Localizing Susceptibility to Adolescent Idiopathic Scoliosis

Summary: Various studies have produced evidence of potentially many genes contributing to AIS susceptibility. The purpose of the present study was to refine the search for causative genes by testing replication of linkage in an independent AIS family cohort. Most significant results were obtained for a region of chromosome 8q (p<0 .01). These results confirm our previous observations and support a role for the 8q region in AIS susceptibility.

Purpose: Adolescent idiopathic scoliosis (AIS) generally displays complex inheritance, suggesting that several genes are responsible for disease. Positional cloning efforts have produced evidence of potentially many chromosomal regions contributing to AIS susceptibility. The purpose of this study was to focus our efforts on significant regions by testing replication in an independent family cohort. Identified regions may then be searched for causative genes.

Methods: We fully evaluated and collected 217 nuclear and extended AIS families. We tested linkage to fourteen candidate regions, derived from our results and published reports, in a subset of the families (106 affected and 107 unaffected individuals). Individuals with minimum lateral curve of 15 degrees diagnosed from standing radiographs and with no other associated disorder were considered affected. Polymorphic microsatellite markers were genotyped in two stages using semi-automated methods. Single nucleotide polymorphisms (SNPs) were genotyped in Taqman allele discrimination assays. Nonparametric lod (NPL) scores and family-based association were tested using Genehunter, TdT AE, and PDT analysis packages.

Results: Small positive lod scores were obtained for regions of chromosomes 1, 8, 9, 17, and X. Most significant results were obtained for 8q (p<=0.02).

Conclusion: The present replication study continues to support a role for the 8q region in AIS susceptibility. We have noted maximum linkage, and potential evidence of association, distal to the 8q SNTG1 candidate gene that we previously reported. We hypothesize that other 8q gene(s) in addition to SNTG1 may contribute to disease. Additional tests of association are required to distinguish this.

Support from the SRS and Fondation Cotrel is gratefully acknowledged.