Fibroids affect 77% of women by onset of menopause in the U.S. and account for $2.1 billion in healthcare costs each year. Fibroids negatively impact reproductive health causing heavy and painful menses, pelvic pain and pressure, pregnancy complications, and interventions including myomectomy and hysterectomy. Until recently, tumor tissue and cell culture studies investigating fibroid growth have been the primary sources for understanding fibroid pathophysiology. Genetic analysis can provide a powerful and cost effective tool to identify etiological and causal factors, especially since a genetic predisposition to fibroids has already been documented from twin studies. As much as 69% of risk is explained by genetic factors. Racial disparities also support a role for genetics with fibroid risk. African American women have earlier age of onset, more numerous and larger fibroids with a greater lifetime incidence compared to Caucasians. We propose to identify genetic markers for risk of fibroids through a genome-wide association study (GWAS) of African American and Caucasian participants, leveraging ancestral differences to narrow down genomic regions for targeted follow- up analyses. To accomplish this we will take advantage of a unique Vanderbilt resource, the BioVU DNA databank. BioVU currently has over 122,470 adults linked to electronic medical records. From BioVU we have already identified 2,902 African American and Caucasian subjects who meet our stringent inclusion criteria to conduct a GWAS of fibroids, including pelvic imaging. Available imaging is critical, because many women with fibroids are asymptomatic and without imaging, studies may misclassify as many as 51% of women. We have also defined definitive controls who reached menopause without fibroids. We have a strong group of nationally known fibroid researchers who will provide over 10,000 samples for replication. Our first Specific Aim is to conduct a GWAS for association between common single nucleotide polymorphisms (SNPs) and fibroid risk. Using a case-control design we will perform a GWAS in 2,902 (1,451 fibroid cases and 1,451 controls) women from BioVU stratified by African American and Caucasian race. Secondary admixture mapping (AM) analyses will also be performed to identify chromosomal regions of interest to prioritize for replication.
Our second Aim i s to resequence chromosome regions identified from GWAS and AM to discover rare variants. Finally, in Aim 3 we will replicate SNPs selected from Aim 1 and 2 in independent samples of at least 3,230 fibroid cases and 7,097 controls. We propose an efficient and cost-effective approach to identify genetic risk factors for fibroids, by taking advantage of imaging information and DNA available through BioVU. This study represents the largest GWAS of uterine fibroids and the first among African Americans leveraging emerging technologies and new statistical approaches to conduct this study. Our proposed study will fundamentally change knowledge about fibroids and lay the ground work for breakthroughs in understanding mechanisms of fibroid formation and in identifying novel therapeutic approaches.

Public Health Relevance

Even though fibroids are heritable and there is a known disparity in fibroid risk, the literature about the genetics of fibroids remains meager. Little progress has been made relative to other complex diseases, despite federal research agencies including the NIH, NICHD, and AHRQ recognizing fibroids among their priority women's health topics. This proposed genome-wide association study that includes leveraging ancestry for targeted fine mapping, targeted next-generation resequencing experiments, and larger-scale replication will be a crucial contribution to knowledge about the genetics of uterine fibroids.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Meikle, Susan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Obstetrics & Gynecology
Schools of Medicine
United States
Zip Code
Mosley, Jonathan D; Feng, QiPing; Wells, Quinn S et al. (2018) A study paradigm integrating prospective epidemiologic cohorts and electronic health records to identify disease biomarkers. Nat Commun 9:3522
Bray, Michael J; Torstenson, Eric S; Jones, Sarah H et al. (2018) Evaluating risk factors for differences in fibroid size and number using a large electronic health record population. Maturitas 114:9-13
Bray, Michael J; Wellons, Melissa F; Jones, Sarah H et al. (2018) Transethnic and race-stratified genome-wide association study of fibroid characteristics in African American and European American women. Fertil Steril 110:737-745.e34
Gamazon, Eric R; Segrè, Ayellet V; van de Bunt, Martijn et al. (2018) Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation. Nat Genet 50:956-967
Borah, Bijan J; Yao, Xiaoxi; Laughlin-Tommaso, Shannon K et al. (2017) Comparative Effectiveness of Uterine Leiomyoma Procedures Using a Large Insurance Claims Database. Obstet Gynecol 130:1047-1056
Giri, Ayush; Edwards, Todd L; Hartmann, Katherine E et al. (2017) African genetic ancestry interacts with body mass index to modify risk for uterine fibroids. PLoS Genet 13:e1006871
Hellwege, Jacklyn N; Torstenson, Eric S; Russell, Shirley B et al. (2017) Evidence of selection as a cause for racial disparities in fibroproliferative disease. PLoS One 12:e0182791
Velez Edwards, Digna R; Hartmann, Katherine E; Wellons, Melissa et al. (2017) Evaluating the role of race and medication in protection of uterine fibroids by type 2 diabetes exposure. BMC Womens Health 17:28
Hellwege, Jacklyn N; Jeff, Janina M; Wise, Lauren A et al. (2017) Erratum to: A multi-stage genome-wide association study of uterine fibroids in African Americans. Hum Genet 136:1497-1498
Bray, Michael J; Edwards, Todd L; Wellons, Melissa F et al. (2017) Admixture mapping of uterine fibroid size and number in African American women. Fertil Steril 108:1034-1042.e26

Showing the most recent 10 out of 16 publications