A missense variant in SLC39A8 is associated with severe idiopathic scoliosis

Nat Commun. 2018 Oct 9;9(1):4171. doi: 10.1038/s41467-018-06705-0.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone and Bones / pathology
  • Cation Transport Proteins / deficiency
  • Cation Transport Proteins / genetics*
  • Exome / genetics
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • HEK293 Cells
  • Humans
  • Ions
  • Movement
  • Mutation, Missense / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Scoliosis / genetics*
  • Zebrafish / genetics


  • Cation Transport Proteins
  • Ions
  • SLC39A8 protein, human