Identification of Genetic Susceptibility in Adolescent Idiopathic Scoliosis

描述（由申请人提供）：青少年特发性脊柱侧凸（AIS）是最常见的儿童脊柱畸形，影响全世界约3%的儿童。AIS严重影响着美国的国民健康，造成超过10%的患者严重毁容和残疾，每年花费数十亿美元用于治疗。我们的长期目标是确定AIS的遗传基础，从而深入了解疾病的发病机制。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患者中系统确定的DNA收集来确定AIS易感位点。我们的目标是通过700个AIS家族三重奏组的全基因组关联测试（GWA）发现疾病相关的遗传位点，并在第二个队列的1400个三重奏组中测试最重要位点的关联复制。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第三个独立队列中筛选最有希望的~2%的复制位点，在美国确定1000个三胞胎，并在这些研究中确定选定基因的因果变异。Aim 1将利用Illumina humancnv70 - duo系统对超过318,000个标记单核苷酸多态性（tagsnp）进行基因分型，并询问约11,000个可疑CNV区域。单标记和多标记（单倍型）统计方法将应用于SNP数据。将评估新生突变和共同拷贝数变异。此外，将开发新的统计方法并将其应用于CNV数据。用这种方法确定的基因座将按显著性排序。将使用与Illumina GoldenGate系统在1400个三人组中获得的基因型相似的统计方法来测试排名靠前的SNP位点的关联复制。基于Taqman和sequenom的平台将被用于在1000个三联组的第三个队列中对最有希望的复制位点进行基因分型。包括计算机方法和直接DNA测序在内的进一步研究将用于确定疾病相关基因中可能的因果变异。这些研究将揭示在患者群体中具有强烈影响的基因中的AIS易感位点。这些发现将对未来许多最终针对预防或替代治疗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.