Integrated analyses of genome sequencing in adolescent idiopathic scoliosis families

项目总结/文摘

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.