@article{89e8d5a0bc334a428d92050c3dce44dd,
title = "A multi-stage genome-wide association study of uterine fibroids in African Americans",
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{\textquoteright}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.",
author = "Hellwege, {Jacklyn N.} and Jeff, {Janina M.} and Wise, {Lauren A.} and Gallagher, {C. Scott} and Melissa Wellons and Hartmann, {Katherine E.} and Jones, {Sarah F.} and Torstenson, {Eric S.} and Scott Dickinson and Ruiz-Narv{\'a}ez, {Edward A.} and Nadin Rohland and Alexander Allen and David Reich and Arti Tandon and Bogdan Pasaniuc and Nicholas Mancuso and Im, {Hae Kyung} and Hinds, {David A.} and Palmer, {Julie R.} and Lynn Rosenberg and Denny, {Joshua C.} and Roden, {Dan M.} and Stewart, {Elizabeth A.} and Morton, {Cynthia C.} and Kenny, {Eimear E.} and Edwards, {Todd L.} and {Velez Edwards}, {Digna R.}",
note = "Funding Information: the Black Women{\textquoteright}s Health Study (BWHS) was supported by Grants R01CA58420 (LR), UM1CA164974 (LR), and R01CA098663 (JP) from the National Cancer Institute, and Grant R01HD057966 (LAW). The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health. We thank the research participants and staff from all studies, as well as the employees of 23andMe, for making this work possible. Funding Information: Acknowledgements This work was supported by the National Institutes of Health Grants R01HD074711 (DRVE), R03HD078567 (DRVE), U01HG08672-01 (DMR), and R01HD060530 (CCM), as well as the Vanderbilt Molecular and Genetic Epidemiology of Cancer (MAGEC) training program, funded by R25CA160056 (PI: X.-O. Shu). One of the data sets used for the analyses described was obtained from Vanderbilt University Medical Center{\textquoteright}s BioVU which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the Vanderbilt CTSA Grant UL1TR000445 from NCATS/NIH. The BioMe Biobank program is supported by The Andrea and Charles Bronfman Philanthropies. The Electronic Medical Records and Genomics Network was initiated and funded by the National Human Genome Research Institute through by eMERGE Network Grant U01HG006380 to Mt. Sinai. The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the National Heart, Lung, and Blood Institute (NHLBI), the Intramural Research Program of the National Institute on Aging (NIA), and an intra-agency agreement between NIA and NHLBI (AG0005). Geno-typing was funded as part of the NHLBI Candidate-gene Association Resource (N01-HC-65226). Uterine fibroid-related work from Funding Information: Conflict of interest DAH is an employee of and owns stock options in 23andMe, Inc. EAS declares the following financial competing interests: consultancy related to uterine fibroids: AbbVie, Allergan, Astellas, Bayer, and Gynesonics, Viteava. Patent applications (pending or actual), including individual applications or those belonging to the institution to which the authors, are affiliated and from which the authors may benefit. US 6440445 (With Nowak, RA, issued 2002, no commercial activity). Research Grants: NIH. R01HD060503, PI. P50 HS023418, Site PI for 3 component parts. R01HD074711, Consultant. K12HD065987, Board Member for Mayo Clinic Site. Other: Focused Ultrasound Surgery Foundation Borah(PI) 11/15/11-11/14/12 Costs of Uterine Fibroid Treatments Including Focused Ultrasound Surgery. Insightec Inc, PI Patient care costs in conjunction with R01HD60530. In addition, the following non-financial competing interests: relationship (paid or unpaid) with organizations and funding bodies including nongovernmental organizations, research institutions, or charities. Registry Steering Committee, REgistry for Leiomyoma International Efficacy of Focused Ultrasound (RELIEF). Writing or consulting for an educational company. Honoraria from: UpToDate, Massachusetts Medical Society.",
year = "2017",
month = oct,
day = "1",
doi = "10.1007/s00439-017-1836-1",
language = "English (US)",
volume = "136",
pages = "1363--1373",
journal = "Human Genetics",
issn = "0340-6717",
publisher = "Springer Verlag",
number = "10",
}