Genome-wide Meta-Analysis of Heavy Menstrual Bleeding Reveals 36 Risk Loci

• HMB shares a significant part of its genetic architecture with other disorders of the female genital tract.

• F5-Leiden was the only common variant known to impact hemostasis with a large and significant effect on HMB

Heavy menstrual bleeding (HMB) is a widespread occurrence among women of reproductive age and inflicts a substantial impact on well-being and healthcare expenses. To better characterize the genetic architecture of HMB, we meta-analyzed GWAS summary statistics from five biobanks, involving up to 84,633 HMB cases and 598,195 controls from several ancestries. Out of 21 signals significantly associated with HMB in a discovery GWAS meta-analysis combining four biobanks, 20 had a concordant direction of effect in the remaining cohort, including 10 significantly replicated. By combining the discovery and replication datasets, 15 additional signals were identified in subsequent meta-analyses. These genetic analyses resulted in 36 signals (33 novel) significantly associated with HMB, and subsequent gene prioritization techniques (e.g., TWAS, PoPS) revealed likely causal genes. Notable discoveries included the strong protective effect of the F5-Leiden variant (rs6025-T, OR=0.75, P=6.8×10-33), variants at the FSHB and LHB/CGB loci, both involved in hormone production regulation, and several signals near genes involved in the Wnt/ß-catenin signaling pathway. We also observed strong and significant genetic correlations with disorders of the female genital tract, including uterine fibroids, endometriosis or ovarian cysts. Overall, we identified 33 novel genetic loci associated with HMB, significantly improving our understanding of the genetic etiology of this condition, which may provide new targets for the development of therapeutic strategies.