Lysosomal genes contribute to Parkinson's disease near agriculture with high intensity pesticide use

Abstract

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.

Fig. 1. Study design.

a Hypothesis. Parkinson’s disease risk is known to be influenced by variants in genes associated with lysosomal function as well as environmental influences such as pesticide exposure (dashed lines). In this study, we investigated the relationship between both lysosomal gene variation and pesticide exposure in a PD cohort. b Patient selection. To assess degree of pesticide exposure as a variable in combination with disease progression, the cohort was sub-divided as shown. c Variant selection and analysis workflow. HGMD: Human Gene Mutation Database.

Fig. 2. Genetic variants enriched in the PEG study patient cohort prioritized by pesticide exposure and disease progression.

All enriched genetic exonic variants are shown and arranged by measures of exposure to the cotton cluster pesticides and disease progression. For pesticide exposure, scores represent scaled values derived from weighting individual pesticides in the cotton cluster by toxicity and exposure occurrence where a score of 1 represents the reference level for the cohort while higher numbers indicate increased toxicity and/or exposure. For disease progression, scores are scaled such that a score of 1 represents baseline symptom severity and rate of progression in the cohort while higher numbers represent faster progression and/or more severe symptoms. Variants with both an average weighted sum of 1 or greater for cotton cluster pesticide exposure and an average disease progression score of 1 or greater are highlighted. Blue points were found to be enriched in subjects of European/non-Hispanic descent while red points represent variants found to be enriched in patients of Hispanic descent. For LAMP1, the same variant is shown in both blue and red as it is enriched in both sub-populations. Genes with multiple variants identified and/or genes with single variants identified in multiple individuals in the patient cohort are highlighted. Arrows indicate single variants while circles represent two variants.