Exome Array Analysis of Reproductive Aging and Breast Cancer in African Americans

非裔美国人生殖衰老和乳腺癌的外显子组阵列分析

• 批准号: 8971142
• 负责人: Song Yao
• 金额: $ 8.78万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8971142
• 关键词: Accounting; Adult; African; African American; Age; Age at Menarche; Aging; American; Biology; Breast Cancer Epidemiology; Breast Cancer Treatment; Chromosome Mapping; Code; Complex; Data; Diabetes Mellitus; Disease; Epidemiologic Studies; Estrogens; European; Event; Family; Female; Frequencies; Genes; Genetic; Genome; Genotype; Haplotypes; Heritability; Insulin; Knowledge; Length; Life; Linkage Disequilibrium; Lipids; Longevity; Malignant Neoplasms; Measures; Menarche; Menopause; Minor; Morbidity - disease rate; Obesity; Osteoporosis; Phenotype; Physiological; Population; Prevention; Preventive Intervention; Research; Risk; Risk Factors; Signal Transduction; Structure; Testing; Time; Twin Studies; Variant; Woman; Women' s Health; base; cancer risk; cost; disorder risk; exome; genetic variant; genome wide association study; girls; malignant breast neoplasm; novel; public health relevance; rare variant; reproductive; reproductive senescence; trait

 DESCRIPTION (provided by applicant): Menarche and menopause are two fundamental physiological events during a woman's life. The timing of these events has a profound and long-lasting impact on women's health later in life, including risk of breast cancer. More than a dozen genome-wide association studies (GWAS) have been conducted in searching for common genetic variants associated with the reproductive aging traits, including age at menarche (AM) and age at natural menopause (ANM). However, the identified common variants collectively explain only a minor proportion of the heritability. Much of the "missing heritability" may be attributable to rare and low-frequency variants. Because African American (AA) girls tend to have menarche at a younger age than European American (EA) girls, the ramification of which on breast cancer risk remains unclear. Moreover, a majority of the previous GWAS for reproductive aging was carried out in women of European ancestry, and AAs have been understudied. By leveraging the existing exome array genotype data from a total of 8,350 AA breast cancer cases and healthy controls in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, we propose to identify rare and low-frequency coding variants associated with reproductive aging. We propose two Specific Aims: 1). To evaluate rare and low-frequency coding variants in the regions identified by previous GWAS for AM and ANM; 2) To identify rare and low-frequency coding variants across the genome associated with reproductive aging phenotypes. To our knowledge, this will be the first study to examine rare and low-frequency variants for reproductive aging phenotypes in AA women. Leveraging the existing exome array data from the largest AA breast cancer study makes our study highly cost-efficient. We expect to identify novel rare and low-frequency variants with large effects, which are beyond the spectrum of previous GWAS signals. The findings may explain the "missing heritability" for those phenotypes. The significance of studying reproductive aging genetics is irrefutably evident in numerous GWAS's performed. Although the variants discovered may not have an immediate impact on the prevention or treatment of breast cancer, this line of research is an important integrative step in advancing our understanding of the biology of reproductive aging and a plethora of diseases and conditions related to it, such as obesity, adult statue, diabetes, and breast cancer, which may, in turn, identify novel targets for intervention and prevention.

 描述（由申请人提供）：初潮和更年期是女性一生中的两个基本生理事件，这些事件的发生时间对女性以后的健康产生深远而持久的影响，包括罹患乳腺癌的风险。全基因组关联研究（GWAS）旨在寻找与生殖衰老特征相关的常见遗传变异，包括初潮年龄（AM）和自然绝经年龄（ANM），然而，已识别的常见变异共同解释了这一点。大部分“缺失遗传力”可能归因于罕见和低频变异，因为非洲裔美国 (AA) 女孩的初潮年龄往往比欧洲裔美国 (EA) 女孩更早。此外，大多数先前针对生殖衰老进行的 GWAS 均针对欧洲血统的女性，并且利用现有的外显子组基因型数据对 AA 进行了充分研究。通过对非裔美国人乳腺癌流行病学和风险 (AMBER) 联盟中总共 8,350 例 AA 乳腺癌病例和健康对照的研究，我们建议确定与生殖衰老相关的罕见和低频编码变异：1) 评估。之前的 GWAS 确定的 AM 和 ANM 中的稀有和低频编码区域；2) 确定整个基因组中与生殖衰老表型相关的稀有和低频编码变异。是第一项检查 AA 女性生殖衰老表型的罕见和低频变异的研究，利用最大的 AA 乳腺癌研究的现有外显子组数据，使我们的研究具有很高的成本效益。影响较大的频率变异，超出了先前 GWAS 信号的范围，这些发现可以解释这些表型的“遗传性缺失”。可能不会对乳腺癌的预防或治疗产生立竿见影的影响，但这一研究方向是推进我们对生殖衰老生物学以及与之相关的多种疾病和病症（例如肥胖、成人雕像、糖尿病和乳腺癌，这反过来可能会确定干预和预防的新目标。