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Utilising population-based collections from the UK to identify genetic risk factors for idiopathic scoliosis

About This PhD Project

Project Description

Adolescent Idiopathic Scoliosis (AIS) accounts for the majority of cases of idiopathic scoliosis, and has a prevalence of approximately 3%. Current knowledge on the causes of initiation or progression of scoliotic curves is scarce. There is considerable interest in exploring the genetic basis of scoliosis, as a means of improving understanding of its pathogenesis and natural history. Twin studies consistently show monozygotic twins have a higher concordance rate for scoliosis than dizygotic twins (73% versus 36%), suggesting an underlying genetic component is important, although the architecture of this effect is unknown. Genome wide studies (GWAS) have been used in a Japanese case-control study and it identified the SNP rs11190870 to be associated with scoliosis risk. This variant has now been replicated in an independent southern Chinese population, but a systematic search for genetic variation associated with scoliosis in European populations has not been performed.

Aims & Objectives
We wish to build our current scoliosis research using ALSPAC by utilising genetic data already collected. In addition, we also wish to extend into another collection, Twins-UK, that has contact with over 12,000 twins, and has collected a wide range of clinical, biological and genetics data similar to ALSPAC. This similarity will allow us to combine data from Twins-UK and ALSPAC, and will increase power to identify rarer genetic determinants, or those with smaller effect sizes.

1. Obtain measures of scoliosis from participants in Twins-UK aged ≤45. The PhD student will apply the DXA Scoliosis Method (DSM) to eligible DXA scans in Twins-UK.
2. Investigate if the SNP rs11190870 is associated with the presence of scoliosis in ALSPAC and Twins-UK. Pilot data shows the allele frequency is similar in ALSPAC to the Asian populations
3. Perform GWAS followed by meta-analysis in ALSPAC and Twins-UK. If SNPs are identified as associated with scoliosis risk with sufficient evidence in ALSPAC alone (P<5x10-8 in tests of association) these data will be replicated using data from Twins-UK. However, in the absence of association identified using ALSPAC alone, a meta-analysis will be performed of the ALSPAC and Twins-UK GWAS data.
4. Evaluate if identified novel SNPs are likely to have biological relevance bioinformatically and by utilising gene expression, DNA methylation and metabolomic data collected across ALSPAC and Twins-UK


Taylor HJ et al Identifying scoliosis in population-based cohorts: Development and validation of a novel method based on total body DXA scans. Calc Tis Int 2013;92:539
Takahashi Y et al A genome-wide association study identifies common variants near LBX1 associated with AIS. Nat Gen 2011;43:1237

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