Evidence that geographic variation in genetic ancestry associates with uterine fibroids.

Jacob M Keaton,Sarah H Jones,Eric S Torstenson,Jacklyn N Hellwege,Digna R Velez Edwards,Todd L Edwards,Elizabeth A Jasper

doi:10.1007/s00439-021-02322-y

Abstract

Uterine fibroids disproportionately impact Black women. Evidence suggests Black women have earlier onset and higher cumulative risk. This risk disparity may be due an imbalance of risk alleles in one parental geographic ancestry subgroup relative to others. We investigated ancestry proportions for the 1000 Genomes phase 3 populations clustered into 6 geographic groups for association with fibroid traits in Black women (n=583 cases, 797 controls) and White women (n=1,195 cases, 1,164 controls). Global ancestry proportions were estimated using ADMIXTURE. Dichotomous (fibroids status and multiple fibroid status) and continuous outcomes (volume and largest dimension) were modeled for association with ancestry proportions using logistic and linear regression adjusting for age. Effect estimates are reported per 10% increase in genetically inferred ancestry proportion. Among AAs, West African (WAFR) ancestry was associated with fibroid risk, East African ancestry was associated with risk of multiple fibroids, Northern European (NEUR) ancestry was protective for multiple fibroids, Southern European ancestry was protective for fibroids and multiple fibroids, and South Asian (SAS) ancestry was positively associated with volume and largest dimension. In EAs, NEUR ancestry was protective for fibroids, SAS ancestry was associated with fibroid risk, and WAFR ancestry was positively associated with volume and largest dimension. These results suggest that a proportion of fibroid risk and fibroid trait racial disparities are due to genetic differences between geographic groups. Further investigation at the local ancestry and single variant levels may yield novel insights about disease architecture and genetic mechanisms underlying ethnic disparities in fibroid risk.

Highlights

Uterine fibroids, or leiomyomata, are benign smooth muscle neoplasms of the uterus and are the most common benign tumors among women of reproductive age(Wallach and Vlahos, 2004)
In European American (EA), Northern European (NEUR) ancestry was protective for fibroids, South Asian (SAS) ancestry was associated with fibroid risk, and West African (WAFR) ancestry was positively associated with volume and largest dimension
In Black subjects, WAFR ancestry was associated with fibroid risk (OR=1.54, 95% CI=1.23-1.92, P=1.79x10-4), East African (EAFR) ancestry was associated with risk of multiple fibroids (OR=1.63, 95% CI=1.02-2.61, P=0.04), NEUR ancestry was protective for multiple fibroids (OR=0.45, 95% CI=0.23-0.87, P=0.02), and SEUR ancestry was protective for fibroids (OR=0.79, 95% CI=0.67-0.95, P=0.01) and multiple fibroids (OR=0.67, 95% CI=0.46-0.97, P=0.04)

Summary

Introduction

Leiomyomata, are benign smooth muscle neoplasms of the uterus and are the most common benign tumors among women of reproductive age(Wallach and Vlahos, 2004). Fibroid incidence increases with age ranging from 20% after menarche up to 80% by the onset of menopause(Baird et al, 2003, Cramer and Patel, 1990, Laughlin et al, 2009, Lippman et al, 2003, Marshall et al, 1997, Zimmermann et al, 2012). Clinical and epidemiology studies have identified numerous predisposing risk factors that may play a role in the pathogenesis. Genetics appear to play a major role. Women with firstdegree relatives with fibroids have an increased risk of developing fibroids compared to those without a family history (Sato et al, 2002, Vikhlyaeva et al, 1995). Race and ethnicity are the biggest risk factors for the development. The contribution of genetic ancestry to fibroid risk has been unclear

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