Genetics of Reproductive Life Period and Health Outcomes

生殖生命期的遗传学和健康结果

• 批准号: 7509705
• 负责人: JOANNE M MURABITO
• 金额: $ 21.69万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7509705
• 关键词: Achievement; Affect; Age; Age at Menarche; Age-Related Bone Loss; Aging; Bioinformatics; Biological; Biotechnology; Cardiovascular Diseases; Clinical Trials; Communities; Complex; Computer Simulation; Condition; Data; Diagnostic; Discipline; Disease; Elderly; Family history of; Female; Framingham Heart Study; Functional disorder; Genes; Genetic; Genetic Databases; Genome Scan; Genotype; Hand; Health; Health behavior; Heritability; Knowledge; Lead; Life; Longitudinal Studies; Measurement; Mediating; Menarche; Menopause; Methods; Osteoporosis; Outcome; Outcome Measure; Pathway interactions; Phase; Phenotype; Postmenopause; Public Health; Range; Rate; Reproduction; Reproductive History; Research; Research Personnel; Resources; Risk; Risk Factors; Sampling; Scanning; Site; Therapeutic Intervention; Time; Variant; Woman; Women' s Health; Work; base; bone; bone loss; cohort; gene discovery; genetic epidemiology; genetic variant; genome wide association study; improved; innovation; insight; malignant breast neoplasm; men; novel; reproductive; sex; statistics; trait

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.

描述（由申请人提供）： 生育期的开始和结束是影响妇女晚年健康的核心因素。初潮年龄和绝经年龄会影响骨质疏松症、心血管疾病和乳腺癌等不良健康结果的风险。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女性晚年常见健康状况的影响。初潮和更年期年龄变化的一半以上可归因于遗传因素，但调节这些性状的基因仍然很大程度上未知。弗雷明汉心脏研究 (FHS) 等纵向研究的数据提供了成年期的大量数据，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 全基因组扫描的现有基因分型。我们假设可以使用密集的全基因组关联研究（GWAS）来识别影响初潮年龄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. 使用现有 550K 基因分型数据，通过 GWAS 识别影响初潮年龄和自然绝经年龄的遗传变异。在独立样本中进行显着关联的计算机复制。目标 2. 检查目标 1 中确定的遗传变异与使用双 X 射线吸收测定法 (DXA) 和手部放射线测量法获得的女性和男性骨质疏松症相关特征之间的关联。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更多见解。表型组扫描还将在男性中进行，以探索性别特异性关联。 550K 基因分型的使用将实现资源有效利用，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展这项研究。该项目的见解可能会导致与女性生殖衰老和相关健康结果相关的基因的发现，进而导致创新的诊断和治疗干预措施，以改善女性甚至男性的整体健康。公共健康相关性：该项目可能会发现与女性生殖衰老（初潮和更年期）相关的基因，进而深入了解导致女性晚年出现重要健康状况的病理生理机制。获得的知识可能会导致创新的诊断和治疗干预措施，以改善女性（甚至可能男性）的整体健康。