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
Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
Hum Genet. 2017 Oct;136(10):1363-1373. doi: 10.1007/s00439-017-1836-1. Epub 2017 Aug 23.
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.
子宫肌瘤是子宫的良性肿瘤，到更年期时影响高达77%的女性。它们是子宫切除术的主要指征，在美国每年花费340亿美元。种族/族裔和年龄是已知最强的风险因素。非裔美国（AA）女性比欧美女性患病率更高、发病更早，肌瘤更大且数量更多。我们对AA女性中的肌瘤风险进行了多阶段全基因组关联研究（GWAS），随后对顶级命中基因进行了计算机遗传预测基因表达谱分析。在第1阶段，通过盆腔成像确认病例和对照，进行基因分型并推算至千人基因组。第2阶段使用来自23andMe公司和黑人女性健康研究的自我报告的肌瘤和GWAS数据。使用针对主成分进行调整的逻辑回归对与肌瘤风险的关联进行建模，随后对结果进行荟萃分析。我们在CYTH4基因的rs739187位点（风险等位基因频率 = 0.27）观察到3399例AA病例和4764例AA对照之间存在显著关联（优势比（95%置信区间）= 1.23（1.16 - 1.30），p值 = 7.82×10）。使用MetaXcan对遗传关联结果进行评估发现，甲状腺组织中CYTH4的预测基因表达较低与肌瘤风险显著相关（p值 = 5.86×10）。在这项针对AA女性的首个多阶段肌瘤GWAS中，我们在CYTH4基因内确定了一个新的肌瘤风险位点，该位点影响甲状腺中的基因表达，并且对肌瘤具有潜在的生物学相关性。
