Étude des déterminants génétiques et moléculaires de la scoliose idiopathique

Idiopathic Scoliosis (IS) is a complex disorder of the spine. It mostly occurs between 10 and 15 years old and affects ~1-4% of the global pediatric population with a much higher prevalence in females. In most cases the underlying cause of IS is unknown, although a genetic component is well recognized. A number of candidate genes and loci have been suggested, but few have been successfully replicated in multiple studies. Genome wide association studies (GWAS) have identified several candidate genes for IS susceptibility. Among these the LBX1 locus is by far the most successfully replicated locus in different populations, although until now it has not been tested in the French-Canadian population. Few studies have attempted to detect rare causal variants in IS and this field of research is still in its infancy. The primary goal of this thesis was to investigate the genetic component of IS through complementary approaches. In the first study, we aimed to find new genes enriched with rare variants, which might contribute to the disease. Hence, we performed whole exome sequencing (WES) in a French-Canadian IS cohort, followed by a second phase of targeted sequencing of the 24 best candidate genes in a replication cohort. In parallel, we performed WES in a unique multiplex family of three affected sisters with healthy parents. Our results implicate a novel gene, FAT3, not previously associated with IS, as a strong candidate for this condition. In the second study we performed a GWAS to test for genetic markers associated with IS in our French-Canadian cohort. The complete results of the GWAS analysis are beyond the scope of this thesis. The main objective of the current analysis was to test association of the LBX1 locus. Our results support an association with the region near the LBX1 gene in our French-Canadian population. In the third study, our approach is a candidate gene approach. We attempted to elucidate the genetic and biochemical correlates of circulating YKL-40 levels with the risk of spinal deformity progression in the context of IS. Our prior works have demonstrated that IS patients exhibit a distinctive G inhibitory (Gi) proteincoupled receptor signaling dysfunction, which enabled their classification into three distinct biological endophenotypes (FG1, FG2 or FG3). Previous microarray analysis revealed a significant elevation in the expression of CHI3L1 gene, encoding for the secreted glycoprotein YKL-40, in IS patients classified in FG1 endophenotype when compared to FG2 and FG3 ones, which are more prone to develop a severe scoliosis. In this study, we demonstrated that IS males classified in FG1 endophenotype exhibit significant higher plasma YKL-40 levels than controls and other IS endophenotypes. Furthermore, the non-severe scoliosis group showed significant higher levels of YKL-40 than controls. SNPs in CHI3L1 gene showed significant association with YKL-40 plasma levels in non-severe cases. Functional in vitro analysis showed that YKL-40 could play a protective role in the context of IS by altering the Gi-signaling dysfunction induced by the elevation of osteopontin in IS. In sum, we propose a novel association of FAT3 gene with IS, replicated the association of LBX1 gene with IS in a new cohort, and propose a new biochemical marker, YKL-40, associated with non-severe forms of IS and has a plausible protective role in IS.

Keyphrases: GWAS, FAT3, LBX1, CHI3L1, YKL-40, Endophenotypes, Idiopathic scoliosis, Whole exome sequencing, Rare variants, French-Canadian population