Osteoporosis is the most prevalent metabolic bone disease responsible for a major public health problem. Osteoporosis is mainly characterized by low bone mineral density (BMD). In general, women have lower BMD and higher risk of osteoporosis than men. Most BMD variation is determined by genetic factors with heritability greater than 60%. However, the specific genes involved are largely unknown. Our studies and the studies of others have demonstrated that some osteoporosis risk genes/genomic regions are gender specific. The GOAL of this SCOR is primarily to identify osteoporosis risk genes and their functional aspects in females and, secondarily, to assess the female specificity of these identified genes/functions in male samples. In addition, we will also perform in-depth molecular and cellular functional studies for specific mechanisms and confirmation of the risk genes identified, by studying two novel genes we discovered recently. This SCOR will pioneer a comprehensive and novel approach in bone genetics by investigating osteoporosis at the genome-, transcriptome-, and proteome-wide levels simultaneously. We will use the samples largely recruited or archived for targeted recruitment and adopt state-of-the-art technologies proved successful in our recent pilot studies. This qenomic convergence approach will pinpoint and consolidate the most significant genes identified in each of the individual projects. The genes identified will be subject to replication studies within and across populations by ourselves and our collaborators. All the genes identified in the genomic convergence approach will be subject to in-depth functional studies for confirmation and functional mechanisms as exemplified in Stage 2 of Project 2 of this SCOR. This SCOR is composed of three projects, all aimed at identifying osteoporosis risk genes but from different genomic approaches. Project 1 is to perform a whole genome association scan using dense SNPs to identify those genes/regions that are associated with risk of osteoporosis. Project 2 is to perform a DMA microarray study to scan >40,000 known human genes and ESTs to identify those mRNAs and corresponding genes associated with osteoporosis. Project 3 is to perform proteomics studies to identify those proteins (and corresponding genes) associated with osteoporosis. The SCOR has three cores: A) Administrative Core;B) Clinical Core;and C) Biostatistics and Bioinformatics Core. Each core serves all the three projects. For example, the Clinical Core recruits samples that are shared by Projects 2 and 3;provides support for clinical related issues (such as choice of important medical and environmental factors for co-variate analyses) and for human subject research issues in Project 1. Identifying genes and their functions for human BMD variation, especially for women, is important for 1) gaining insights into the fundamental molecular mechanisms underlying risk of osteoporosis, 2) discovering new pathways and targets for therapeutic cures;3) identifying genetically susceptible individuals, so that future preventions and interventions can be targeted to and based on individuals'specific genotypes.
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