Inheritance and genetics in idiopathic scoliosis

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.

List of scientific papers

I. Grauers A, Rahman I, Gerdhem P. Heritability of scoliosis. Eur Spine J. 2012; 21: 1069-1074.
https://doi.org/10.1007/s00586-011-2074-1

II. Grauers A, Danielsson A, Karlsson MK, Ohlin A, Gerdhem P. Family history and its association to curve size and treatment in 1463 patients with idiopathic scoliosis. Eur Spine J. 2013; 22: 2421-2426.
https://doi.org/10.1007/s00586-013-2860-z

III. Grauers A, Topalis C, Möller H, Normelli H, Karlsson MK, Danielsson A, Gerdhem P. Prevalence of back problems in 1069 adults with idiopathic scoliosis and 158 adults without scoliosis. Spine. 2014; 39: 886-892.
https://doi.org/10.1097/BRS.0000000000000312

IV. Grauers A, Wang J, Einarsdottir E, Simony A, Danielsson A, Åkesson K, Ohlin A, Halldin K, Grabowski P, Tenne M, Laivuori H, Dahlman I, Andersen M, Christensen SB, Karlsson MK, Jiao H, Kere J, Gerdhem P. Candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis. [Submitted]