Sex-Stratified Genetic Analyses Mapping the Influences of Sedentary Behaviors and Physical Activity on Female Reproductive Health

we performed sex-stratified genome-wide association studies of 5 lifestyle factors in European participants from UK Biobank, including self-reported leisure screen time (LST), sedentary behaviors at work and during commuting, time spent in driving, and daily physical activity. We identified 18 novel sex-stratified variants associated with these exposures and showed that LST was more heritable in women (8.6%) than in men (6.9%). Mendelian randomization (MR) analyses using women-related instruments on 4 female reproductive outcomes demonstrated that per 1-h longer LST a day was robustly associated with elevated risks of menorrhagia (odds ratio [OR] = 1.31, 95% confidence interval [CI] = 1.10 to 1.55), endometriosis (OR = 1.34, 95% CI = 1.11 to 1.60), polycystic ovarian syndrome (OR = 3.05, 95% CI = 1.65 to 5.65), and ectopic pregnancy (OR = 1.35, 95% CI = 1.11 to 1.65), while little evidence was found for sedentary behaviors at work or during commuting. Mediation MR showed that the associations with these outcomes were independent from body mass index, except polycystic ovarian syndrome. Nonlinear MR suggested that LST ≥4 h/day was robustly associated with increased risks of endometriosis and menorrhagia. The findings were independently validated using additional genetic data from the European population and survey data from the National Health and Nutrition Examination Survey. In summary, a simple and actionable lifestyle modification, sitting less, is likely to have independently beneficial influences on multiple reproductive disorders.