Abstract
Genetic factors predictive of severe adolescent idiopathic scoliosis (AIS) are largely unknown. To identify genetic variation associated with severe AIS, we performed an exome-wide association study of 457 severe AIS cases and 987 controls. We find a missense SNP in SLC39A8 (p.Ala391Thr, rs13107325) associated with severe AIS (P = 1.60 × 10−7, OR = 2.01, CI = 1.54–2.62). This pleiotropic SNP was previously associated with BMI, blood pressure, cholesterol, and blood manganese level. We replicate the association in a second cohort (841 cases and 1095 controls) resulting in a combined P = 7.02 × 10−14, OR = 1.94, CI = 1.63–2.34. Clinically, the minor allele of rs13107325 is associated with greater spinal curvature, decreased height, increased BMI and lower plasma manganese in our AIS cohort. Functional studies demonstrate reduced manganese influx mediated by the SLC39A8 p.Ala391Thr variant and vertebral abnormalities, impaired growth, and decreased motor activity in slc39a8 mutant zebrafish. Our results suggest the possibility that scoliosis may be amenable to dietary intervention.
Highlights
Genetic factors predictive of severe adolescent idiopathic scoliosis (AIS) are largely unknown
While the etiology of adolescent idiopathic scoliosis (AIS) is not well understood, recent genomewide association studies have identified common variants near neural cell adhesion molecules[4], ladybird homeobox 1 (LBX1)[5], G-protein-coupled receptor 126 (GPR126)[6], and the transcription factor BNC27 that are modestly associated with AIS
We present an exome-wide association study of severe adolescent idiopathic scoliosis and identify an association with a missense single-nucleotide polymorphisms (SNPs) in the gene SLC39A8. We replicate this finding in a second independent cohort and show that in addition to scoliosis risk, the SNP is associated with several related traits in our AIS cohort including height, BMI, and curve severity
Summary
Genetic factors predictive of severe adolescent idiopathic scoliosis (AIS) are largely unknown. A Japanese genome-wide association study identified a common variant in MIR4300HG (the host gene of microRNA MIR4300) that influences scoliosis curve progression[13], but additional studies are needed to develop population-specific prevention strategies that can be applied for short durations during the adolescent growth period when spinal curves progress. We present an exome-wide association study of severe adolescent idiopathic scoliosis and identify an association with a missense SNP in the gene SLC39A8. We replicate this finding in a second independent cohort and show that in addition to scoliosis risk, the SNP is associated with several related traits in our AIS cohort including height, BMI, and curve severity. We further show that the minor allele affects manganese transport in vitro and that disruption of slc39a8 in zebrafish leads to vertebral abnormalities, impaired growth, and decreased motor activity
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