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Evidence that geographic variation in genetic ancestry associates with uterine fibroids

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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 six geographic groups for association with fibroid traits in Black women (n = 583 cases, 797 controls) and White women (n = 1195 cases, 1164 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 Black women, 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 White women, 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 into disease architecture and genetic mechanisms underlying ethnic disparities in fibroid risk.

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The data underlying this article will be shared on reasonable request to the corresponding author.

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Funding

The BioVU dataset used for the analyses described was obtained from Vanderbilt University Medical Center’s BioVU which is supported by institutional funding and by the Vanderbilt CTSA grant ULTR000445 from NCATS/NIH. D.R.V.E. was supported by National Institute of Health grants R01HD074711, R01HD093671, and R03HD078567. J.N.H. was supported by K12HD04348 (PI K.E. Hartmann). J.M.K. and E.A.J. were supported by the National Human Genome Research Institute training grant 5T32HG008341.

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Author notes

  1. Jacob M. Keaton and Elizabeth A. Jasper are co-first authors.

Authors and Affiliations

  1. Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    Jacob M. Keaton

  2. Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Jacob M. Keaton, Eric S. Torstenson & Todd L. Edwards

  3. Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA

    Elizabeth A. Jasper, Jacklyn N. Hellwege, Eric S. Torstenson, Todd L. Edwards & Digna R. Velez Edwards

  4. Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA

    Elizabeth A. Jasper & Digna R. Velez Edwards

  5. Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, 37203, USA

    Elizabeth A. Jasper & Digna R. Velez Edwards

  6. Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Jacklyn N. Hellwege

  7. Vanderbilt Epidemiology Center, Vanderbilt University, Nashville, TN, USA

    Jacklyn N. Hellwege & Sarah H. Jones

  8. Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, TN, USA

    Todd L. Edwards & Digna R. Velez Edwards

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  1. Jacob M. Keaton
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  7. Digna R. Velez Edwards
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Contributions

JMK assisted with analysis and drafting manuscript. EAJ assisted with analysis and drafting manuscript. JNH assisted with analysis and data quality control and edited the final draft. SHJ assisted with data management and edited final draft. EST assisted with data management and quality controls and edited final draft. TLE helped develop the study design and analysis plan and edited the manuscript. DRV Edwards helped develop the study design and analysis plan and edited the manuscript.

Corresponding author

Correspondence to Digna R. Velez Edwards.

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The study was approved by the Institutional Review Board at Vanderbilt University Medical Center (#110407).

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Keaton, J.M., Jasper, E.A., Hellwege, J.N. et al. Evidence that geographic variation in genetic ancestry associates with uterine fibroids. Hum Genet 140, 1433–1440 (2021). https://doi.org/10.1007/s00439-021-02322-y

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