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BET1L and TNRC6B associate with uterine fibroid risk among European Americans

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Abstract

Uterine fibroid (UFs) affect 77 % of women by menopause and account for $9.4 billion in healthcare costs each year. Although UFs are heritable, genetic risk is poorly understood. The first genome-wide association study (GWAS) of UFs was recently performed in a Japanese population, with reported genome-wide significance for single nucleotide polymorphisms (SNPs) across three chromosomal regions. We tested these SNPs for association with UFs in US cohorts. Women were enrolled in the Right from the Start (RFTS) cohort and the BioVU DNA repository. UF status in both cohorts was determined by pelvic imaging. We tested 65 candidate and haplotype-tagging SNPs for association with UFs presence using logistic regression in RFTS and the top three GWAS-associated SNPs in BioVU. We also combined association results from both cohorts using meta-analysis. 1,086 European American (EA) cases and 1,549 controls were examined. Two SNP associations replicated [blocked early in transport 1 homolog (BET1L) rs2280543, RFTS–BioVU meta-odds ratio (OR) = 0.67 95 % confidence interval (CI) 0.38–0.96, Q = 0.70, I = 0, p = 6.9 × 10−3; trinucleotide repeat containing 6B (TNRC6B) rs12484776, RFTS–BioVU meta-OR = 1.21, 95 % CI 1.07–1.35, Q = 0.24, I = 28.37, p = 8.7 × 10−3). Meta-analyses combining evidence from RFTS, BioVU, and prior GWAS showed little heterogeneity in effect sizes across studies, with meta-p values between 7.45 × 10−8 and 3.89 × 10−9, which were stronger than prior GWAS and supported associations observed for all previously identified loci. These data suggest common variants increase risk for UF in both EA and Japanese populations. However, further research is needed to assess the role of these genes across other racial groups.

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Acknowledgments

The field research for Right from the Start was supported by grants from the National Institute of Child and Human Development (R01HD043883 and R01HD049675) and the American Water Works Association Research Foundation (2579). Additional funds were provided by the Building Interdisciplinary Research Careers in Women’s Health career development program (2K12HD043483-11) to DRVE, the Vanderbilt Clinical and Translational Research Scholar Award 5KL2RR024977 to TLE from the National Center for Advancing Translational Sciences, the Vanderbilt CTSA award UL1TR000445 from the National Center for Advancing Translational Sciences, and 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. The content of this manuscript are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.

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  1. Vanderbilt Epidemiology Center, Vanderbilt University, 2525 West End Ave., Suite 600 6th Floor, Nashville, TN, 37203, USA

    Todd L. Edwards, Kara A. Michels, Katherine E. Hartmann & Digna R. Velez Edwards

  2. Institute for Medicine and Public Health, Vanderbilt University, Nashville, TN, USA

    Todd L. Edwards, Kara A. Michels, Katherine E. Hartmann & Digna R. Velez Edwards

  3. Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA

    Todd L. Edwards & Digna R. Velez Edwards

  4. Division of Epidemiology, Department of Medicine, Vanderbilt University, Nashville, TN, USA

    Todd L. Edwards

  5. Department of Obstetrics and Gynecology, Vanderbilt University, Nashville, USA

    Katherine E. Hartmann & Digna R. Velez Edwards

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  1. Todd L. Edwards
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T. L. Edwards and K. A. Michels are joint first authors.

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439_2013_1306_MOESM1_ESM.docx

Supplemental Figure 1. Candidate and haplotype tagging SNPs near BET1L. BET1L is oriented 5′ to 3′ and labeled in center. In bold are labeled GWAS index SNPs (DOCX 38 kb)

439_2013_1306_MOESM2_ESM.docx

Supplemental Figure 2. Candidate and haplotype tagging SNPs near SLK. SLK is oriented 5′ to 3′. In bold are labeled GWAS index SNPs (DOCX 35 kb)

439_2013_1306_MOESM3_ESM.docx

Supplemental Figure 3. Candidate and haplotype tagging SNPs near TNRC6B. TNRC6B is oriented 5′ to 3′ and labeled in center. In bold are labeled GWAS index SNPs (DOCX 137 kb)

439_2013_1306_MOESM4_ESM.docx

Supplemental Figure 4. Right from the Start linkage disequilibrium structure among European Americans. LD plots are presented for EAs cases and controls. All figures are oriented 5′ to 3′, right to left, relative to the minus strand. r 2 (shades of black) are indicated in percentages within squares in the LD plots, with solid blocks with numbers indicating r 2 = 1. Strong LD is indicated by dark gray and like gray and white indicate weak LD and/or low confidence values (DOCX 460 kb)

439_2013_1306_MOESM5_ESM.docx

Supplemental Table 1. Summary of adjusted index SNP and strongest (p ≤ 0.05) single locus associations with UFs among the Right from the Start and BioVU cohorts (DOCX 20 kb)

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Edwards, T.L., Michels, K.A., Hartmann, K.E. et al. BET1L and TNRC6B associate with uterine fibroid risk among European Americans. Hum Genet 132, 943–953 (2013). https://doi.org/10.1007/s00439-013-1306-3

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