Poster #4- Stephanie Mohammed

From Phenome to Casuality: A Multilayered Analysis of Age at Natural Menopause and its Health-Related Consequences

Stephanie Mohammed, Ph.D 1, Lindsay Guare 2, Tess Cherlin 1, Penn Medicine Biobank, Regeneron Genetics Center, Marylyn D. Ritchie, Molly A. Hall, Shefali S. Verma Ph.D 1,2,3  1 Department of Pathology and Laboratory Medicine, University of Pennsylvania 2 Institute for Biomedical Informatics, University of Pennsylvania 3 Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania

By 2030, an estimated 1.2 billion women will have entered menopause or transitioned into postmenopause, reflecting global aging demographic. The timing of age at natural menopause (ANM) is shaped by genetic, hormonal, environmental, and lifestyle factors. Early menopause is associated with increased risk of type 2 diabetes and cardiovascular disease, whereas later menopause is linked to elevated risk of endometrial and other gynecologic malignancies. To investigate the phenotypic and genetic architecture of ANM, we analyzed electronic health record and genomic data from three large-scale biobanks: Penn Medicine Biobank (PMBB), All of Us (AoU), and UK Biobank (UKBB), comprising 137,778 women (PMBB: 1,893; AoU: 21,016; UKBB: 114,869). ANM-Wide association studies (ANM-WAS) identified 404 significant phenotypes associated with ANM in European ancestry participants (Bonferroni p < 6.13 × 10⁻⁵), 174 in African ancestry (p < 9.86 × 10⁻⁵), and 118 in admixed American (AMR) ancestry (p < 1.24 × 10⁻⁴). We assessed shared genetic architecture using linkage disequilibrium score regression (LDSR), leveraging the largest available European ANM GWAS (h² = 0.25 ± 0.02, λGC = 1.33) and AoU+UKBB summary statistics. A total of 242 phenotypes were genetically correlated with ANM (p < 0.05), of which 25 were concordant with ANM-WAS signals, including anxiety disorders, type 2 diabetes, atherosclerosis, chronic obstructive pulmonary disease (COPD), major depressive disorder, heart failure, breast cancer, and sleep-related movement disorders. Bidirectional Mendelian randomization (MR) was performed across 194 genetically correlated trait pairs to evaluate whether associations reflected potential causal relationships or arose from shared genetic architecture. . Three exposure-outcome pairs showed significant causal effects after Bonferroni correction (p < 2.58 × 10⁻⁴). Earlier menopause was associated with increased risk of sleep-related movement disorders (Egger: β = −0.6629, SE = 0.1769, 14 SNPs), while later menopause was causally linked to COPD using both the Median (β = 0.4405, SE = 0.0797) and Lasso (β = 0.4428, SE = 0.0560, z = −3.17) methods These findings illuminate both causal and pleiotropic links between ANM and a spectrum of chronic diseases, offering insights into shared genetic pathways and informing precision medicine strategies in women's health.