Genome-wide association studies (GWAS) have increased our understanding of Parkinson’s disease (PD) genetics by identifying common disease-associated variants. However, much of the heritability remains unaccounted for and we hypothesized that this could be partly explained 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 PD GWAS 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 replication stage, successfully replicating three epistasis signals located nearby SNCA and within MAPT and WNT3. Admixture analysis showed that the epistatic effect on PD of those variants at these loci was observed in both European ancestry and Native American ancestry individuals. We assessed the functional impact of the epistasis signals across a range of functional/-omics datasets identifying significant single-variant eQTLs across brain tissues, epistasis eQTL signals in whole-blood, PD-relevant pathways and ontologies, and chromatin interactions between the regions of the interacting SNPs. In conclusion, we identified and replicated novel epistatic signals associated with PD risk across multiple diverse genetic ancestry cohorts, highlighting their enrichment in pathways relevant to Parkinson’s disease.

中文翻译：

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全基因组上位性分析揭示了与帕金森病风险相关的显著上位信号


全基因组关联研究 （GWAS） 通过识别常见的疾病相关变异，增加了我们对帕金森病 （PD） 遗传学的理解。然而，大部分遗传力仍未得到解释，我们假设这可以部分由上位性解释，上位性是两个或多个遗传变异之间的统计相互作用。在这里，我们开发了一种全基因组非详尽的上位性筛选管道，称为通过可变阈值的变体-变体相互作用 （VARI3），并将其应用于不同的 PD GWAS 队列。我们使用 14 个欧洲血统队列 （14,671 例和 17,667 例对照） 作为发现阶段，确定了 14 个重要的候选变体-变体相互作用。然后，我们使用四个独立队列 （13,377 例和 413,789 例对照） 作为复制阶段，成功复制了位于 SNCA 附近以及 MAPT 和 WNT3 内的三个上位性信号。混合分析表明，在欧洲血统和美洲原住民血统个体中均观察到这些变异在这些位点对 PD 的上位效应。我们在一系列功能/组学数据集中评估了上位信号的功能影响，这些数据集确定了脑组织中重要的单变体 eQTL、全血中上位性 eQTL 信号、PD 相关通路和本体，以及相互作用的 SNP 区域之间的染色质相互作用。总之，我们在多个不同的遗传祖先队列中识别并复制了与 PD 风险相关的新上位性信号，突出了它们在与帕金森病相关的通路中的富集。