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

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%。这种相关性与出生体重和成人体重指数（BMI）无关，并且在雌激素受体阴性（ER-）疾病中明显更强。然而，根本原因仍然是一个谜，特别是因为年轻时的大体型与青春期提前有关，这是乳腺癌的一个已知风险因素。自我报告的儿童体型，在文献中被描述为“儿童肥胖”的表型，是一个高度遗传的性状。儿童肥胖与成人BMI之间的相关性仅为适度（r=0.24-0.20），儿童肥胖的估计遗传率为70-80%，而成人BMI为40-70%。尽管如此，关于儿童体型相关表型的遗传关联的文献非常稀少，迄今为止，还没有研究对与儿童肥胖相关的基因座进行全基因组搜索。 在这里，我们提出了一个全基因组关联研究（GWAS）的儿童身体肥胖。我们将在护士健康研究（NHS）中使用现有的高质量基因分型和插补数据，对9,000名女性的250万个单核苷酸多态性（SNP）进行分析。作为结果，我们将使用回忆的儿童身体脂肪平均超过5岁和10岁的9级数字绘图评估。先前的验证研究表明，回忆的身体肥胖和测量的BMI之间存在高度相关性（5岁时r=0.60，10岁时r=0.65），这表明这些数字绘图提供了对年轻时身体尺寸的准确评估。我们将在1,600名瑞典妇女（SASBAC研究）和3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名白色非西班牙裔儿童）中复制最强相关的SNP。将使用来自NHS 1、NHS 2和SASBAC内巢式病例对照研究的4，000例乳腺癌病例和5，000例对照以及来自NCI乳腺癌和前列腺癌队列联盟（BPC 3）的另外2，100例ER-乳腺癌病例的数据来测试确认的变异与乳腺癌风险的关联。我们还将调查与乳腺癌的关联是否与激素受体状态不同。 NHS的丰富资源和已经完成的16，000人的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识别高危女性，并为制定预防和治疗策略提供平台。 公共卫生相关性：一个一致但知之甚少的观察结果是，体型大的年轻女孩一生中患乳腺癌的风险降低了15-30%。在这项研究计划中，我们的目标是进行全基因组搜索，寻找儿童肥胖的遗传预测因子，并测试确定的变异是否会影响乳腺癌风险。最终，这项研究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。

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.