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弯（AIS）是最常见的小儿脊柱畸形，影响了全球约3％的儿童。 AIS对美国的国家健康产生重大影响，对超过10％的患者造成严重的毁容和残疾，每年造成数十亿美元的治疗。我们的长期目标是确定AIS中的遗传基础，以提供对疾病发病机理的见解。在本应用中，我们建议使用在主要儿科骨科中心接受的AIS患者系统确定的DNA收集识别AIS敏感性基因座。我们的目的是通过700 AIS家族三重奏的缔合测试（GWA）发现与疾病相关的遗传基因座，并在第二次1,400个三重奏中测试最重要的基因座的关联复制。第三个目的是评估与AIS敏感性相关的拷贝数变化（CNV）。第四和第五的目的是在美国确定的第三个独立的1,000个三个三下的独立队列中筛选最有前途的约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。 AIM 1将利用Illumina Humancnv370-Duo系统来超过318,000个标记单核苷酸多态性（TAGSNP），并询问〜1,000个可疑CNV区域。单标记（单倍型）统计方法将应用于SNP数据。将评估从头突变和公共拷贝数变化。同样，新型统计方法将被开发并应用于CNV数据。以这种方式识别的基因座将按照意义进行排名。将使用适用于1,400个三重奏中的Illumina Goldengate系统获得的基因型的类似统计方法对顶级SNP基因座的关联复制进行测试。 Taqman和基于序列素的平台将用于基因型，这是第三个三重奏组的第三个队列中最有前途的，复制的基因座。进一步的研究（包括计算机方法和直接DNA测序）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AIS敏感性基因座的基因中具有强烈影响的患者人群的基因座。这些发现对于许多未来的研究最终针对预防或替代治疗将很重要。

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