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 language | English (US) |
|---|---|
| Pages (from-to) | 1363-1373 |
| Number of pages | 11 |
| Journal | Human Genetics |
| Volume | 136 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 1 2017 |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
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 journal › Article
}
TY - JOUR
T1 - A multi-stage genome-wide association study of uterine fibroids in African Americans
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.
PY - 2017/10/1
Y1 - 2017/10/1
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85028009079&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85028009079&partnerID=8YFLogxK
U2 - 10.1007/s00439-017-1836-1
DO - 10.1007/s00439-017-1836-1
M3 - Article
C2 - 28836065
AN - SCOPUS:85028009079
VL - 136
SP - 1363
EP - 1373
JO - Human Genetics
JF - Human Genetics
SN - 0340-6717
IS - 10
ER -