Gene-environment interactions for Parkinson’s disease

Abstract

ABSTRACTImportanceParkinson’s disease (PD) is a neurodegenerative disorder with complex aetiology. Multiple genetic and environmental factors have been associated with PD, but most PD risk remains unexplained.ObjectiveThe aim of this study was to test for statistical interactions between PD-related genetic and environmental exposures/phenotypic traits in the 23andMe, Inc. research dataset.DesignNested cross-sectional case-control study.SettingPopulation-based cohort.ParticipantsPD subjects were recruited to join the 23andMe, Inc study population in collaboration with the Michael J. Fox Foundation and other PD patient advocacy groups, and/or via online surveys. Participants that reported a change or uncertainty in diagnosis during follow-up were excluded. Controls were recruited from 23andMe participants that did not report a diagnosis of PD at entry or on subsequent follow-up surveys.ExposuresUsing a validated PD polygenic risk score (PRS) and common PD-associated variants in theGBAgene, we explored interactions between genetic susceptibility factors and phenotypic traits: body mass index (BMI), type 2 diabetes (T2D), tobacco use, caffeine consumption, pesticide exposure, head injury, and physical activity (PA).Main Outcomes and MeasuresSelf-reported PD case/control status.ResultsThe dataset contained 18,819 PD cases (40.2% female) and 545,751 controls (55.7% female). The average age of PD cases and controls was 73.1 and 73.0 years, respectively (SDPD= 10.8 years, SDcontrol= 10.8 years). In models without gene-by-environment interactions, we observed that higher BMI, T2D, caffeine consumption, and tobacco use were associated with lower odds of PD, while head injury, pesticide exposure, andGBAcarrier status were associated with increased odds. We observed no significant association between PA and PD. PRS was associated with increased odds of PD and there was statistical evidence for an interaction between PRS and BMI, PRS and T2D, PRS and PA, and PRS and tobacco use (p=4.314E-4; p=6.502E-8; p=8.745E-5, p=2.236E-3, respectively). Whilst BMI and tobacco use were associated with lower odds of PD regardless of the extent of individual genetic liability, the direction of the relationship between odds of PD and T2D as well as PA, varied depending on PRS.Conclusions and RelevanceWe provide preliminary evidence that associations between phenotypic traits and PD may be modified by genotype.