Inheritance and genetics in idiopathic scoliosis

Sammanfattning: Idiopathic scoliosis is the most common spine deformity, affecting approximately 3% of children and adolescents. Its aetiology is still unknown. However, relatives of individuals with idiopathic scoliosis have a higher risk of developing scoliosis compared to the general population. The aim of this thesis was to improve our understanding of the hereditary and genetic background of idiopathic scoliosis. Self - reported data on scoliosis in twins (n=64,578) in the population - based Swedish Twin Registry were an alysed to estimate the relative importance of genetic effects on the phenotypic variance – that is, the heritability of scoliosis. Using structural equation model ing, we estimated that 38% of the phenotypic variance of scoliosis is due to additive genetic effects and 62% to unique environmental effects. In ScoliGeneS, an ongoing multi - centre study, we included individuals with idiopathic scoliosis and controls. The importance of a family history of scoliosis wa s investigated in 1,463 individuals with idiop athic scoliosis . Among those treated with a brace or surgery for scoliosis, 53% reported one or more relatives with scoliosis compared to 46% of the untreated, indicating a higher risk of treatment in the presence of a family history of scoliosis (odds rat io 1.32; 95% confidence interval 1.06 – 1.64). The prevalence of back problems was investigated in 1,069 adults with idiopathic scoliosis and in 1 58 controls. B ack problems were reported in 64% of the individuals with scoliosis compared to 29% of the control s (p<0.001, adjusted for sex, age and smoking). No differences betwee n untreated and treated individuals with idiopathic scoliosis regarding the prevalence of back problems in adulthood were seen. Four common single - nucleotide variants, previously shown to be associated with idiopathic scoliosis, were genotyped in 1,739 individuals with idiopathic scoliosis from the ScoliGeneS cohort and in 1,812 controls. In addition, the protein - coding regions of the genome – the exome – was sequenced in pooled samples (10x10) from 100 surgically treated patients in the ScoliGeneS cohort. We found a strong associ ation of idiopathic scoliosis with a common previously known variant downstream of the LBX1 gene (OR=1.5 3; p=7.0x 10 - 18 ). We identified twenty novel variants by exome sequencing after filtering and an initial genotyping validation. No significant association was f ound with idiopathic scoliosis in the large cohort of 1,739 cases and 1,812 controls. In summary, inherited factors are of importance in the development and progression of idiopathic scoliosis. A genetic variant downstream of the LBX1 gene is strongly associated with idiopathic scoliosis. We were unable to find genes of similar or stronger effect.