Identification of Genetic Susceptibility in Adolescent Idiopathic Scoliosis

青少年特发性脊柱侧凸遗传易感性鉴定

• 批准号: 8279117
• 负责人: CAROL A WISE
• 金额: $ 39.69万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8279117
• 关键词: Adolescent; Affect; Alleles; Area; Biological Testing; Child; Childhood; Collection; Computer Simulation; Copy Number Polymorphism; DNA; DNA Sequence; Data; Deformity; Diagnostic; Disease; Evaluation; Family; Future; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genotype; Haplotypes; Health; Idiopathic scoliosis; Indium; Institution; Measures; Methods; Modeling; Mutation; Onset of illness; Orthopedics; Pathogenesis; Patients; Predisposition; Prevention; Publications; Sampling; Single Nucleotide Polymorphism; Spinal; Staging; Statistical Methods; Surgeon; Susceptibility Gene; System; Testing; Variant; alternative treatment; base; cohort; cost; disability; follow-up; genome wide association study; genome-wide; insight; novel; offspring; patient population; prospective; statistics; transmission process

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.

描述（由申请人提供）：青少年特发性脊柱侧凸 (AIS) 是最常见的小儿脊柱畸形，影响全球约 3% 的儿童。 AIS 严重影响美国国民健康，导致超过 10% 的患者严重毁容和残疾，每年治疗费用达数十亿美元。我们的长期目标是确定 AIS 的遗传基础，从而深入了解疾病发病机制。在本申请中，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 集合来识别 AIS 易感位点。我们的目标是通过全基因组关联测试 (GWA) 在 700 个 AIS 家族三人组中发现与疾病相关的遗传位点，并在第二组 1,400 个三人组中测试最重要基因座的关联复制。第三个目标是评估与 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由 1,000 个三人组成的第三个独立队列中筛选最有希望的约 2% 的复制基因座，并确定这些研究确定的选定基因中的因果变异。目标 1 将利用 Illumina HumanCNV370-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。将评估从头突变和常见拷贝数变异。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按重要性排序。将使用应用于 Illumina GoldenGate 系统在 1,400 个三人组中获得的基因型的类似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 的平台将用于对第三组 1,000 个三人组中最有希望的复制基因座进行基因分型。包括计算机方法和直接 DNA 测序在内的进一步研究将用于识别疾病相关基因中可能的致病变异。这些研究将揭示基因中的 AIS 易感性位点，对患者群体产生强烈影响。这些发现对于未来许多最终针对预防或替代治疗的研究非常重要。

项目成果

Genomic Analyses of Patients With Unexplained Early-Onset Scoliosis.

• DOI: 10.1016/j.jspd.2014.04.014
• 发表时间: 2014-09
• 期刊: SPINE DEFORMITY
• 影响因子: 1.6
• 作者: Gao, Xiaochong;Gotway, Garrett;Rathjen, Karl;Johnston, Charles;Sparagana, Steven;Wise, Carol A
• 通讯作者: Wise, Carol A

ptk7 mutant zebrafish models of congenital and idiopathic scoliosis implicate dysregulated Wnt signalling in disease.

• DOI: 10.1038/ncomms5777
• 发表时间: 2014-09-03
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Hayes, Madeline;Gao, Xiaochong;Yu, Lisa X.;Paria, Nandina;Henkelman, R. Mark;Wise, Carol A.;Ciruna, Brian
• 通讯作者: Ciruna, Brian

TDT-HET: a new transmission disequilibrium test that incorporates locus heterogeneity into the analysis of family-based association data.

• DOI: 10.1186/1471-2105-13-13
• 发表时间: 2012-01-20
• 期刊: BMC bioinformatics
• 影响因子: 3
• 作者: Londono D;Buyske S;Finch SJ;Sharma S;Wise CA;Gordon D
• 通讯作者: Gordon D