Introduction: Familial idiopathic scoliosis (FIS) is a complex genetic disorder potentially resulting from multiple genetic interactions and variants. A previous genome wide screen in a large population of families with FIS followed by fine mapping utilizing STRP’s identified and narrowed critical regions on chromosomes 9 and 16. A high density SNP map was then designed across these regions. This array was then assayed within the same population in an effort to link and/or associate specific genetic intervals or candidate genes with the expressed phenotype.

Methods: A sample of families with IS (202 families, 1198 individuals) was recruited with IRB approval and underwent a genomic screen. Results were analysed by model-independent linkage analysis (SIBPAL). Following initial analyses, families were then stratified according to mode of inheritance. 101 families (550 individuals) represented an autosomal dominant mode of heritability and underwent fine mapping in the candidate regions.

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).

Results:

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.

Discussion: The current work has significance in the stepwise confirmation and narrowing of genomic regions which are potentially meaningful in the aetiology of FIS. Stratification of the initial sample into subgroups, initially by heritability and then by threshold of disease resulted in heightened significance at specific markers demonstrating the heterogeneity of this disorder. Ultimately, the independent association of genetic loci and this disorder will enhance the ability to elucidate prognosis, counsel patients, and guide therapeutic plans.