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

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 highe...

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Published inHuman genetics Vol. 136; no. 10; pp. 1363 - 1373
Main Authors 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.
Format Journal Article
LanguageEnglish
Published Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2017
Springer
Springer Nature B.V
Subjects
Adult
African Americans
Alleles
Biomedical and Life Sciences
Biomedicine
Black or African American - genetics
Cell Adhesion Molecules - biosynthesis
Cell Adhesion Molecules - genetics
Consumer research
Female
Fibroids
Gene expression
Gene Expression Regulation, Neoplastic
Gene Frequency
Gene Function
Genetic Loci
Genome-wide association studies
Genome-Wide Association Study
Genomes
Genomics
Guanine Nucleotide Exchange Factors - biosynthesis
Guanine Nucleotide Exchange Factors - genetics
Human Genetics
Humans
Hysterectomy
Leiomyoma - genetics
Leiomyoma - metabolism
Menopause
Metabolic Diseases
Middle Aged
Minority & ethnic groups
Molecular Medicine
Neoplasm Proteins - biosynthesis
Neoplasm Proteins - genetics
Original Investigation
Pelvis
Risk Factors
Thyroid
Thyroid cancer
Thyroid gland
Tumors
Uterine fibroids
Uterine Neoplasms - genetics
Uterine Neoplasms - metabolism
Uterus
Women's health
Online AccessGet full text

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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.
AbstractList 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.
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.
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 x 10.sup.-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 x 10.sup.-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.
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 ). 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 ). 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.
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.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.
Audience Academic
Author Pasaniuc, Bogdan
Torstenson, Eric S.
Gallagher, C. Scott
Morton, Cynthia C.
Velez Edwards, Digna R.
Roden, Dan M.
Palmer, Julie R.
Rosenberg, Lynn
Rohland, Nadin
Hartmann, Katherine E.
Jeff, Janina M.
Wellons, Melissa
Allen, Alexander
Mancuso, Nicholas
Ruiz-Narváez, Edward A.
Tandon, Arti
Wise, Lauren A.
Hellwege, Jacklyn N.
Dickinson, Scott
Im, Hae Kyung
Reich, David
Hinds, David A.
Denny, Joshua C.
Jones, Sarah F.
Kenny, Eimear E.
Edwards, Todd L.
Stewart, Elizabeth A.
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/28836065$$D View this record in MEDLINE/PubMed
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Copyright Springer-Verlag GmbH Germany 2017
COPYRIGHT 2017 Springer
Human Genetics is a copyright of Springer, 2017.
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Snippet 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...
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StartPage 1363
SubjectTerms Adult
African Americans
Alleles
Biomedical and Life Sciences
Biomedicine
Black or African American - genetics
Cell Adhesion Molecules - biosynthesis
Cell Adhesion Molecules - genetics
Consumer research
Female
Fibroids
Gene expression
Gene Expression Regulation, Neoplastic
Gene Frequency
Gene Function
Genetic Loci
Genome-wide association studies
Genome-Wide Association Study
Genomes
Genomics
Guanine Nucleotide Exchange Factors - biosynthesis
Guanine Nucleotide Exchange Factors - genetics
Human Genetics
Humans
Hysterectomy
Leiomyoma - genetics
Leiomyoma - metabolism
Menopause
Metabolic Diseases
Middle Aged
Minority & ethnic groups
Molecular Medicine
Neoplasm Proteins - biosynthesis
Neoplasm Proteins - genetics
Original Investigation
Pelvis
Risk Factors
Thyroid
Thyroid cancer
Thyroid gland
Tumors
Uterine fibroids
Uterine Neoplasms - genetics
Uterine Neoplasms - metabolism
Uterus
Women's health
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Title A multi-stage genome-wide association study of uterine fibroids in African Americans
URI https://link.springer.com/article/10.1007/s00439-017-1836-1
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Volume 136
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