Journal Article

Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes

Swarkar Sharma, Xiaochong Gao, Douglas Londono, Shonn E. Devroy, Kristen N. Mauldin, Jessica T. Frankel, January M. Brandon, Dongping Zhang, Quan-Zhen Li, Matthew B. Dobbs, Christina A. Gurnett, Struan F.A. Grant, Hakon Hakonarson, John P. Dormans, John A. Herring, Derek Gordon and Carol A. Wise

in Human Molecular Genetics

Volume 20, issue 7, pages 1456-1466
Published in print April 2011 | ISSN: 0964-6906
Published online January 2011 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddq571
Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes

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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.

Journal Article.  7273 words.  Illustrated.

Subjects: Genetics and Genomics

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