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

Kathie J Ngo; Kimberly C Paul; Darice Wong; Cynthia D J Kusters; Jeff M Bronstein; Beate Ritz; Brent L Fogel

doi:10.1038/s41531-024-00703-4

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

NPJ Parkinsons Dis. 2024 Apr 25;10(1):87. doi: 10.1038/s41531-024-00703-4.

Authors

Kathie J Ngo^#¹, Kimberly C Paul^#¹, Darice Wong^{1

2}, Cynthia D J Kusters³, Jeff M Bronstein¹, Beate Ritz^{1

3

4}, Brent L Fogel^{5

6

7}

Affiliations

¹ Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
² Clinical Neurogenomics Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
³ Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA.
⁴ Department of Environmental Health Sciences, UCLA Fielding School of Public Health, Los Angeles, CA, USA.
⁵ Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA. bfogel@ucla.edu.
⁶ Clinical Neurogenomics Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA. bfogel@ucla.edu.
⁷ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA. bfogel@ucla.edu.

^# Contributed equally.

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.

Abstract

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