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

• 批准号: 8386863
• 负责人: Sara Lindstroem
• 金额: $ 9.08万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 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/8386863
• 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' 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

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. PUBLIC HEALTH RELEVANCE: A consistent but poorly understood observation is that young girls with large body size have a 15-30% reduced risk of developing breast cancer throughout life. In this research proposal, we aim to conduct a genome-wide search for genetic predictors of childhood body fatness and test if identified variants affect breast cancer risk. Ultimately, this research will provide invaluable insights into developmental and long-term processes that eventually affect breast cancer risk.

描述（由申请人提供）：体型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，在雌激素受体阴性（ER-）疾病中更为明显。然而，潜在的原因仍然是一个谜，特别是因为年轻时体型大与青春期提前有关，而青春期提前是已知的乳腺癌风险因素。自我报告的童年体型是一种表型，在文献中被描述为“童年体胖”，是一种高度遗传的特征。儿童期体脂与成人BMI之间的相关性不大（r=0.24-0.20），儿童期体脂的估计遗传率为70-80%，而成人BMI的遗传率为40-70%。然而，关于儿童体型相关表型的遗传关联的文献非常少，迄今为止，还没有研究对与儿童身体肥胖相关的基因座进行全基因组搜索。我们在此提出一项儿童体胖的全基因组关联研究（GWAS）。我们将使用护士健康研究（NHS）中9000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输入数据。作为结果，我们将使用回忆的5岁和10岁的平均儿童体脂，并通过9级图形图进行评估。先前的验证研究表明，回忆体脂与测量的BMI之间存在高度相关性（5岁时r=0.60, 10岁时r=0.65），表明这些图形提供了对年轻时身体尺寸的准确评估。我们将在瑞典1600名女性人群（SASBAC研究）和三个儿童人群（包括3000名非裔美国儿童、1400名西班牙裔儿童和1600名非西班牙裔白人儿童）中复制最强相关snp。将使用来自NHS1、NHS2和SASBAC内嵌套病例对照研究的4000例乳腺癌病例和5000例对照的数据，以及来自NCI乳腺癌和前列腺癌队列联盟（BPC3）的另外2100例ER-乳腺癌病例的数据，对已确认的变异与乳腺癌风险的相关性进行测试。我们还将调查与乳腺癌的关系是否因激素受体状态而异。NHS的丰富资源和已经完成的16000个人全基因组扫描提供了出色的统计能力和独特的机会，以高度经济有效的方式研究这些关键问题。确定儿童身体肥胖的遗传预测因子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，解开乳腺癌的复杂病因将有助于确定高危妇女，并为制定预防和治疗策略提供平台。