Osteoporosis candidate genes: In silico aided discovery

描述(申请人提供)：我们对构成分子发病机制的基因相互作用的了解正在迅速扩大，然而，尽管该领域的技术不断进步，常见疾病的基因研究仍然昂贵和耗时。最初的连锁和/或基因组扫描研究很少是决定性的，需要进一步的重点基因随访和/或验证研究，通常是在更多的患者队列上。目前的解决方案包括样本池，以支付全基因组研究的可观基因分型成本，或者减少和选择性焦点候选基因方法。然而，后者的成功取决于对疾病和途径的了解，这些知识正在增长，但仍然有限。我们的目标是确定在测试这些候选基因之前模拟假定候选基因的生物路径是否能够使我们能够更准确地针对更高可能性的候选基因，减少识别与疾病相关的基因所涉及的成本和时间，并确定这些目标在未来诊断或治疗环境中的可能作用。我们将在骨质疏松症的遗传学研究中测试这一点，目的是确定与染色体1p36的潜在连锁的基因(S)。骨质疏松症是一种骨矿密度(BMD)降低的疾病，与骨折风险增加有关，每年治疗和护理髋部骨折的费用超过90亿美元。许多双胞胎和家庭研究表明，高达80%的个人BMD风险是由基因控制的。此外，该病的遗传基础可能是多基因的，涉及多种基因产物，涉及骨骼建模(生长)和重塑(丢失和增加)。我们在这一阶段的研究目标是：1)在新型生物建模和仿真平台“BoneFusion”中评估1p36连锁区域的所有基因在骨重建中的影响和重要性；2)在被确定为高价值候选基因中对SNPs进行分型，以确定候选基因与骨质疏松症之间的关联，并测试该模型；以及3)进一步使用BoneFusion计算机模拟来确定任何与骨质疏松症密切相关的基因作为治疗靶标和/或诊断标志物的潜力。

DESCRIPTION (provided by applicant): Our understanding of the gene interactions that underlie molecular pathogenesis is expanding rapidly, yet despite continuing technical advances in the area, genetic studies of common diseases remain costly and time consuming. Initial linkage and/or genome scan studies are rarely definitive, and require further focused genetic follow-up and/or validation studies often on additional patient cohorts. Current solutions include sample pooling to defray the considerable genotyping costs of whole genome studies, or reduced and selective focal candidate gene approaches. The success of the latter, however, depends on knowledge of the disease and pathways, which is growing but still limited. Our goal is to determine whether simulating the biological pathways of putative candidate genes prior to testing those candidates, can enable us to more accurately target higher-likelihood candidates and reduce both the cost and time involved in identifying the genes associated with disease, as well as to define the likely role of these targets in a future diagnostic or therapeutic setting. We will test this in a genetic study of Osteoporosis aimed at identifying the gene(s) underlying the observed linkage to chromosome 1p36. Osteoporosis is a disease of reduced bone mineral density (BMD) that is associated with increased risk of bone fracture and for which the treatment and care of hip fractures exceeds $9 billion annually. Numerous twin and family studies have shown that as much as 80% of the individual risk in BMD is under genetic control. Moreover the genetic basis of the disease is likely to be polygenic, involving multiple gene products implicated in both bone modeling (growth) and remodeling (loss and gain). Our goals in this phase of the study are 1) to evaluate all genes in the linkage region 1p36 in a novel biological modeling and simulation platform, "BoneFusion", for their impact and importance in bone remodeling, 2) to genotype SNPs in the genes identified as high value candidates in order to identifying associations between the gene candidates and osteoporosis, and test the model, and 3) to further use the BoneFusion computer simulation to define the potential of any genes showing strong association with the disease, as a therapeutic target and/or diagnostic marker.