Unraveling Musculoskeletal Pleiotropy Using Genome-Wide Association

描述（由申请人提供）： 骨质疏松性骨折的风险可被视为载荷条件和人体骨骼承受载荷能力的函数。骨骼几何形状是骨骼脆弱性的重要预测因子;骨骼负荷主要由肌肉活动决定。骨骼几何形状和肌肉质量都是可遗传的，并且共享遗传决定因素。拟议的工作将利用现有的队列，其中有大量的成年男性和女性，骨骼和肌肉测量可用，以及现存的全基因组多态性。在FOS研究中进行基于人群和家族的全基因组关联分析后，我们的结果将在其他美国白人队列的男性和女性中重复，即心血管健康研究（CHS）、宾夕法尼亚州阿米什人家庭和来自印第安纳州的兄弟姐妹，以及荷兰的鹿特丹研究和冰岛的AGES-Reykjavik研究。该项目的总体目标是识别导致两种表型的遗传因素，这两种表型在骨强度的测定中起重要作用。我们的具体目标是：目标1。在股骨研究中对下肢的横截面骨几何形状和肌肉质量进行全基因组关联分析，然后识别骨几何形状和肌肉质量共有的染色体区域/候选基因。AIM 2.在具有相同（或相似）表型的其他高加索人样本中复制相关结果，以选择后续的候选区域。AIM 3.探讨骨/肌肉界面上基因与基因和基因与环境的相互作用。识别骨骼和肌肉的重要遗传变异，用最先进的技术测量并在其他大型队列中复制，将为风险分层的重要潜在目标提供有价值的见解，并可能转化为预防和个性化治疗骨质疏松性骨折的新方法。 公共卫生相关性： 这些影响骨质疏松症和肌肉减少症的基因的鉴定可能导致（i）早期识别风险人群，实施预防策略，（ii）开发更有效的药物和更个性化的治疗，以及（iii）更好地了解基因和选择的环境如何共同调节肌肉力量和骨质疏松症的风险。上述措施将大大提高生活质量，降低数百万美国中年人和老年人的医疗保健费用。

DESCRIPTION (provided by applicant): The risk of osteoporotic fracture can be viewed as a function of loading conditions and the ability of human bone to withstand the load. Bone geometry is an important predictor of skeletal fragility; skeletal loads are dominated by muscle action. Bone geometry and muscle mass are both heritable and share genetic determinants. The proposed work will take advantage of available cohorts with large numbers of adult men and women with bone and muscle measures available, as well as extant genome-wide polymorphisms. Following the population- and family-based genome-wide association analyses in Framingham Osteoporosis Study (FOS), our results will be replicated in men and women from other US Caucasian cohorts, namely Cardiovascular Health Study (CHS), Pennsylvania Amish families, and siblings from Indiana, as well as the Rotterdam Study from the Netherlands and AGES-Reykjavik from Iceland. The OVERALL GOAL of the proposed project is to discern genetic factors contributing to two phenotypes that play an important role in the determination of bone strength. Our specific aims are: AIM 1. To perform genome-wide association analyses for cross-sectional bone geometry and muscle mass in the lower extremity in the Framingham Study, and then to identify chromosomal regions/ candidate genes shared by bone geometry and muscle mass. AIM 2. To replicate association findings in other Caucasian samples with the same (or similar) phenotypes, to select candidate regions for the follow-up. AIM 3. To explore gene-by-gene and gene-by-environment interaction on the bone/muscle interface. Identifying significant genetic variants underlying both bones and muscles, measured with state-of-art technology and replicated in other large cohorts, will provide valuable insight into important potential targets for risk stratification and may translate into new approaches to the prevention and personalized therapy for osteoporotic fractures. PUBLIC HEALTH RELEVANCE: The identification of these genes that influence osteoporosis and sarcopenia could lead to (i) earlier identification of people at risk, to implement preventive strategies, (ii) the development of more effective medications and more individualized therapy, and (iii) better knowledge how the genes and selected environment work together to regulate both muscle strength and the risk for osteoporosis. The above will improve substantially quality of life and decrease health care costs for millions of middle-aged and elderly Americans.