GWAS on childhood body fatness as an intermediate phenotype of breast cancer

GWAS 将儿童身体肥胖作为乳腺癌的中间表型

基本信息

批准号：
8527746
负责人：
Sara Lindstroem
金额：
$ 8.34万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-09 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8527746
关键词：
Adult Affect African American Age Birth Weight Body Size Body mass index Breast Breast Cancer Risk Factor Case-Control Studies Caucasians Caucasoid Race Child Childhood Complex Computer Simulation Data Development Disease Estrogen Receptor Status Estrogen receptor negative Etiology European Genetic Genetic Determinism Genetic Predisposition to Disease Genetic Research Genotype Grant Heritability High Risk Woman Hispanics Hormone Receptor Individual Knowledge Life Literature Malignant neoplasm of prostate Mammographic Density Measures Nested Case-Control Study Not Hispanic or Latino Nurses&apos Health Study Outcome Patient Self-Report Phenotype Population Prevention strategy Process Progesterone Receptors Publishing Reporting Research Research Infrastructure Research Proposals Resources Risk Risk Factors Single Nucleotide Polymorphism Testing Variant Woman Work cancer risk cohort cost genetic association genetic variant genome wide association study genome-wide girls insight malignant breast neoplasm novel pubertal timing trait treatment strategy validation studies

项目摘要

DESCRIPTION (provided by applicant): Girls with large body size have a 15-30% reduced risk of developing breast cancer throughout life. This association is independent of both birth weight and adult body mass index (BMI) and is significantly stronger for estrogen receptor negative (ER-) disease. However, the underlying causes remain a mystery, especially since large body size at young age is correlated with earlier pubertal timing, a known risk factor for breast cancer. Self-reported childhood body size, a phenotype which is described in the literature as "childhood body fatness", is a highly heritable trait. The correlation between childhood body fatness and adult BMI is only modest (r=0.24-0.20) and the estimated heritability of childhood body fatness is 70-80% compared to 40-70% for adult BMI. Still, the literature on genetic associations in pediatric body size-related phenotypes is very sparse and to date, no study has conducted a genome-wide search for loci associated with childhood body fatness. We here propose a genome-wide association study (GWAS) of childhood body fatness. We will use existing high-quality genotyped and imputed data for 2.5 million single nucleotide polymorphisms (SNPs) in 9,000 women in the Nurses' Health Study (NHS). As outcome, we will use recalled childhood body fatness averaged over ages 5 and 10 as assessed by a 9-level figure drawing. Previous validation studies have showed a high correlation between recalled body fatness and measured BMI (r=0.60 at age 5 and r=0.65 at age 10) indicating that these figure drawings provide an accurate assessment of body size at young ages. We will replicate the strongest associated SNPs in a Swedish population of 1,600 women (the SASBAC study), and three populations of children including 3,000 African-American children, 1,400 Hispanic children and 1,600 White non-Hispanic children. Confirmed variants will be tested for association with breast cancer risk using data from 4,000 breast cancer cases and 5,000 controls from nested case-control studies within NHS1, NHS2 and SASBAC and additional 2,100 ER- breast cancer cases from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We will also investigate if the association with breast cancer differs with hormone receptor status. The rich resources in NHS and already completed genome-wide scans for 16,000 individuals provide excellent statistical power and a unique opportunity to study these critical questions in a highly cost-efficient manner. Identifying genetic predictors of childhood body fatness will provide invaluable insights into developmental and long-term processes that eventually affect breast cancer risk. Ultimately, untangling the complex etiology of breast cancer will help identify women at high risk as well as provide a platform for development of preventive and treatment strategies.

描述（由申请人提供）：体型较大的女孩一生中患乳腺癌的风险降低 15-30%。这种关联与出生体重和成人体重指数 (BMI) 无关，并且对于雌激素受体阴性 (ER-) 疾病而言明显更强。然而，根本原因仍然是个谜，特别是因为年轻时体型较大与青春期提前有关，而青春期是乳腺癌的已知危险因素。自我报告的儿童体型，一种在文献中被描述为“儿童期身体肥胖”的表型，是一种高度遗传的特征。儿童身体脂肪与成人 BMI 之间的相关性不大（r=0.24-0.20），儿童身体脂肪的估计遗传率为 70-80%，而成人 BMI 为 40-70%。尽管如此，关于儿科体型相关表型的遗传关联的文献仍然非常少，迄今为止，还没有研究对与儿童体型肥胖相关的基因座进行全基因组搜索。我们在此提出一项关于儿童身体肥胖的全基因组关联研究（GWAS）。我们将使用护士健康研究 (NHS) 中 9,000 名女性的 250 万个单核苷酸多态性 (SNP) 的现有高质量基因分型和估算数据。作为结果，我们将使用回忆的 5 岁和 10 岁儿童平均体脂率，通过 9 级图形绘图进行评估。先前的验证研究表明，回忆的身体脂肪与测量的 BMI 之间存在高度相关性（5 岁时 r=0.60，10 岁时 r=0.65），这表明这些图形图可以准确评估年轻时的体型。我们将在由 1,600 名女性组成的瑞典人口（SASBAC 研究）和三个儿童群体（包括 3,000 名非洲裔美国儿童、1,400 名西班牙裔儿童和 1,600 名非西班牙裔白人儿童）中复制最强相关的 SNP。将使用来自 NHS1、NHS2 和 SASBAC 内嵌套病例对照研究的 4,000 例乳腺癌病例和 5,000 例对照数据以及来自 NCI 乳腺癌和前列腺癌队列联盟的另外 2,100 例 ER-乳腺癌病例的数据，测试已确认的变异与乳腺癌风险的关联。（BPC3）。我们还将调查激素受体状态与乳腺癌的关系是否有所不同。 NHS 的丰富资源以及已经完成的 16,000 人全基因组扫描提供了出色的统计能力和以高度成本效益的方式研究这些关键问题的独特机会。确定儿童身体肥胖的遗传预测因素将为最终影响乳腺癌风险的发育和长期过程提供宝贵的见解。最终，弄清楚乳腺癌复杂的病因将有助于识别高危女性，并为制定预防和治疗策略提供平台。