Integrated analyses of genome sequencing in adolescent idiopathic scoliosis families

青少年特发性脊柱侧凸家族基因组测序的综合分析

• 批准号: 10491053
• 负责人: CAROL A WISE
• 金额: $ 13.12万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10491053
• 关键词: Adolescent; Affect; Biological Response Modifier Therapy; Candidate Disease Gene; Catalogs; Child; Childhood; Code; Collaborations; Complex; Copy Number Polymorphism; Data; Data Set; Databases; Deformity; Diagnosis; Disease; Etiology; Exhibits; Family; Filtration; Future; Genes; Genetic; Genetic Risk; Genome; Goals; Health; Idiopathic scoliosis; Mutation; Names; Operative Surgical Procedures; Parents; Participant; Pathogenesis; Pathogenicity; Pathway interactions; Pediatric Research; Population; Prevention; Proteins; Regulatory Element; Research Personnel; Single Nucleotide Polymorphism; Spinal; Structural Congenital Anomalies; Susceptibility Gene; Technology; Testing; Untranslated RNA; Variant; Work; alternative treatment; cohort; congenital heart disorder; cost; disability; disease-causing mutation; disorder risk; exome; exome sequencing; gene discovery; genetic risk factor; genome analysis; genome sequencing; genome wide association study; high risk; innovation; insight; next generation sequencing; patient population; population based; proband; programs; rare variant; risk variant; scoliosis; sexual dimorphism; whole genome

Project Summary/Abstract Adolescent Idiopathic scoliosis (AIS) is the most common pediatric spinal deformity and exhibits a remarkable sexual dimorphism. AIS affects ~3% of children worldwide, and significantly impacts national health in the U.S., creating severe disfigurement and disability and costing billions of dollars annually for treatment. AIS is a genetically complex disease, and the majority of genetic risk alleles have not been defined. Our long-term objective is to identify genetic underpinnings in AIS that will provide insights into disease pathogenesis in order to enable pre-symptomatic diagnosis and develop biologic treatments and cures. Our group and other researchers previously identified and validated common variant associations with AIS by population-based genome-wide association studies (GWAS). Although GWASs have succeeded in explaining a small fraction of the genetic components in AIS, recent advances in next-generation sequencing technologies, such as whole genome sequencing (GS) and whole exome sequencing (ES), would rapidly facilitate discovery of rare single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) that are expected to contribute substantially to disease risk. We have partnered with the Gabriella Miller Kids First (GMKF) initiative and sequenced 591 genomes of multiplex AIS families. The primary purpose of the studies described in this proposal is to perform an integrated analysis of GS, ES and regulome data to define new, biologically-interpretable genetic risk factors. Aim 1 is to perform comprehensive risk allele discovery analyses with emphasis on rare, high-risk variants (SNVs and CNVs) using GS data in 190 AIS families. We will search for rare variants in both protein- coding and non-coding regulatory elements in our unique AIS family cohort by combined linkage, inheritance and de novo mapping strategies. This will be further powered by utilizing GS data from 10,746 non-scoliosis participants in 9 additional GMKF studies to generate a database of at least 1000 genome controls for rare variant annotation and filtration. Then in Aim 2, we will assess the overlap of AIS candidate genes from Aim 1 with genes identified by burden tests in an independent cohort of 1,320 AIS exomes and 7,500 ancestry-matched control exomes. Candidates identified in Aim 1 will be compared to these analyses to enable identification of common genes or pathways. Scoliosis often occurs in children diagnosed with other structural birth defects such as congenital heart disease. We have noted that 452 probands (excluding our own) in the GMKF portal are listed as having scoliosis. We will endeavor to work with other GMKF investigators to evaluate candidate genes in common across diagnoses. These studies will reveal AIS susceptibility loci in genes with strong effects across patient populations. These findings will form the cornerstone of many future studies ultimately targeting alternative treatments and preventions.

项目摘要/摘要 青少年特发性脊柱侧凸(AIS)是最常见的儿童脊柱畸形，表现出显著的 性二型性。AIS影响全球约3%的儿童，并显著影响美国的国民健康， 造成严重的毁容和残疾，每年花费数十亿美元进行治疗。AIS是一种 遗传性复杂疾病，大多数遗传风险等位基因尚未定义。我们的长期合作 目的是确定AIS的遗传基础，从而为疾病的发病机制提供深入的见解 能够进行症状前诊断并开发生物治疗和治愈方法。我们组和其他人 研究人员之前通过基于人群的方法识别和验证了与AIS的常见变异关联 全基因组关联研究(GWAS)。尽管GWAS已经成功地解释了一小部分 AIS中的遗传成分，下一代测序技术的最新进展，如全基因组 基因组测序(GS)和全外显子组测序(ES)将迅速促进稀有单基因的发现 核苷酸多态(SNPs)和拷贝数变异(CNV) 很大程度上增加了疾病风险。我们与加布里埃拉·米勒儿童优先(GMKF)倡议建立了合作伙伴关系 测序了AIS多个家系的591个基因组。本提案中描述的研究的主要目的 是对GS、ES和调节组数据进行综合分析，以确定新的、生物学上可解释的基因 风险因素。目标1是执行全面的风险等位基因发现分析，重点是罕见的、高风险的 190个AIS家系中使用GS数据的变异(SNV和CNV)。我们将在这两种蛋白质中寻找罕见的变异- 我们独特的AIS家族队列中的编码和非编码调控元件通过组合的连锁、遗传 和从头绘制地图的战略。这将通过利用10,746名非脊柱侧凸患者的GS数据进一步得到支持 参与另外9项GMKF研究，以生成一个至少包含1000个稀有基因对照的数据库 不同的注释和过滤。然后在目标2中，我们将评估来自目标1的AIS候选基因的重叠 通过负荷测试在由1320个AIS外显子和7500个祖先匹配的独立队列中鉴定出基因 控制外星人。目标1中确定的候选人将与这些分析进行比较，以确定 共同的基因或途径。脊柱侧弯通常发生在被诊断为患有其他结构性出生缺陷的儿童中，如 是先天性心脏病。我们注意到，GMKF门户网站上列出了452名先证者(不包括我们自己的先证者 患有脊柱侧弯。我们将努力与其他GMKF研究人员合作，评估候选基因在 在诊断中很常见。这些研究将揭示AIS易感基因中具有强烈影响的基因 患者群体。这些发现将成为许多未来研究的基石，最终目标是 替代治疗和预防。