Organophosphates (OP) are widely used insecticides that acutely inhibit acetylcholinesterase enzyme activity. In our population-based of Parkinson's disease (PD), we have shown differential DNA methylation levels associated with OP exposure. Here we aim to describe the OP exposure related epigenetic profile using the PANTHER gene ontology classification system. We measured genome-wide DNA methylation levels (Illumina 450k) in 839 participants. We then first performed an epigenome-wide association study to assess the relationship between OP exposure (GIS-based) and methylation. After we assessed the associations between genome-wide methylation markers and OPs, we generated two sets of gene lists. First, genes from the significantly OP-associated CpGs (70 CpGs, p<10e-07, 41 genes), and second, genes of CpGs less strictly associated (p<5e-04; 1077 CpGs, 662 genes). Using the PANTHER software, we compared these gene lists with the human gene database (21,042 genes) to test for overrepresentation of molecular functions, biologic processes, and PANTHER pathways using a Fisher's exact test with false discovery rate (FDR) correction. We found among both PD patients and controls, OP exposure was associated with acetylcholine pathways. From the top 41 genes, the most enriched pathway was nicotinic acetylcholine receptor signaling pathway, fold enrichment=15.63, p-value=1.01e-03, FDR=1.64e-01. From the 662 genes, the top pathway was muscarinic acetylcholine receptor 1 and 3 signaling, fold enrichment=3.90, p-value=5.36e-04, FDR=4.73e-02. A number of other molecular functions, biological processes, and cellular components were also enriched in the group of 662 genes. These include pyrophosphatase related catalytic activity (p-value=2.75e-05, FDR=2.64-03) and postsynaptic membrane components (p-value=1.33e-03, FDR=2.13e-02). In this investigation, our results suggest that OP exposure influences DNA methylation levels in genes specifically related to acetylcholine pathways.
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