Effect Modification between Genes and Environment and Parkinson's Disease Risk

Abstract

Parkinson's disease (PD) is a complex neurodegenerative condition in which genetic and environmental factors interact to contribute to its etiology. Remarkable progress has been made in deciphering disease etiology through genetic approaches, but there is limited data about how environmental and genetic factors interact to modify penetrance, risk, and disease severity. Here, we provide insights into environmental modifiers of PD, discussing precedents from other neurological and non-neurological conditions. Based on these examples, we outline genetic and environmental factors contributing to PD and review potential environmental modifiers of penetrance and clinical variability in monogenic and idiopathic PD. We also highlight the potential challenges and propose how future studies might tackle these important questions. ANN NEUROL 2022;92:715-724.

FIGURE 1

A model of the interplay among gene–environment interactions, epigenetic changes, and stochastic events in Parkinson's disease (PD). Interactions between genetic factors and environmental exposures (the “exposome”) are thought to be major contributors to the etiology of PD. Emerging evidence has shown that epigenetics may play an important role in the pathophysiology of PD, potentially representing a mechanistic bridge between the gene–environment interactions. However, most of the variation remains unexplained, illustrating the inherently stochastic nature of PD. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 2

Factors regulating the pathogenesis of LRRK2‐associated Parkinson's disease. Several studies have recognized various risk factors, including genetic variation, non‐genetic factors, as well as epigenetic mechanisms that may alter LRRK2 dynamics. Examples of genetic variants include Arg1628Pro, Gly2019Ser, Gly2385Arg, and Arg1441Gly. Non‐genetic factors comprise age, sex, nonsteroidal anti‐inflammatory drugs (NSAIDs), caffeine, urate, tobacco, and tea. Examples of epigenetic modifiers include DNA methylation (DNA‐m) and microRNAs (miRNAs). [Color figure can be viewed at www.annalsofneurology.org]