title: Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes.
abstract: Adolescent idiopathic scoliosis (AIS) is an unexplained and common spinal deformity seen in otherwise healthy children. Its pathophysiology is poorly understood despite intensive investigation. Although genetic underpinnings are clear, replicated susceptibility loci that could provide insight into etiology have not been forthcoming. To address these issues, we performed genome-wide association studies (GWAS) of ∼327 000 single nucleotide polymorphisms (SNPs) in 419 AIS families. We found strongest evidence of association with chromosome 3p26.3 SNPs in the proximity of the CHL1 gene (P < 8 × 10(-8) for rs1400180). We genotyped additional chromosome 3p26.3 SNPs and tested replication in two follow-up case-control cohorts, obtaining strongest results when all three cohorts were combined (rs10510181 odds ratio = 1.49, 95% confidence interval = 1.29-1.73, P = 2.58 × 10(-8)), but these were not confirmed in a separate GWAS. CHL1 is of interest, as it encodes an axon guidance protein related to Robo3. Mutations in the Robo3 protein cause horizontal gaze palsy with progressive scoliosis (HGPPS), a rare disease marked by severe scoliosis. Other top associations in our GWAS were with SNPs in the DSCAM gene encoding an axon guidance protein in the same structural class with Chl1 and Robo3. We additionally found AIS associations with loci in CNTNAP2, supporting a previous study linking this gene with AIS. Cntnap2 is also of functional interest, as it interacts directly with L1 and Robo class proteins and participates in axon pathfinding. Our results suggest the relevance of axon guidance pathways in AIS susceptibility, although these findings require further study, particularly given the apparent genetic heterogeneity in this disease.
authors.affiliation: Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX, USA.
authors.forename: Swarkar
authors.initials: S
authors.lastname: Sharma
authors.forename: Xiaochong
authors.initials: X
authors.lastname: Gao
authors.forename: Douglas
authors.initials: D
authors.lastname: Londono
authors.forename: Shonn E
authors.initials: SE
authors.lastname: Devroy
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Mauldin
authors.forename: Jessica T
authors.initials: JT
authors.lastname: Frankel
authors.forename: January M
authors.initials: JM
authors.lastname: Brandon
authors.forename: Dongping
authors.initials: D
authors.lastname: Zhang
authors.forename: Quan-Zhen
authors.initials: QZ
authors.lastname: Li
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Dobbs
authors.forename: Christina A
authors.initials: CA
authors.lastname: Gurnett
authors.forename: Struan F A
authors.initials: SF
authors.lastname: Grant
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: John P
authors.initials: JP
authors.lastname: Dormans
authors.forename: John A
authors.initials: JA
authors.lastname: Herring
authors.forename: Derek
authors.initials: D
authors.lastname: Gordon
authors.forename: Carol A
authors.initials: CA
authors.lastname: Wise
mesh_terms: D000293:Adolescent; D001369:Axons; D015815:Cell Adhesion Molecules / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D005190:Family; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic / Q000235:genetics; D012600:Scoliosis / Q000235:genetics* / Q000473:pathology; D000097905:Roundabout Proteins
chemical_list: D015815:Cell Adhesion Molecules; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C490650:CHL1 protein, human; C403049:CNTNAP2 protein, human; C110833:DSCAM protein, human; C499630:ROBO3 protein, human; D000097905:Roundabout Proteins