Clinical studies have shown distinct differences in later-onset idiopathic scoliosis (IS) between men and women, including curve severity, stiffness, and ease of operative intervention. Therefore, significant scoliosis in men was used as criteria to create a phenotypical subset of families with IS. The goal of this study is to identify genetic determinants that relate specifically to men with a scoliotic curvature of 30° or more. We identified 25 families (208 individuals) in which a male was diagnosed with 30° or more IS curvature in adolescence. 123 individuals were affected (48 male; 75 female), and 85 were unaffected (45 male; 40 female). Initially, a genomic screen was done with a modified CHLC (version 9) marker set. After initial linkage analyses, the group underwent finemapping with a custom single-nucleotide polymorphism (SNP) panel and ABI Taqman methodology on an ABI 377 platform. The initial genome-wide screen and subsequent analyses were analysed by model-independent linkage analysis with SIBPAL (SAGE, version 5).Introduction
Methods
Custom SNP pools were designed for the candidate regions at a density of 1 SNP/58Kb. DNA from 550 individuals (AD group) were genotyped using the Illumina platform. A total of 1536 SNP markers were attempted, of which 1324 were released; 519 SNPs were genotyped on 9q32-24 and 805 SNPs genotyped on 16p12-q22. The map was generated using NCBI dbSNP chromosome report on Build 34. Overall missing rate was 0.06%; the overall duplicate error rate was 0.05%. FIS was analysed both as a qualitative trait with an arbitrary threshold, and as a quantitative trait, or the degree of lateral curvature. Model independent sib-pair linkage analysis was performed on the subsets (SIBPAL, S. A. G. E. v4.5).
Chromosome 9: Multipoint model-independent qualitative analysis (threshold at ten degrees) did not result in any p values of <
0.05. When the threshold was set at 30 degrees, several regions with p values of <
0.005 were observed. One region spanned 10 Mb, and coincides with the region found to be most suggestive of linkage at the 0.05 level for the quantitative analysis which was 6 Mb in length. Chromosome 16: Multipoint model-independent qualitative analysis (threshold at ten degrees) resulted in a region spanning 23Mb with p values of <
0.05. The region included both regions adjacent to the centromere. When analysis was performed at a threshold of 30 degrees, the p values became more significant within a region of 30 Mb significant at the 0.05 level. The region best defined at a 0.01 level was located in an 8 Mb region on the q arm.