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（由适用提供）：初潮和绝经是女人一生中的两个基本事件。这些事件的时机对妇女的健康产生了深远而持久的影响，包括患乳腺癌的风险。在寻找与生殖衰老特征相关的常见遗传变异方面，已经进行了十多个全基因组关联研究（GWAS），包括初潮（AM）的年龄和自然更年期的年龄（ANM）。但是，确定的常见变体共同解释了遗传力的一小部分。许多“缺失的遗传力”可能归因于罕见和低频变体。由于非裔美国人（AA）女孩往往比欧美（EA）女孩的初潮往往，因此乳腺癌风险的后果尚不清楚。此外，欧洲血统的妇女进行了大多数以前的GWA繁殖衰老的GWA，并且已经了解了AAS。通过利用来自非裔美国乳腺癌流行病学和风险（Amber）财团中总共8,350种AA乳腺癌病例和健康对照的现有外显阵阵列基因型数据，我们建议确定与生殖衰老相关的稀有和低频编码变体。我们提出了两个具体目标：1）。评估以前GWAS识别的AM和ANM识别的区域中的罕见和低频编码变体； 2）确定与生殖衰老表型相关的基因组中的罕见和低频编码变体。据我们所知，这将是第一项研究AA女性生殖衰老表型的罕见和低频变体的研究。利用最大的AA乳腺癌研究中现有的外显子阵列数据使我们的研究具有很高的成本效益。我们希望确定具有较大效果的新型稀有和低频变体，这些变体超出了以前的GWAS信号的范围。这些发现可能解释了这些表型的“缺失遗传力”。在许多GWAS执行的许多GWAS中，研究生殖衰老遗传学的重要性是无可辩驳的。尽管发现的变体可能不会直接影响乳腺癌的预防或治疗，但是这一研究是促进我们对生殖衰老的生物学的理解以及与肥胖，成人状况，成人状态，糖尿病和乳腺癌等相关的多种疾病和状况的重要一步，可以介入新颖的目标，以介绍新型的目标和预防。