Sex and gender differences in the molecular etiology of Parkinson's disease: considerations for study design and data analysis

Abstract

Parkinson’s disease (PD) is more prevalent in men than women, and presents with different clinical features in each sex. Despite widespread recognition of these differences, females are under-represented in clinical and experimental studies of PD, and much remains to be elucidated regarding the biological underpinnings of sex differences in PD. In this review, we summarize known contributors to sex differences in PD etiology across the life course, with a focus on neurological development and gene regulation. Sex differences that are established at conception and heightened during adolescence and midlife may partially embed future PD risk, due to the complex interactions between gonadal hormones, gene regulation, lifestyle factors, and aging. While the neuroprotective properties of estrogen are strongly implicated in reduced prevalence of PD in women, interactions with genotype and gender-biased lifestyle factors are incompletely understood. Consideration of sex and genderrelated factors in study design, data analysis, and interpretation have the power to expedite our knowledge of the etiology of PD in men and in women, and to inform prevention and therapeutic strategies tailored to each sex. Plain english summary Parkinson’s disease (PD) more commonly affects men, and is known to have different symptoms in men and women. While this is in part due to the protective effects of estrogen in women, our understanding of why there is a sex difference in PD, and how it develops in each sex, is currently incomplete. This article provides an overview of factors throughout the lifespan that contribute to the differences between men and women in brain health and risk for PD, with a focus on hormones, gene regulation, and their intersections with lifestyle factors. We also discuss how researchers can consider sex and gender in future studies to enhance our understanding of how PD develops, and potentially develop sex-tailored prevention and treatment strategies. Highlights • Genetic risk for PD is similar between men and women. • Transcriptomic and epigenetic differences in men and women with PD have been reported, particularly in substantia nigra tissue. • Emerging evidence suggests interactions between gene regulation, sex hormones, and lifestyle factors contribute to disease pathogenesis in each sex. • Statistical approaches can be used to balance sex ratios and explore sex as a contributor to PD etiology, rather than a confounder. • Increasing representation of women in PD clinical studies is a priority for future research endeavors.