Cisterna-Garcia Alejandro, Bustos Bernabe I, Bandres-Ciga Sara, Leal Thiago P, Sarihan Elif I, Jok Christie, Krainc Dimitri, Mata Ignacio F, Lubbe Steven J, Botia Juan A
Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, Murcia 30100, Spain.
Ken and Ruth Davee Department of Neurology and Simpson Querrey Center for Neurogenetics, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
Brain. 2025 Jun 3;148(6):2060-2074. doi: 10.1093/brain/awae398.
Genome-wide association studies have increased our understanding of Parkinson's disease genetics by identifying common disease-associated variants. However, much of the heritability remains unaccounted for, and we hypothesized that this could be explained, in part, by epistasis, the statistical interaction between two or more genetic variants. Here, we developed a genome-wide non-exhaustive epistasis screening pipeline called variant-variant interaction through variable thresholds (VARI3) and applied it to diverse Parkinson's disease genome-wide association study cohorts. We used 14 cohorts of European ancestry (14 671 cases and 17 667 controls) as a discovery stage, identifying 14 significant candidate variant-variant interactions. We then used four independent cohorts (13 377 cases and 413 789 controls) as the replication stage, successfully replicating three epistasis signals located near to SNCA and within MAPT and WNT3. Admixture analysis showed that the epistatic effect on Parkinson's disease of those variants at these loci was observed in individuals with both European ancestry and Native American ancestry. We assessed the functional impact of the epistasis signals across a range of functional/-omics datasets, identifying significant single-variant expression quantitative trait loci across brain tissues, epistasis expression quantitative trait locus signals in whole blood, Parkinson's disease-relevant pathways and ontologies, and chromatin interactions between the regions of the interacting single nucleotide polymorphisms. In conclusion, we identified and replicated novel epistatic signals associated with Parkinson's disease risk across multiple cohorts with diverse genetic ancestry, highlighting their enrichment in pathways relevant to Parkinson's disease.
全基因组关联研究通过识别常见的疾病相关变异，增进了我们对帕金森病遗传学的理解。然而，许多遗传力仍无法解释，我们推测这可能部分是由上位性（两个或更多基因变异之间的统计相互作用）造成的。在此，我们开发了一种名为通过可变阈值进行变异-变异相互作用分析（VARI3）的全基因组非详尽上位性筛选流程，并将其应用于不同的帕金森病全基因组关联研究队列。我们将14个欧洲血统的队列（14671例病例和17667例对照）作为发现阶段，识别出14个显著的候选变异-变异相互作用。然后，我们将4个独立队列（13377例病例和413789例对照）作为复制阶段，成功复制了位于SNCA附近以及MAPT和WNT3内的3个上位性信号。混合分析表明，在欧洲血统和美洲原住民血统的个体中均观察到这些位点的变异对帕金森病的上位性效应。我们在一系列功能/组学数据集中评估了上位性信号的功能影响，识别出跨脑组织的显著单变异表达数量性状位点、全血中的上位性表达数量性状位点信号、与帕金森病相关的通路和本体，以及相互作用的单核苷酸多态性区域之间的染色质相互作用。总之，我们在多个具有不同遗传血统的队列中识别并复制了与帕金森病风险相关的新型上位性信号，突出了它们在与帕金森病相关通路中的富集情况。
