Skip to main content

Evidence that geographic variation in genetic ancestry associates with uterine fibroids

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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Data availability

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

Code availability

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

References

  1. Alexander DH, Lange K (2011) Enhancements to the ADMIXTURE algorithm for individual ancestry estimation. BMC Bioinformatics 12:246

    PubMed  PubMed Central  Article  Google Scholar 

  2. Alexander DH, Novembre J, Lange K (2009) Fast model-based estimation of ancestry in unrelated individuals. Genome Res 19:1655–1664

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. August P, Suthanthiran M (2003) Transforming growth factor beta and progression of renal disease. Kidney Int Suppl 64:S99–S104

    Article  Google Scholar 

  4. Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM (2003) High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol 188:100–107

    PubMed  Article  Google Scholar 

  5. Barnes KC, Grant AV, Hansel NN, Gao P, Dunston GM (2007) African Americans with asthma: genetic insights. Proc Am Thorac Soc 4:58–68

    PubMed  PubMed Central  Article  Google Scholar 

  6. Bray MJ, Edwards TL, Wellons MF, Jones SH, Hartmann KE, Velez Edwards DR (2017) Admixture mapping of uterine fibroid size and number in African American women. Fertil Steril 108:1034-1042.e26

    PubMed  PubMed Central  Article  Google Scholar 

  7. Cardozo ER, Clark AD, Banks NK, Henne MB, Stegmann BJ, Segars JH (2012) The estimated annual cost of uterine leiomyomata in the United States. Am J Obstet Gynecol 206(211):e211–e219

    Google Scholar 

  8. Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ (2015) Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4:7

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. Ciavattini A, Di Giuseppe J, Stortoni P, Montik N, Giannubilo SR, Litta P, Islam MS, Tranquilli AL, Reis FM, Ciarmela P (2013) Uterine fibroids: pathogenesis and interactions with endometrium and endomyometrial junction. Obstet Gynecol Int 2013:173184

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  10. Commandeur AE, Styer AK, Teixeira JM (2015) Epidemiological and genetic clues for molecular mechanisms involved in uterine leiomyoma development and growth. Hum Reprod Update 21:593–615

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Cramer SF, Patel A (1990) The frequency of uterine leiomyomas. Am J Clin Pathol 94:435–438

    CAS  PubMed  Article  Google Scholar 

  12. Dustan HP (1992) Growth factors and racial differences in severity of hypertension and renal diseases. Lancet 339:1339–1340

    CAS  PubMed  Article  Google Scholar 

  13. Feingold-Link L, Edwards TL, Jones S, Hartmann KE, Velez Edwards DR (2014) Enhancing uterine fibroid research through utilization of biorepositories linked to electronic medical record data. J Womens Health (larchmt) 23:1027–1032

    Article  Google Scholar 

  14. Flake GP, Andersen J, Dixon D (2003) Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect 111:1037–1054

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Giri A, Edwards TL, Hartmann KE, Torstenson ES, Wellons M, Schreiner PJ, Velez Edwards DR (2017) African genetic ancestry interacts with body mass index to modify risk for uterine fibroids. PLoS Genet 13:e1006871

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  16. Hellwege JN, Torstenson ES, Russell SB, Edwards TL, Velez Edwards DR (2017) Evidence of selection as a cause for racial disparities in fibroproliferative disease. PLoS ONE 12:e0182791

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. Huang C, Ogawa R (2012) Fibroproliferative disorders and their mechanobiology. Connect Tissue Res 53:187–196

    CAS  PubMed  Article  Google Scholar 

  18. Kjerulff KH, Langenberg P, Seidman JD, Stolley PD, Guzinski GM (1996) Uterine leiomyomas. Racial differences in severity, symptoms and age at diagnosis. J Reprod Med 41:483–490

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Laughlin SK, Baird DD, Savitz DA, Herring AH, Hartmann KE (2009) Prevalence of uterine leiomyomas in the first trimester of pregnancy: an ultrasound-screening study. Obstet Gynecol 113:630–635

    PubMed  PubMed Central  Article  Google Scholar 

  20. Lester LA, Rich SS, Blumenthal MN, Togias A, Murphy S, Malveaux F, Miller ME, Dunston GM, Solway J, Wolf RL et al (2001) Ethnic differences in asthma and associated phenotypes: collaborative study on the genetics of asthma. J Allergy Clin Immunol 108:357–362

    CAS  PubMed  Article  Google Scholar 

  21. Lippman SA, Warner M, Samuels S, Olive D, Vercellini P, Eskenazi B (2003) Uterine fibroids and gynecologic pain symptoms in a population-based study. Fertil Steril 80:1488–1494

    PubMed  Article  Google Scholar 

  22. Marshall LM, Spiegelman D, Barbieri RL, Goldman MB, Manson JE, Colditz GA, Willett WC, Hunter DJ (1997) Variation in the incidence of uterine leiomyoma among premenopausal women by age and race. Obstet Gynecol 90:967–973

    CAS  PubMed  Article  Google Scholar 

  23. Mayes MD, Lacey JV Jr, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, Schottenfeld D (2003) Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum 48:2246–2255

    PubMed  Article  Google Scholar 

  24. Morris DA, Peracha MO, Shin DH, Kim C, Cha SC, Kim YY (1999) Risk factors for early filtration failure requiring suture release after primary glaucoma triple procedure with adjunctive mitomycin. Arch Ophthalmol 117:1149–1154

    CAS  PubMed  Article  Google Scholar 

  25. Murray T, Beaty TH, Mathias RA, Rafaels N, Grant AV, Faruque MU, Watson HR, Ruczinski I, Dunston GM, Barnes KC (2010) African and non-African admixture components in African Americans and an African Caribbean population. Genet Epidemiol 34:561–568

    PubMed  Article  Google Scholar 

  26. Newth CJ, Meert KL, Clark AE, Moler FW, Zuppa AF, Berg RA, Pollack MM, Sward KA, Berger JT, Wessel DL et al (2012) Fatal and near-fatal asthma in children: the critical care perspective. J Pediatr 161:214-221.e3

    PubMed  PubMed Central  Article  Google Scholar 

  27. Nickel R, Beck LA, Stellato C, Schleimer RP (1999) Chemokines and allergic disease. J Allergy Clin Immunol 104:723–742

    CAS  PubMed  Article  Google Scholar 

  28. Niessen FB, Spauwen PH, Schalkwijk J, Kon M (1999) On the nature of hypertrophic scars and keloids: a review. Plast Reconstr Surg 104:1435–1458

    CAS  PubMed  Article  Google Scholar 

  29. Polednak AP (1987) Connective tissue responses in blacks in relation to disease: further observations. Am J Phys Anthropol 74:357–371

    CAS  PubMed  Article  Google Scholar 

  30. R Core Team (2015) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Austria, Vienna

    Google Scholar 

  31. Racette L, Wilson MR, Zangwill LM, Weinreb RN, Sample PA (2003) Primary open-angle glaucoma in blacks: a review. Surv Ophthalmol 48:295–313

    PubMed  Article  Google Scholar 

  32. Richman IB, Taylor KE, Chung SA, Trupin L, Petri M, Yelin E, Graham RR, Lee A, Behrens TW, Gregersen PK et al (2012) European genetic ancestry is associated with a decreased risk of lupus nephritis. Arthritis Rheum 64:3374–3382

    PubMed  Article  Google Scholar 

  33. Roden DM, Pulley JM, Basford MA, Bernard GR, Clayton EW, Balser JR, Masys DR (2008) Development of a large-scale de-identified DNA biobank to enable personalized medicine. Clin Pharmacol Ther 84:362–369

    CAS  PubMed  Article  Google Scholar 

  34. Ross RK, Pike MC, Vessey MP, Bull D, Yeates D, Casagrande JT (1986) Risk factors for uterine fibroids: reduced risk associated with oral contraceptives. Br Med J (clin Res Ed) 293:359–362

    CAS  Article  Google Scholar 

  35. Russell SB, Smith JC, Huang M, Trupin JS, Williams SM (2015) Pleiotropic effects of immune responses explain variation in the prevalence of fibroproliferative diseases. PLoS Genet 11:e1005568

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  36. Ryan GL, Syrop CH, Van Voorhis BJ (2005) Role, epidemiology, and natural history of benign uterine mass lesions. Clin Obstet Gynecol 48:312–324

    PubMed  Article  Google Scholar 

  37. Rybicki BA, Maliarik MJ, Major M, Popovich J Jr, Iannuzzi MC (1998) Epidemiology, demographics, and genetics of sarcoidosis. Semin Respir Infect 13:166–173

    CAS  PubMed  Google Scholar 

  38. Sato F, Mori M, Nishi M, Kudo R, Miyake H (2002) Familial aggregation of uterine myomas in Japanese women. J Epidemiol 12:249–253

    PubMed  Article  Google Scholar 

  39. Suthanthiran M, Li B, Song JO, Ding R, Sharma VK, Schwartz JE, August P (2000) Transforming growth factor-beta 1 hyperexpression in African-American hypertensives: a novel mediator of hypertension and/or target organ damage. Proc Natl Acad Sci USA 97:3479–3484

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Vikhlyaeva EM, Khodzhaeva ZS, Fantschenko ND (1995) Familial predisposition to uterine leiomyomas. Int J Gynaecol Obstet 51:127–131

    CAS  PubMed  Article  Google Scholar 

  41. Wallach EE, Vlahos NF (2004) Uterine myomas: an overview of development, clinical features, and management. Obstet Gynecol 104:393–406

    PubMed  Article  Google Scholar 

  42. Wechter ME, Stewart EA, Myers ER, Kho RM, Wu JM (2011) Leiomyoma-related hospitalization and surgery: prevalence and predicted growth based on population trends. Am J Obstet Gynecol 205(492):e491–e495

    Google Scholar 

  43. Whiteman MK, Hillis SD, Jamieson DJ, Morrow B, Podgornik MN, Brett KM, Marchbanks PA (2008) Inpatient hysterectomy surveillance in the United States, 2000–2004. Am J Obstet Gynecol 198(34):e31–e37

    Google Scholar 

  44. Wise LA, Ruiz-Narvaez EA, Palmer JR, Cozier YC, Tandon A, Patterson N, Radin RG, Rosenberg L, Reich D (2012) African ancestry and genetic risk for uterine leiomyomata. Am J Epidemiol 176:1159–1168

    PubMed  PubMed Central  Article  Google Scholar 

  45. Zhang K, Wiener H, Aissani B (2015) Admixture mapping of genetic variants for uterine fibroids. J Hum Genet 60:533–538

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Zimmermann A, Bernuit D, Gerlinger C, Schaefers M, Geppert K (2012) Prevalence, symptoms and management of uterine fibroids: an international internet-based survey of 21,746 women. BMC Womens Health 12:6

    PubMed  PubMed Central  Article  Google Scholar 

Download references

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.

Author information

Affiliations

Authors

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.

Ethics declarations

Conflict of interest

There are no conflicts of interest relevant to this article.

Ethics approval

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

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 139 KB)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation