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 i s 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.
|Haller, Gabe; Alvarado, David; Mccall, Kevin et al. (2016) A polygenic burden of rare variants across extracellular matrix genes among individuals with adolescent idiopathic scoliosis. Hum Mol Genet 25:202-9|
|Sharma, Swarkar; Londono, Douglas; Eckalbar, Walter L et al. (2015) A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females. Nat Commun 6:6452|
|Hayes, Madeline; Gao, Xiaochong; Yu, Lisa X et al. (2014) ptk7 mutant zebrafish models of congenital and idiopathic scoliosis implicate dysregulated Wnt signalling in disease. Nat Commun 5:4777|
|Londono, Douglas; Kou, Ikuyo; Johnson, Todd A et al. (2014) A meta-analysis identifies adolescent idiopathic scoliosis association with LBX1 locus in multiple ethnic groups. J Med Genet 51:401-6|
|Gao, Xiaochong; Gotway, Garrett; Rathjen, Karl et al. (2014) Genomic analyses of patients with unexplained early onset scoliosis. Spine Deform 2:324-332|
|Londono, Douglas; Buyske, Steven; Finch, Stephen J et al. (2012) TDT-HET: a new transmission disequilibrium test that incorporates locus heterogeneity into the analysis of family-based association data. BMC Bioinformatics 13:13|
|Sharma, Swarkar; Gao, Xiaochong; Londono, Douglas et al. (2011) Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes. Hum Mol Genet 20:1456-66|
|McGregor, Tracy L; Gurnett, Christina A; Dobbs, Matthew B et al. (2011) Common polymorphisms in human lysyl oxidase genes are not associated with the adolescent idiopathic scoliosis phenotype. BMC Med Genet 12:92|
|Shyy, William; Wang, Kai; Gurnett, Christina A et al. (2010) Evaluation of GPR50, hMel-1B, and ROR-alpha melatonin-related receptors and the etiology of adolescent idiopathic scoliosis. J Pediatr Orthop 30:539-43|