Genome-wide meta-analysis of heavy menstrual bleeding reveals 36 risk loci Available to Purchase

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

• F5-Leiden was the only common coagulation-affecting variant 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 their well-being and on health care expenses. To better characterize the genetic architecture of HMB, we conducted a meta-analysis of the summary statistics of genome-wide association studies (GWAS) from 5 biobanks that included up to 84 633 HMB cases and 598 195 controls from several ancestries. Of the 21 signals significantly associated with HMB in a discovery GWAS meta-analysis that combined 4 biobanks, 20 had a concordant direction of effect in the remaining cohort, including 10 that were significantly replicated. By combining the discovery and replication data sets, 15 additional signals were identified in subsequent meta-analyses. These genetic analyses identified 36 signals (33 novel) that were significantly associated with HMB, and gene prioritization techniques (eg, transcriptome-wide association studies, polygenic priority score) subsequently revealed likely causal genes. Notable discoveries included the strong protective effect of the F5-Leiden variant (rs6025-T; odds ratio, 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/β-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, thereby significantly improving our understanding of the genetic etiology of this condition, which may provide new targets for the development of therapeutic strategies.