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Transethnic and race-stratified genome-wide association study of fibroid characteristics in African American and European American women.

ABSTRACT: OBJECTIVE:To identify, through genome-wide association studies, genetic loci that associate with differences in fibroid size and number in a population of African American and European American women. DESIGN:Cross-sectional study. SETTING:Not applicable. PATIENT(S):Using BioVU, a clinical population from the Vanderbilt University Medical Center, and the Coronary Artery Risk Development in Young Adults cohort, a prospective cohort, we identified 1520 women (609 African American and 911 European American) with documented fibroid characteristics. INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):Outcome measurements include volume of largest fibroid, largest fibroid dimension, and number of fibroids (single vs. multiple). RESULT(S):In race-stratified analyses we achieved genome-wide significance at a variant located between MAT2B and TENM2 (rs57542984, ? = 0.13; 95% confidence interval 0.09, 0.17) for analyses of largest fibroid dimension in African Americans. The strongest signal for transethnic analyses was at a variant on 1q31.1 located between PLA2G4A and BRINP3 (rs6605005, ? = 0.24; 95% confidence interval 0.15, 0.33) for fibroid volume. Results from MetaXcan identified an association between predicted expression of the gene ER degradation enhancing alpha-mannosidase like protein 2 (EDEM2) in the thyroid and number of fibroids (Z score = -4.51). CONCLUSION(S):This study identified many novel associations between genetic loci and fibroid size and number in both race-stratified and transethnic analyses. Future studies are necessary to further validate our study findings and to better understand the mechanisms underlying these associations.

SUBMITTER: Bray MJ

PROVIDER: S-EPMC6132266 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Transethnic and race-stratified genome-wide association study of fibroid characteristics in African American and European American women.

Bray Michael J MJ Wellons Melissa F MF Jones Sarah H SH Torstenson Eric S ES Edwards Todd L TL Velez Edwards Digna R DR

Fertility and sterility 20180901 4

<h4>Objective</h4>To identify, through genome-wide association studies, genetic loci that associate with differences in fibroid size and number in a population of African American and European American women.<h4>Design</h4>Cross-sectional study.<h4>Setting</h4>Not applicable.<h4>Patient(s)</h4>Using BioVU, a clinical population from the Vanderbilt University Medical Center, and the Coronary Artery Risk Development in Young Adults cohort, a prospective cohort, we identified 1520 women (609 Africa ...[more]

PMID: 30196971

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Project description:ImportanceUterine fibroids are an understudied condition, with earlier onset in Black than White women. Prior studies of the importance of family history on fibroid development are limited by reliance on hospital-based participant selection, poorly defined measures of family history, and nonsystematic fibroid assessment.ObjectiveTo examine whether family history is a risk factor for fibroid development using prospective ultrasonography data to identify incident fibroids and measure fibroid growth and standardized methods to ascertain family history.Design, setting, and participantsThis prospective community cohort of Black and African American women from the Detroit, Michigan, area was conducted from January 1, 2010, to December 31, 2018, using 4 standardized ultrasonographic examinations during 5 years to detect fibroids 0.5 cm or larger in diameter and measure fibroid growth. Data analysis was performed between May 2022 and January 2024.ExposuresMaternal fibroid history data were gathered directly from participants' mothers when possible (1425/1628 [88%]), and 2 exposure variables were created: maternal history of fibroids (diagnosed vs not diagnosed) and age at maternal fibroid diagnosis (20-29, 30-39, or ≥40 years vs not diagnosed).Main outcomes and measuresFibroid incidence was assessed using multivariable Cox proportional hazards regression models; fibroid growth was calculated as change in log-volume per 18 months for fibroids matched at successive ultrasonograms.ResultsA total of 1610 self-identified Black and/or African American women aged 23 to 35 years (mean [SD] age, 29.2 [3.4] years) with no prior clinical diagnosis of fibroids at enrollment were available for analysis. Of 1187 fibroid-free participants at enrollment, 442 (37%) had mothers who were diagnosed with fibroids. Compared with participants without a maternal history of fibroids, those reporting maternal history had an adjusted hazard ratio (AHR) of 1.21 (95% CI, 0.96-1.52). Risk was strongest in those whose mothers were diagnosed at a younger age (20-29 years: AHR, 1.56; 95% CI, 1.11-2.21; 30-39 years: AHR, 1.03; 95% CI, 0.71-1.49; ≥40 years: AHR, 1.11; 95% CI, 0.81-1.52; P = .053 for trend). Fibroid growth rates were higher when mothers were diagnosed with fibroids vs not diagnosed (8.0% increased growth; 95% CI, -1.2% to 18.0%).Conclusions and relevanceIn this prospective cohort study, results supported maternal history of fibroids as a risk factor for incident fibroids, especially when mothers were diagnosed at a younger age. Maternal history was also associated with increased fibroid growth. Asking patients about their family history of fibroids could encourage patient self-advocacy and inform care.

Project description:BackgroundHeritability estimates (including twin and single nucleotide polymorphism [SNP]-based heritability studies) for fibroids have been inconsistent across prior studies ranging between 9 and 69%. These inconsistencies are due to variations in study design and included populations. A major design issue has been lack of imaging confirmation to identify controls, where asymptomatic women without imaging confirmation may be misclassified as controls leading to an attenuation of heritability estimates. To reconcile the differences in prior heritability estimates and the impact of misclassification of controls on heritability, we determined SNP-based heritability and characterized the genetic architecture of pelvic image-confirmed fibroid cases and controls.MethodsAnalyses were performed among women of European American descent using genome-wide SNP data from BioVU, a clinical database composed of DNA linked to de-identified electronic health records. We estimated the genetic variance explained by all SNPs using Genome-Wide Complex Trait Analysis on imputed data. Fibroid cases and controls were identified using a previously reported phenotyping algorithm that required pelvic imaging confirmation.ResultsIn total, we used 1,067 image-confirmed fibroid cases and 1,042 image-confirmed fibroid controls. The SNP-based heritability estimate for fibroid risk was h2 = 0.33 ± 0.18 (p = 0.040). We investigated the relationship between heritability per chromosome and chromosome length (r2 < 1%), with chromosome 8 explaining the highest proportion of variance for fibroid risk. There was no enrichment for intergenic or genic SNPs for the fibroid SNP-based heritability. Excluding loci previously associated with fibroid risk from genome-wide association study did not attenuate fibroid heritability suggesting that loci associating with fibroid risk are yet to be discovered.ConclusionsWe observed that fibroid SNP-based heritability was higher than the previous estimate using genome-wide SNP data that relied on self-reported outcomes, but within the range of prior twin pair studies. Furthermore, these data support that imprecise phenotyping can significantly affect the ability to estimate heritability using genotype data.

Dataset Information

Transethnic and race-stratified genome-wide association study of fibroid characteristics in African American and European American women.

Publications

Transethnic and race-stratified genome-wide association study of fibroid characteristics in African American and European American women.

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