Parkinson’s disease (PD), the second most common neurodegenerative disorder, develops sporadically, likely through a combination of polygenic and environmental factors. Previous studies associate pesticide exposure and genes involved in lysosomal function with PD risk. We evaluated the frequency of variants in lysosomal function genes among patients from the Parkinson’s, Environment, and Genes (PEG) study with ambient pesticide exposure from agricultural sources. 757 PD patients, primarily of White European/non-Hispanic ancestry (75%), were screened for variants in 85 genes using a custom amplicon panel. Variant enrichment was calculated against the Genome Aggregation Database (gnomAD). Enriched exonic variants were prioritized by exposure to a cluster of pesticides used on cotton and severity of disease progression in a subset of 386 patients subdivided by race/ethnicity. Gene enrichment analysis identified 36 variants in 26 genes in PEG PD patients. Twelve of the identified genes (12/26, 46%) had multiple enriched variants and/or a single enriched variant present in multiple individuals, representing 61% (22/36) of the observed variation in the cohort. The majority of enriched variants (26/36, 72%) were found in genes contributing to lysosomal function, particularly autophagy, and were bioinformatically deemed functionally deleterious (31/36, 86%). We conclude that, in this study, variants in genes associated with lysosomal function, notably autophagy, were enriched in PD patients exposed to agricultural pesticides suggesting that altered lysosomal function may generate an underlying susceptibility for developing PD with pesticide exposure. Further study of gene-environment interactions targeting lysosomal function may improve understanding of PD risk in individuals exposed to pesticides.

帕金森病 (PD) 是第二常见的神经退行性疾病，呈散发性，可能是多基因和环境因素共同作用的结果。先前的研究将农药接触和参与溶酶体功能的基因与帕金森病风险联系起来。我们评估了帕金森病、环境和基因 (PEG) 研究中暴露于农业来源环境农药的患者中溶酶体功能基因变异的频率。使用定制扩增子组对 757 名 PD 患者（主要是欧洲白人/非西班牙裔血统 (75%)）进行了 85 个基因的变异筛查。变异富集是根据基因组聚合数据库（gnomAD）计算的。根据种族/族裔细分的 386 名患者的子集，根据接触棉花使用的一系列农药以及疾病进展的严重程度，对丰富的外显子变异进行优先排序。基因富集分析鉴定出 PEG PD 患者 26 个基因的 36 个变异。已识别的基因中有 12 个 (12/26, 46%) 在多个个体中存在多个富集变异和/或单个富集变异，占队列中观察到的变异的 61% (22/36)。大多数富集变异（26/36，72％）是在促进溶酶体功能（特别是自噬）的基因中发现的，并且在生物信息学上被认为是功能有害的（31/36，86％）。我们的结论是，在这项研究中，与溶酶体功能（尤其是自噬）相关的基因变异在接触农业农药的帕金森病患者中丰富，这表明溶酶体功能的改变可能会对接触农药的帕金森病产生潜在的易感性。针对溶酶体功能的基因-环境相互作用的进一步研究可能会提高对接触农药的个体的PD风险的了解。