Integrated analyses of genome sequencing in adolescent idiopathic scoliosis families

项目总结/摘要 青少年特发性脊柱侧凸（AIS）是最常见的儿童脊柱畸形， 两性异形AIS影响全球约3%的儿童，并严重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用于治疗。AIS是一个 遗传复杂的疾病，大多数遗传风险等位基因尚未确定。我们的长期 目的是确定AIS的遗传基础，这将为疾病发病机制提供见解， 以实现症状前诊断并开发生物治疗和治愈。我们的团队和其他 研究人员先前通过基于人群的研究， 全基因组关联研究（GWAS）。虽然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 基因组测序（GS）和全外显子组测序（ES），将迅速促进发现罕见的单一的 核苷酸多态性（SNP）和拷贝数变异（CNVs），预计有助于 在很大程度上是疾病风险。我们与加布里埃拉米勒儿童第一（GMKF）倡议合作， 对591个多发病AIS家系的基因组进行了测序。本提案所述研究的主要目的是 是对GS、ES和调节组数据进行综合分析，以确定新的、生物学上可解释的遗传学特征， 危险因素目的1是进行全面的风险等位基因发现分析，重点是罕见的，高风险的 变异（SNV和CNV）使用GS数据在190 AIS家庭。我们将寻找两种蛋白质的罕见变异- 编码和非编码调控元件在我们独特的AIS家族队列中通过联合连锁、遗传 和从头映射策略。这将通过利用来自10，746例非脊柱侧凸患者的GS数据得到进一步支持。 参与了另外9项GMKF研究，以生成至少1000个基因组对照的数据库， 变体注释和过滤。然后在目标2中，我们将评估目标1中AIS候选基因的重叠 在一个由1,320个AIS外显子组和7,500个祖先匹配的独立队列中通过负荷测试确定的基因， 控制外显子组。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。脊柱侧凸通常发生在被诊断患有其他结构性出生缺陷的儿童中， 先天性心脏病我们注意到GMKF门户网站中列出了452个先证者（不包括我们自己的先证者） 脊柱侧弯我们将奋进与其他GMKF研究人员合作，评估候选基因， 常见的诊断。这些研究将揭示AIS易感基因位点在基因中的强烈影响， 患者人群。这些发现将成为未来许多研究的基石， 替代治疗和预防。

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.