Identification of Genetic Susceptibility in Adolescent Idiopathic Scoliosis

描述(申请人提供)：青少年特发性脊柱侧凸(AIS)是最常见的儿童脊柱畸形，影响全球约3%的儿童。人工授精严重影响了美国的国民健康，造成超过10%的患者严重毁容和残疾，每年的治疗成本高达数十亿美元。我们的长期目标是确定AIS的遗传基础，这将为疾病发病机制提供见解。在目前的应用中，我们建议使用从主要儿科骨科中心治疗的AIS患者系统确定的DNA收集来识别AIS易感基因。我们的目标是通过全基因组关联测试(GWA)在700个AIS家系中发现与疾病相关的遗传基因座，并在第二个1400个三联体队列中测试最重要的基因座的关联性复制。第三个目的是评估与AIS易感性相关的拷贝数变异(CNV)。第四和第五个目标是在美国各地确定的1000个Trio的第三个独立队列中筛选最有希望的~2%的重复基因，并确定这些研究确定的选定基因中的因果变异。目的1将利用Illumina Human CNV370-Duo系统对318,000多个标签单核苷酸多态(Tag SNP)进行分型，并询问大约11,000个疑似CNV区域。单标记和多标记(单倍型)统计方法将应用于SNP数据。将对从头突变和常见拷贝数变异进行评估。此外，还将开发新的统计方法并将其应用于CNV数据。以这种方式识别的基因座将根据重要性进行排序。排名靠前的SNP基因座的相关性复制将使用类似的统计方法进行测试，这些方法适用于Illumina GoldenGate系统在1,400个三人组中获得的基因类型。基于TaqMan和Sequenom的平台将被用来对第三个1000个三联体队列中最有希望的重复基因座进行基因分型。进一步的研究，包括电子计算机方法和直接DNA测序，将被用来确定疾病相关基因中可能的因果变异。这些研究将揭示AIS易感基因中对患者群体有强烈影响的基因。这些发现将对未来许多最终以预防或替代治疗为目标的研究具有重要意义。

DESCRIPTION (provided by applicant): Adolescent idiopathic scoliosis (AIS) is the most common pediatric spinal deformity, affecting ~3% of children worldwide. AIS significantly impacts national health in the U.S., creating severe disfigurement and disability for over 10% of patients and costing billions of dollars annually for treatment. Our long-term objective is to identify genetic underpinnings in AIS that will provide insights into disease pathogenesis. In the present application we propose to identify AIS susceptibility loci using DNA collections systematically ascertained from AIS patients treated at major pediatric orthopedic centers. Our aims are to discover disease-associated genetic loci via genome-wide tests of association (GWA) in 700 AIS family trios, and to test replication of association for most significant loci in a second cohort of 1,400 trios. A third aim is to assess copy number variation (CNV) associated with AIS susceptibility. Fourth and fifth aims are to screen most promising ~2% of replicated loci in a third, independent cohort of 1,000 trios ascertained throughout the U.S., and to identify causal variants in selected genes identified by these studies. Aim 1 will utilize the Illumina HumanCNV370-Duo system to genotype over 318,000 tagging single nucleotide polymorphisms (tagSNPs), and to interrogate ~11,000 regions of suspected CNV. Single- and multi-marker (haplotype) statistical methods will be applied to the SNP data. De novo mutations and common copy number variation will be assessed. Also, novel statistical methods will be developed and applied to CNV data. Loci identified in this way will be ranked by significance. Replication of association for top-ranked SNP loci will be tested using similar statistical methods applied to genotypes obtained with the Illumina GoldenGate system in the 1,400 trios. Taqman and Sequenom-based platforms will be utilized to genotype the most promising, replicated loci in the third cohort of 1,000 trios. Further studies including in silico methods and direct DNA sequencing will be used to identify possible causal variants in disease-associated genes. These studies will reveal AIS susceptibility loci in genes with strong effects across patient populations. These findings will be important for many future studies ultimately targeting prevention or alternative treatments.