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 Rosenberg; Joshua C. Denny; Dan M. Roden; Elizabeth A. Stewart; Cynthia C. Morton; Eimear E. Kenny; Todd L. Edwards; Digna R. Velez Edwards

doi:10.1007/s00439-017-1836-1

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 Rosenberg

Joshua C. Denny, Dan M. Roden, Elizabeth A. Stewart, Cynthia C. Morton, Eimear E. Kenny, Todd L. Edwards, Digna R. Velez Edwards

Producción científica: Article › revisión exhaustiva

43 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	1363-1373
Número de páginas	11
Publicación	Human Genetics
Volumen	136
N.º	10
DOI	https://doi.org/10.1007/s00439-017-1836-1
Estado	Published - oct 1 2017

Nota bibliográfica

Publisher Copyright:
© 2017, Springer-Verlag GmbH Germany.

Financiación

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’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 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. the Black Women’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.

Financiadores	Número del financiador
CTSA Grant UL1TR000445
Insightec Inc
The Coronary Artery Risk Development in Young Adults Study
REgistry for Leiomyoma International Efficacy of Focused Ultrasound
AbbVie
UpToDate
Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center	UL1TR000445
NIH training program
Board Member for Mayo Clinic Site
Biobank program
NIH NCATS
Massachusetts Medical Society
WHO International Pathogen Surveillance Network Catalytic Grant Fund
NIH Intramural Research Program
1S10RR025141-01 instrumentation award
National Institute on Aging
National Childhood Cancer Registry – National Cancer Institute	R01CA058420, U01CA164974, R01CA098663, R25CA160056
NIA and NHLBI	AG0005
National Human Genome Research Institute	HHSN268200900041C, HHSN268201300029C, U01HG006380, U01HG008672
Eunice Kennedy Shriver National Institute of Child Health and Human Development	R03HD078567, R01HD074711, R01HD057966
Focused Ultrasound Surgery Foundation Borah	11/15/11-11/14/12
Allergan, Astellas, Bayer	US 6440445
NIH National Institute of Child Health and Human Development National Center for Medical Rehabilitation Research	R01HD060530, R01HD093671
NIH Office of the Director	S10OD020154, S10OD018522, S10OD023680
PI Patient	R01HD60530
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	R25GM062459
NHLBI Candidate-gene Association Resource	N01-HC-65226
National Heart, Lung, and Blood Institute (NHLBI)	R01HL065226
National Center for Research Resources	S10RR025141
Vanderbilt Molecular and Genetic Epidemiology of Cancer	R25CA160056
National Center for Advancing Translational Sciences (NCATS)	UL1TR000445
National Institutes of Health (NIH)	P50 HS023418, K12HD065987, R01HD060503
National Institutes of Health Grants R01HD074711	R01HD060530, DMR, U01HG08672-01, R03HD078567, R01HD074711

ASJC Scopus subject areas

Genetics
Genetics(clinical)

Acceder al documento

10.1007/s00439-017-1836-1

Otros archivos y enlaces

Citar esto

Hellwege, J. N., Jeff, J. M., Wise, L. A., Gallagher, C. S., Wellons, M., Hartmann, K. E., Jones, S. F., Torstenson, E. S., Dickinson, S., Ruiz-Narváez, E. A., Rohland, N., Allen, A., Reich, D., Tandon, A., Pasaniuc, B., Mancuso, N., Im, H. K., Hinds, D. A., Palmer, J. R., ... 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

@article{ad20611f20c941b3b37a476ed32c7ad0,

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 = "Publisher Copyright: {\textcopyright} 2017, Springer-Verlag GmbH Germany.",

year = "2017",

month = oct,

day = "1",

doi = "10.1007/s00439-017-1836-1",

language = "English",

volume = "136",

pages = "1363--1373",

number = "10",

}

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, n.º 10, pp. 1363-1373. https://doi.org/10.1007/s00439-017-1836-1

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 - https://www.scopus.com/pages/publications/85028009079

UR - https://www.scopus.com/pages/publications/85028009079#tab=citedBy

U2 - 10.1007/s00439-017-1836-1

DO - 10.1007/s00439-017-1836-1

M3 - Article

C2 - 28836065

AN - SCOPUS:85028009079

SN - 0340-6717

VL - 136

SP - 1363

EP - 1373

JO - Human Genetics

JF - Human Genetics

IS - 10

ER -

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

Resumen

Nota bibliográfica

Financiación

ASJC Scopus subject areas

Acceder al documento

Otros archivos y enlaces

Huella

Citar esto