Although sex, genetics, and exposures can individually influence risk for sporadic Parkinson’s disease (PD), the joint contributions of these factors to the epigenetic etiology of PD have not been comprehensively assessed. Here, we profiled sex-stratified genome-wide blood DNAm patterns, SNP genotype, and pesticide exposure in agricultural workers (71 early-stage PD cases, 147 controls) and explored replication in three independent samples of varying demographics (n = 218, 222, and 872). Using a region-based approach, we found more associations of blood DNAm with PD in females (69 regions) than in males (2 regions, Δβ_adj| ≥0.03, p_adj ≤ 0.05). For 48 regions in females, models including genotype or genotype and pesticide exposure substantially improved in explaining interindividual variation in DNAm (p_adj ≤ 0.05), and accounting for these variables decreased the estimated effect of PD on DNAm. The results suggested that genotype, and to a lesser degree, genotype-exposure interactions contributed to variation in PD-associated DNAm. Our findings should be further explored in larger study populations and in experimental systems, preferably with precise measures of exposure.

尽管性别、遗传和暴露可以单独影响散发性帕金森病 (PD) 的风险，但这些因素对 PD 表观遗传病因学的共同影响尚未得到全面评估。在这里，我们分析了农业工人中性别分层的全基因组血液 DNAm 模式、SNP 基因型和农药暴露情况（71 名早期 PD 病例，147 名对照），并探讨了在不同人口统计的三个独立样本中的复制情况（n  = 218, 222和 872）。使用基于区域的方法，我们发现女性（69 个区域）的血液 DNAm 与 PD 的关联性高于男性（2 个区域，Δβ _adj | ≥0.03，p _adj  ≤ 0.05）。对于女性的 48 个区域，包括基因型或基因型和农药暴露在内的模型在解释 DNAm 个体间变异方面得到了显着改善（p _adj  ≤ 0.05），并且考虑这些变量降低了 PD 对 DNAm 的估计影响。结果表明，基因型以及较小程度的基因型-暴露相互作用导致了 PD 相关 DNAm 的变异。我们的研究结果应该在更大的研究人群和实验系统中进一步探索，最好是通过精确的暴露测量。