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Parkinson’s disease (PD) is a complex neurodegenerative disorder influenced by a combination of genetic and environmental factors. The molecular mechanisms that underlie PD are unknown; however, oxidative stress and impairment of antioxidant defence mechanisms have been implicated as major contributors to disease pathogenesis. Previously, we have reported a PD patient-derived cellular model generated from biopsies of the olfactory mucosa, termed hONS cells, in which the NRF2-mediated antioxidant response pathway genes were among the most differentially-expressed. To date, few studies have examined the role of the NRF2 encoding gene,  NFE2L2 , and PD. In this study, we comprehensibly assessed whether rare and common  NFE2L2  genetic variations modify susceptibility to PD using a large Australian case-control sample (PD=1338, controls=1379). We employed a haplotype-tagging approach that identified an association with the tagging SNP rs2364725 and PD (OR = 0.849 (0.760-0.948),  P  = 0.004). Further genetic screening in hONS cell lines produced no obvious pathogenic variants in the coding regions of  NFE2L2 . Finally, we investigated the relationship between xenobiotic exposures and NRF2 function, through gene-environment interactions, between  NFE2L2  SNPs and smoking or pesticide exposure. Our results demonstrated a significant interaction between rs2706110 and pesticide exposure (OR = 0.597 (0.393-0.900),  P  = 0.014). In addition, we were able to identify some age-at-onset modifying SNPs and replicate an ‘early-onset’ haplotype that contains a previously identified ‘functional promoter’ SNP (rs6721961). Our results suggest a role of  NFE2L2  genetic variants in modifying PD susceptibility and onset. Our findings also support the utility of testing gene-environment interactions in genetic studies of PD.

Comprehensive Assessment of Genetic Sequence Variants in the Antioxidant ‘Master Regulator’ Nrf2 in Idiopathic Parkinson’s Disease