Integrating Environmental, Genomic, and Functional Data to Characterize Individual Risk for Parkinson's Disease

The overall purpose of this work is to identify methods for characterizing which individuals may be particularly susceptible to specific toxic insults, and the underlying mechanisms. We have three Aims: 1) use iPSC-derived neuronal cell lines to validate and extend our prior work that found an 11-fold increased risk of Parkinson's disease (PD) in persons exposed to the herbicide paraquat who lacked functional glutathione-S-transferase T1 (GSTT1), a key metabolic enzyme with anti-oxidant function; 2) perform whole genome sequencing of existing DNA specimens from a PD study with highly characterized pesticide exposures, using bioinformatic tools to identify likely functional gene-environment interactions; and 3) test our predictions using iPSC-derived neuronal cell lines that model these genetic variations, and exposing cellular lines to these same environmental agents. This is a partnering PI project with W81XWH-20-1-0709. The scope of the -0710 project is to accomplish Aims 1 and 3. To date, for Aims 1 and 3, we have established 3 clones of iPSC-derived dopamineergic neurons and have down-regulated GSTT1 in one of these lines so far. We have also established markers of oxidative stress and cell death, and used these markers to established dose-response curves for the 6 toxicants pertinent to this study. For Aim 2, we have completed sequencing of genomic DNA of 270 individuals, 5 more than specified in the SOW. In combination with existing sequencing data for this population we now have sequencing data for 340 study participants. Using a range of curation approaches and imputation of GWAS data we have and continue to identify compelling gene-pesticide interactions. In the next year of the project we will incorporate sequencing data to identify likely causal variants which will be validated as Aim 3.