  4 , Esraa Eltaraifee  5 , Ana Jimena Hernández-Medrano  6   7 , Pin-Jui Kung  8   9 , Miriam Ostrožovičová  10   11   12 , Alexandra Zirra  12 , Eduardo Pérez-Palma  3 , Niccolò E Mencacci  13 , Ignacio J Keller Sarmiento  13 , Huw R Morris  14 , Ignacio F Mata  15 , Juliana Acosta-Uribe  16   17 , Zih-Hua Fang  18 , Sara Bandres-Ciga  4 ; Global Parkinson's Genetics Program (GP2)
Collaborators, Affiliations

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

Kathryn Step et al. Mov Disord. .

Abstract

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. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Keywords: genome‐wide homozygosity; global Parkinson's Genetics Program (GP2); multi‐ancestral analysis; parkinson's disease; runs of homozygosity.

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References

    1. Bandres‐Ciga S, Diez‐Fairen M, Kim JJ, Singleton AB. Genetics of Parkinson's disease: an introspection of its journey towards precision medicine. Neurobiol Dis 2020;137:104782.
    1. Khani M, Cerquera‐Cleves C. Towards a global view of Parkinson's disease genetics. Ann Neurol 2024;95:831–842.
    1. Foo JN, Chew EGY. Identification of risk loci for Parkinson disease in Asians and comparison of risk between Asians and Europeans: a genome‐wide association study. JAMA Neurol 2020;77:746–754.
    1. Global Parkinson's Genetics Program. GP2: the global Parkinson's genetics program. Mov Disord 2021;36:842–851.
    1. Loesch DP, Horimoto ARVR. Characterizing the genetic architecture of Parkinson's disease in Latinos. Ann Neurol 2021;90:353–365.

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