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: 10195530
• 负责人: CAROL A WISE
• 金额: $ 13.77万
• 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/10195530
• 关键词: Adolescent; Affect; Biological; 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弯（AIS）是最常见的小儿脊柱畸形，表现出了显着的 性二态性。 AI在全球范围内影响约3％的儿童，并显着影响美国国家健康， 造成严重的毁容和残疾，每年造成数十亿美元的治疗。 AI是一个 尚未定义遗传复杂的疾病，大多数遗传风险等位基因尚未定义。我们的长期 目的是识别AIS中的遗传基础，该基础将为疾病发病机理提供深入的见解。 为了启用症状前诊断并开发生物治疗和治疗方法。我们的小组和其他 研究人员先前通过基于人群的AIS确定并验证了与AIS的共同变体关联 全基因组关联研究（GWAS）。尽管Gwass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，例如整体 基因组测序（GS）和整个外显子组测序（ES）将迅速促进稀有单一的发现 核苷酸多态性（SNP）和拷贝数变化（CNV）有望有助于 基本上是疾病的风险。我们已经与Gabriella Miller Kids First（GMKF）倡议合作， 测序的591个多重AIS家族的基因组。本提案中描述的研究的主要目的 是对GS，ES和调节数据进行集成分析，以定义新的，生物学上可区分的遗传 风险因素。 AIM 1是进行全面的风险等位基因发现分析，重点是稀有，高风险 使用190个AIS系列中的GS数据的变体（SNV和CNV）。我们将在两种蛋白质中搜索稀有变体 我们独特的AIS家族队列中的编码和非编码调节元素通过联合链接，继承 和从头映射策略。这将通过利用10,746个非抗衰变的GS数据进一步启动 参加9项GMKF研究的参与者，以生成至少1000个基因组控制的数据库 变体注释和过滤。然后在AIM 2中，我们将评估AIM 1的AIS候选基因的重叠 通过负担测试确定的基因在1,320个AIS的独立队列中，并匹配7,500个祖先匹配 控制异构体。将在AIM 1中确定的候选人将其与这些分析进行比较，以识别 常见基因或途径。脊柱侧弯通常发生在被诊断出患有其他结构性先天缺陷的儿童中 作为先天性心脏病。我们已经注意到，列出了GMKF门户中的452个概率（不包括我们自己的） 作为脊柱侧弯。我们将努力与其他GMKF研究人员合作，以评估候选基因 跨诊断常见。这些研究将揭示AIS易感性基因座的基因中的基因 患者人群。这些发现将构成许多未来研究的基石 替代治疗和预防。