Age at Natural Menopause and Disease Patterns Across the Lifespan: Phenome-Wide and Genetic Evidence from Multi-Ancestry Biobanks

By 2030, an estimated 1.2 billion women will have transitioned into menopause, reflecting a rapidly aging global demographic. The timing of age at natural menopause (ANM) is influenced by genetic, hormonal, environmental, and lifestyle factors and is a key determinant of long-term women’s health. Earlier menopause is associated with increased risk of type 2 diabetes and cardiovascular disease, whereas later menopause increases risk of endometrial and other gynecologic malignancies. Despite these established links, the broader phenotypic and genetic architecture of ANM across the life course remains incompletely characterized. To address this gap, we applied a multi-stage regression framework using electronic health record (EHR) and genomic data from three large biobanks: Penn Medicine Biobank, All of Us, and UK Biobank, encompassing 137,778 women (PMBB: 1,893; AoU: 21,016; UKBB: 114,869). This framework included EHR-wide predictor scans, menopause age predictor studies, and prospective and cross-sectional ANM-PheWAS (ANM-WAS) to model pre-, peri-, and post-menopausal disease associations across different genetically informed ancestries. In the present study, earlier ANM was consistently associated with increased risk of psychiatric, pain, sleep, inflammatory, and endocrine disorders, whereas later ANM showed stronger associations with lipid and glucose dysregulation. Pre-menopausal predictors of earlier menopause clustered around infection, inflammation, and neuropsychological symptoms, while post-menopausal analyses revealed elevated risk of psychiatric, pain, and cardiometabolic outcomes, underscoring the lasting health impact of menopausal timing across the lifespan. We further assessed shared genetic architecture using linkage disequilibrium score regression (LDSR) on European ANM GWAS and AoU+UKBB summary statistics, identifying 242 genetically correlated phenotypes (p < 0.05), 25 of which overlapped with ANM-WAS signals, including anxiety, diabetes, atherosclerosis, COPD, depression, heart failure, breast cancer, and sleep-related movement disorders. Bidirectional Mendelian randomization across 194 correlated trait pairs identified three significant causal relationships (Bonferroni p < 2.58 × 10⁻⁴): earlier menopause increased risk of sleep-related movement disorders, whereas later menopause increased COPD risk. Together, these findings integrate phenome-wide and genetic evidence to reveal both causal and pleiotropic links between ANM and chronic disease, positioning menopause as a central biological axis bridging reproductive aging with systemic women’s health.