PB0139 - Heavy menstrual bleeding GWAS meta-analysis in >40,000 cases and >383,000 controls reveals 29 loci suggesting multiple contributing pathways of etiology

Sunday, June 25, 2023

18:30 – 19:30 ET

Room: Exhibition

Presenting Author(s)

Jason A. Cunha, B.A. (he/him/his)

Postbaccalaureate IRTA Fellow
National Heart Lung and Blood Institute, Division of Intramural Research, Bethesda, MD, USA
Framingham, Massachusetts, United States

Co-Author(s)

Florian Thibord, PhD

Post-Doctoral Fellow
Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, MA, USA.
Jamaica Plain, Massachusetts, United States
JH

Jennifer E. Huffman

Scientific Director for Genomics Research
Center for Population Genomics, VA Boston Healthcare System
Boston, Massachusetts, United States
PW

Peter Wilson

Director of Epidemiology and Genomic Medicine
Atlanta VA Medical Center, Decatur, GA, USA
Atlanta, Georgia, United States
KC

Kelly Cho

Director, Data Science and Analytics
Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA
Boston, Massachusetts, United States
Jill M. Johnsen, MD (she/her/hers)

Associate Professor, Division of Hematology
University of Washington, Institute for Stem Cell and Regenerative Medicine, Seattle, WA, USA
Seattle, Washington, United States
MC

Ming-Huei Chen

Staff Scientist
Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, Massachusetts, USA
Framingham, Massachusetts, United States
Andrew D. D. Johnson, PhD (he/him/his)

Professor
Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, MA, USA.
Framingham, Massachusetts, United States

Background: Heavy menstrual bleeding (HMB) is the most prevalent global clinical bleeding issue and contributes to iron deficiency anemia and negative quality-of-life outcomes. Large biobanks such as UK Biobank (UKBB), the VA Million Veteran Program (MVP), and FINNGEN could help discover HMB genetic risk loci using a well-powered genome-wide association study (GWAS). To our knowledge this is the first study to report a GWAS focused specifically on HMB in the general population.

Aims: To identify genome-wide significant variants associated with HMB among individuals from UKBB, MVP, and FINNGEN.

Methods: Study Population: Data from individuals with HMB ICD-9/10 codes was sourced from UKBB (13,500 cases/247,045 total), FINNGEN (19,024 cases/119,687 total), and MVP (7,550 cases/56,898 total). GWAS and Meta-Analysis: UKBB, MVP, and FINNGEN used generalized mixed effects models implemented in SAIGE and REGENIE that account for relatedness and population structure with adjustments for age, genetic principal components, and cohort-specific covariates. For the meta-analysis, we applied a fixed-effects approach using METAL.

Results: Multi-population meta-analysis: GWAS signals (p < 5E-8) (Figure 1) were identified in regions previously associated with uterine fibroids (UFs) (e.g.,CDC42/WNT4, GATA2, TP53, SYNE1), coagulation (FV), and several relevant cancers (e.g., ovarian, uterine, breast). Some novel candidate genes are highly expressed in uterine tissues according to GTeX (e.g., GMNC, STK26). The strongest single association was a protective effect of the FV Leiden variant (OR=0.69 [0.66-0.74], P=1.8E-33). European, Hispanic, African analyses: Population-specific, genome-wide significant variants were identified in regions previously associated with breast cancer (TSPYL6); T-cell leukemia (IKZF2); endometriosis (CADM2) and Crohn’s Disease (PRKCQ), respectively.

Conclusion(s): Variants were identified in loci with genes highly expressed in the uterus, or identified in prior UF or malignant female growth loci, suggesting major enrichment of these in HMB. Aside from FV Leiden, there were relatively few overlaps with genetic signals for platelet phenotypes (GATA2), anemia, hemostasis or coagulation loci.