Familial Idiopathic Scoliosis: Evidence of Autosomal Susceptibility Loci

Introduction: Familial idiopathic scoliosis is a common structural curvature of the spine whose genetic determinants and pattern of inheritance are not clear. The goal of this research is to define the genes responsible for this disorder utilizing a large, well-defined population. This strategy is based on the high prevalence of the disorder within the general population, and the variability of disease presentation, suggesting significant clinical and genetic heterogeneity.

Methods: Families with two or more affected individuals identified through evidence of a ten-degree saggital curvature on standing anterioposterior radiographs were recruited. A genomic-wide scan of the population (202 families, 1208 individuals) was completed utilizing a standard marker set (Weber Screening Set 9). This set consists of 387 primer pairs spaced every ten centimorgans throughout the genome. Model-independent sib-pair linkage analyses implemented in SIBPAL were utilized to screen each trait for evidence of linkage. Multiple strategies for the identification of significant subgroups of families were utilized in order to identify potential genomic locus(i) that influence disease expression. First, families were stratified according to potential mode of inheritance. Second, scoliosis was categorized either as a quantitative trait, that is, a measurable degree of curvature within any individual, or a qualitative or dichotomous trait with a variable threshold of 10, 20, 30 or 40 degrees as the criteria of the affected status.

Results: Within the studied population, quantitative analysis of the 50% of families exhibiting an autosomal dominant mode of inheritance indicated linkage ( > 2 adjacent markers p<0 .05) in regions of chromosomes 3, 6, and 9. When scoliosis was considered a qualitative trait with 10 degrees as the threshold criteria, analysis 50% families resulted on 8, 12, 17. As increased incrementally, linked to disease were found 1, 5, 9, 16. Areas chromosome 9 16 became increasingly significant increased. The flanking markers identified are: 6 - D6S1053;D6S1021, 8 D8S1132;D8S373, D9S938;D9S1826, D16S764;D16S2624.

Discussion: Genomic screening combined with statistical linkage analysis is an effective method in the identification of genetic loci and specific genes responsible for complex disorders. Given the variability of familial idiopathic scoliosis, a large carefully identified population has been selected for study in order to enhance the possibility that analyses will yield meaningful results. In order to minimize the effects of heterogeneity, multiple strategies for the stratification of the initial population were implemented. By first categorizing scoliosis as a quantitative trait, an arbitrary definition of the disease state is not required, therefore, one utilizes all of the information from the dataset. As a qualitative trait, one restricts the definition of the phenotype, thus, potentially eliminating mild, sporadic forms of the disease, which may confound statistical analysis. The combination of these approaches utilized in a step-wise fashion has resulted in evidence of significant genetic linkage of scoliosis to several potential loci. Further work includes fine mapping of the genetic loci in order to corroborate findings and to narrow the identified linkage intervals.