Genetics of Reproductive Life Period and Health Outcomes

描述（申请人提供）：生殖生命期的开始和结束是影响妇女晚年健康的主要因素。初潮年龄和绝经年龄影响不良健康结果的风险，包括骨质疏松症、心血管疾病和乳腺癌。需要进一步的科学研究来阐明更年期和生殖因素与衰老本身对妇女晚年常见健康状况的影响。月经初潮和绝经年龄的变化有一半以上归因于遗传因素，但调控这些特征的基因在很大程度上仍然未知。来自纵向研究的数据，如心脏病研究（FHS），提供了大量的成年数据，包括女性和男性的生殖因素，疾病发生和健康行为。FHS是多代的，包括一个广泛的遗传学数据库，其中包含通过NHLBI的SNP健康协会资源（SHARe）项目获得的550K全基因组扫描的现存基因分型。我们假设，可以使用密集的全基因组关联研究（GWAS）确定影响初潮和自然绝经年龄的新遗传变异。该提案有以下具体目标：目标1。通过GWAS使用现存的550K基因分型数据来鉴定影响初潮年龄和自然绝经年龄的遗传变异。在独立样本中进行重要关联的计算机模拟复制。目标2.研究目的1中确定的遗传变异与使用双能X线吸收测定法（DXA）和手动放射测量法获得的女性和男性的乳腺癌相关性状之间的关联。目标3：使用与生殖衰老相关的基因型进行表型扫描，以确定其他相关表型，这些表型可能为介导女性相关性的潜在生物学机制提供额外的见解。表型扫描也将在男性中进行，以探索性别特异性关联。使用550K基因分型将是资源有效的，我们的工作将通过位于NCBI的FHS SHARe项目公开，允许世界各地的研究人员开始这项研究。该项目的见解可能导致发现与女性生殖老化和相关健康结果有关的基因，从而导致创新的诊断和治疗干预措施，以改善妇女和男性的整体健康。公共卫生相关性：该项目可能会导致发现与女性生殖衰老（初潮和绝经）相关的基因，从而深入了解导致女性晚年重要健康状况的病理生理机制。所获得的知识可能会导致创新的诊断和治疗干预措施，以改善妇女的整体健康，并可能改善男子的整体健康。

DESCRIPTION (provided by applicant): The onset and conclusion of the reproductive life period are central factors influencing women's health later in life. Age at menarche and menopausal age affect risk for adverse health outcomes including osteoporosis, cardiovascular disease, and breast cancer. Further scientific study is needed to elucidate the contribution of menopause and reproductive factors versus aging per se to health conditions common in women in later life. More than half the variation in age at menarche and menopause is attributable to genetic factors yet the genes regulating these traits remain largely unknown. Data from longitudinal studies, such as the Framingham Heart Study (FHS), provide a wealth of data across adulthood including reproductive factors, disease occurrence, and health behaviors in both women and men. The FHS is multigenerational and includes an extensive genetics database with extant genotyping from a 550K genome-wide scan obtained through the NHLBI's SNP Health Association Resource (SHARe) project. We postulate that novel genetic variants influencing the age of menarche and natural menopause can be identified using a dense genome-wide association study (GWAS). This proposal has the following specific aims: Aim 1. To identify genetic variants that influence age at menarche and age at natural menopause through a GWAS using extant 550K genotyping data. To perform in silico replication of significant associations in independent samples. Aim 2. To examine the associations between genetic variants identified in aim 1 and osteoporosis-related traits obtained using dual x-ray absorptiometry (DXA) and hand radiogrammetry, in women as well as in men. Aim 3. To perform a phenome scan using the genotypes associated with reproductive aging to identify other associated phenotypes that may provide additional insights into underlying biological mechanisms mediating the associations in women. The phenome scan will also be performed in men to explore sex-specific associations. The use of the 550K genotyping will be resource effective and our work will be publicly available through the FHS SHARe Project located at the NCBI permitting investigators around the world to embark on this research. Insights from this project may lead to the discovery of genes related to female reproductive aging and associated health outcomes and in turn lead to innovative diagnostic and therapeutic interventions to improve the overall health of women and possibly of men. PUBLIC HEALTH RELEVANCE: This project may lead to the discovery of genes related to female reproductive aging (menarche and menopause) and in turn provide insights into the pathophysiologic mechanisms leading to important health conditions later in life in women. Knowledge gained may lead to innovative diagnostic and therapeutic interventions to improve the overall health of women and possibly of men.