Step Kathryn, Hernández Carlos F, Eltaraifee Esraa, Hernández-Medrano Ana Jimena, Kung Pin-Jui, Ostrožovičová Miriam, Zirra Alexandra, Pérez-Palma Eduardo, Mencacci Niccolò E, Keller Sarmiento Ignacio J, Morris Huw R, Mata Ignacio F, Acosta-Uribe Juliana, Fang Zih-Hua, Bandres-Ciga Sara
Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town.
medRxiv. 2025 May 22:2025.05.21.25328076. doi: 10.1101/2025.05.21.25328076.
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.
We analyzed runs of homozygosity (ROHs) for total length (S), number (N), average length (AV), and genomic inbreeding coefficient (F). 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.
Significant differences in S, AV, N, and F 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.
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.
我们开展了首次帕金森病（PD）的大规模、多祖先调查，以研究全基因组纯合性对疾病风险和发病年龄的影响。利用来自全球帕金森病遗传学项目九个祖先群体的16599例PD病例和13585例对照的基因分型、推算及全基因组测序（WGS）数据，我们旨在识别对PD遗传性有贡献的新的纯合区域。
我们分析了纯合片段（ROH）的总长度（S）、数量（N）、平均长度（AV）和基因组近亲繁殖系数（F）。将ROH与已知的PD、苍白球-锥体综合征和非典型帕金森病基因区域及风险位点进行交叉分析，以评估多态性或多效性贡献。纯合性定位确定了家族、近亲个体和早发性PD（EOPD）病例中的ROH重叠情况。
在多个祖先群体的病例和对照之间观察到S、AV、N和F存在显著差异，在排除已知的与PD相关的隐性基因后仍然存在。我们的分析揭示了与发病年龄相关的ROH富集的不同模式，表明在不同祖先背景下存在PD的隐性遗传修饰因子。纯合性定位确定了672个病例特有的ROH池、21个优先变异和1300个在病例中富集的ROH。最后，近亲个体和EOPD中的167个ROH与已知的PD和风险位点重叠。
我们的研究结果表明，在全球范围内，ROH区域对PD遗传性有贡献，部分归因于隐性等位基因结构。我们开发了一个用于无偏倚纯合性定位的开放科学框架。未来的研究应使用更大、更多样化的队列和WGS数据来揭示与PD易感性相关的罕见隐性变异。
