A polygenic burden of rare variants across extracellular matrix genes among individuals with adolescent idiopathic scoliosis

Abstract

Adolescent idiopathic scoliosis (AIS) is a complex inherited spinal deformity whose etiology has been elusive. While common genetic variants are associated with AIS, they explain only a small portion of disease risk. To explore the role of rare variants in AIS susceptibility, exome sequence data of 391 severe AIS cases and 843 controls of European ancestry were analyzed using a pathway burden analysis in which variants are first collapsed at the gene level then by Gene Ontology terms. Novel non-synonymous/splice-site variants in extracellular matrix genes were significantly enriched in AIS cases compared with controls (P = 6 × 10(-9), OR = 1.7, CI = 1.4-2.0). Specifically, novel variants in musculoskeletal collagen genes were present in 32% (126/391) of AIS cases compared with 17% (146/843) of in-house controls and 18% (780/4300) of EVS controls (P = 1 × 10(-9), OR = 1.9, CI = 1.6-2.4). Targeted resequencing of six collagen genes replicated this association in combined 919 AIS cases (P = 3 × 10(-12), OR = 2.2, CI = 1.8-2.7) and revealed a highly significant single-gene association with COL11A2 (P = 6 × 10(-9), OR = 3.8, CI = 2.6-7.2). Importantly, AIS cases harbor mainly non-glycine missense mutations and lack the clinical features of monogenic musculoskeletal collagenopathies. Overall, our study reveals a complex genetic architecture of AIS in which a polygenic burden of rare variants across extracellular matrix genes contributes strongly to risk.

Genetic Markers for Adolescent Idiopathic Scoliosis on Chromosome 19p13.3 among Saudi Arabian Girls

“…For a long time, it was believed that the inheritance was a result of autosomal dominant [222324] and because of a lack of male to female transmissions [25]. In our study, we found a similarity between patients and fathers rather than between patients and mothers at the genetic level.…”

Genetics and pathogenesis of idiopathic scoliosis

“…Two other common variants of interest have recently been found to be associated with IS, but have yet to be replicated (Table 2) [63, 68]. New methodologies such as exome-sequencing have made it possible to identify rare variants associated with idiopathic scoliosis [47–49, 81]. The importance of these findings in the general idiopathic scoliosis population, however, remains to be seen.…”

“…Haller et al [49] exome-sequenced 391 severe adolescent IS cases and 843 controls. Using a pathway burden analysis, they found that variants in extracellular matrix genes, especially in musculoskeletal collagen, were significantly enriched in adolescent IS cases compared to controls.…”

A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3

“…Ostensibly, it extends a simplistic paradigm in which damaging mutations with large effects cause Mendelian disorders whereas less damaging coding variants (e.g., hypomorphic or inhibitory) or regulatory polymorphisms confer risk of common forms of the same disorder. 45,46 However, it is clear that the relationship between genotype and phenotype at the GRHL3 locus is not so simplistic. In our previous work, we demonstrated that dominant GRHL3 mutations cause VWS.…”