A multi-stage genome-wide association study of uterine fibroids in African Americans

Jacklyn N. Hellwege, Janina M. Jeff, Lauren A. Wise, C. Scott Gallagher, Melissa Wellons, Katherine E. Hartmann, Sarah F. Jones, Eric S. Torstenson, Scott Dickinson, Edward A. Ruiz-Narváez, Nadin Rohland, Alexander Allen, David Reich, Arti Tandon, Bogdan Pasaniuc, Nicholas Mancuso, Hae Kyung Im, David A. Hinds, Julie R. Palmer, Lynn RosenbergJoshua C. Denny, Dan M. Roden, Elizabeth A Stewart, Cynthia C. Morton, Eimear E. Kenny, Todd L. Edwards, Digna R. Velez Edwards

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Uterine fibroids are benign tumors of the uterus affecting up to 77% of women by menopause. They are the leading indication for hysterectomy, and account for $34 billion annually in the United States. Race/ethnicity and age are the strongest known risk factors. African American (AA) women have higher prevalence, earlier onset, and larger and more numerous fibroids than European American women. We conducted a multi-stage genome-wide association study (GWAS) of fibroid risk among AA women followed by in silico genetically predicted gene expression profiling of top hits. In Stage 1, cases and controls were confirmed by pelvic imaging, genotyped and imputed to 1000 Genomes. Stage 2 used self-reported fibroid and GWAS data from 23andMe, Inc. and the Black Women’s Health Study. Associations with fibroid risk were modeled using logistic regression adjusted for principal components, followed by meta-analysis of results. We observed a significant association among 3399 AA cases and 4764 AA controls at rs739187 (risk-allele frequency = 0.27) in CYTH4 (OR (95% confidence interval) = 1.23 (1.16–1.30), p value = 7.82 × 10−9). Evaluation of the genetic association results with MetaXcan identified lower predicted gene expression of CYTH4 in thyroid tissue as significantly associated with fibroid risk (p value = 5.86 × 10−8). In this first multi-stage GWAS for fibroids among AA women, we identified a novel risk locus for fibroids within CYTH4 that impacts gene expression in thyroid and has potential biological relevance for fibroids.

Original languageEnglish (US)
Pages (from-to)1363-1373
Number of pages11
JournalHuman Genetics
Volume136
Issue number10
DOIs
StatePublished - Oct 1 2017

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Genome-Wide Association Study
Leiomyoma
African Americans
Thyroid Gland
Gene Expression
Gene Expression Profiling
Women's Health
Menopause
Hysterectomy
Gene Frequency
Uterus
Meta-Analysis
Logistic Models
Genome
Confidence Intervals

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Hellwege, J. N., Jeff, J. M., Wise, L. A., Gallagher, C. S., Wellons, M., Hartmann, K. E., ... Velez Edwards, D. R. (2017). A multi-stage genome-wide association study of uterine fibroids in African Americans. Human Genetics, 136(10), 1363-1373. https://doi.org/10.1007/s00439-017-1836-1

A multi-stage genome-wide association study of uterine fibroids in African Americans. / Hellwege, Jacklyn N.; Jeff, Janina M.; Wise, Lauren A.; Gallagher, C. Scott; Wellons, Melissa; Hartmann, Katherine E.; Jones, Sarah F.; Torstenson, Eric S.; Dickinson, Scott; Ruiz-Narváez, Edward A.; Rohland, Nadin; Allen, Alexander; Reich, David; Tandon, Arti; Pasaniuc, Bogdan; Mancuso, Nicholas; Im, Hae Kyung; Hinds, David A.; Palmer, Julie R.; Rosenberg, Lynn; Denny, Joshua C.; Roden, Dan M.; Stewart, Elizabeth A; Morton, Cynthia C.; Kenny, Eimear E.; Edwards, Todd L.; Velez Edwards, Digna R.

In: Human Genetics, Vol. 136, No. 10, 01.10.2017, p. 1363-1373.

Research output: Contribution to journalArticle

Hellwege, JN, Jeff, JM, Wise, LA, Gallagher, CS, Wellons, M, Hartmann, KE, Jones, SF, Torstenson, ES, Dickinson, S, Ruiz-Narváez, EA, Rohland, N, Allen, A, Reich, D, Tandon, A, Pasaniuc, B, Mancuso, N, Im, HK, Hinds, DA, Palmer, JR, Rosenberg, L, Denny, JC, Roden, DM, Stewart, EA, Morton, CC, Kenny, EE, Edwards, TL & Velez Edwards, DR 2017, 'A multi-stage genome-wide association study of uterine fibroids in African Americans', Human Genetics, vol. 136, no. 10, pp. 1363-1373. https://doi.org/10.1007/s00439-017-1836-1
Hellwege JN, Jeff JM, Wise LA, Gallagher CS, Wellons M, Hartmann KE et al. A multi-stage genome-wide association study of uterine fibroids in African Americans. Human Genetics. 2017 Oct 1;136(10):1363-1373. https://doi.org/10.1007/s00439-017-1836-1
Hellwege, Jacklyn N. ; Jeff, Janina M. ; Wise, Lauren A. ; Gallagher, C. Scott ; Wellons, Melissa ; Hartmann, Katherine E. ; Jones, Sarah F. ; Torstenson, Eric S. ; Dickinson, Scott ; Ruiz-Narváez, Edward A. ; Rohland, Nadin ; Allen, Alexander ; Reich, David ; Tandon, Arti ; Pasaniuc, Bogdan ; Mancuso, Nicholas ; Im, Hae Kyung ; Hinds, David A. ; Palmer, Julie R. ; Rosenberg, Lynn ; Denny, Joshua C. ; Roden, Dan M. ; Stewart, Elizabeth A ; Morton, Cynthia C. ; Kenny, Eimear E. ; Edwards, Todd L. ; Velez Edwards, Digna R. / A multi-stage genome-wide association study of uterine fibroids in African Americans. In: Human Genetics. 2017 ; Vol. 136, No. 10. pp. 1363-1373.
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AU - Hellwege, Jacklyn N.

AU - Jeff, Janina M.

AU - Wise, Lauren A.

AU - Gallagher, C. Scott

AU - Wellons, Melissa

AU - Hartmann, Katherine E.

AU - Jones, Sarah F.

AU - Torstenson, Eric S.

AU - Dickinson, Scott

AU - Ruiz-Narváez, Edward A.

AU - Rohland, Nadin

AU - Allen, Alexander

AU - Reich, David

AU - Tandon, Arti

AU - Pasaniuc, Bogdan

AU - Mancuso, Nicholas

AU - Im, Hae Kyung

AU - Hinds, David A.

AU - Palmer, Julie R.

AU - Rosenberg, Lynn

AU - Denny, Joshua C.

AU - Roden, Dan M.

AU - Stewart, Elizabeth A

AU - Morton, Cynthia C.

AU - Kenny, Eimear E.

AU - Edwards, Todd L.

AU - Velez Edwards, Digna R.

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N2 - Uterine fibroids are benign tumors of the uterus affecting up to 77% of women by menopause. They are the leading indication for hysterectomy, and account for $34 billion annually in the United States. Race/ethnicity and age are the strongest known risk factors. African American (AA) women have higher prevalence, earlier onset, and larger and more numerous fibroids than European American women. We conducted a multi-stage genome-wide association study (GWAS) of fibroid risk among AA women followed by in silico genetically predicted gene expression profiling of top hits. In Stage 1, cases and controls were confirmed by pelvic imaging, genotyped and imputed to 1000 Genomes. Stage 2 used self-reported fibroid and GWAS data from 23andMe, Inc. and the Black Women’s Health Study. Associations with fibroid risk were modeled using logistic regression adjusted for principal components, followed by meta-analysis of results. We observed a significant association among 3399 AA cases and 4764 AA controls at rs739187 (risk-allele frequency = 0.27) in CYTH4 (OR (95% confidence interval) = 1.23 (1.16–1.30), p value = 7.82 × 10−9). Evaluation of the genetic association results with MetaXcan identified lower predicted gene expression of CYTH4 in thyroid tissue as significantly associated with fibroid risk (p value = 5.86 × 10−8). In this first multi-stage GWAS for fibroids among AA women, we identified a novel risk locus for fibroids within CYTH4 that impacts gene expression in thyroid and has potential biological relevance for fibroids.

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