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

A missense variant in SLC39A8 is associated with severe idiopathic scoliosis.

Author information

1
Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA.
2
Food Science and Human Nutrition Department, University of Florida, Gainesville, FL, USA.
3
Department of Neurology, Washington University, St. Louis, MO, USA.
4
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA.
5
Department of Orthopaedic Surgery, University of Colorado, Denver, CO, USA.
6
Department of Psychiatry, Washington University, St. Louis, MO, USA.
7
Department of Neurology, Columbia University, New York, NY, USA.
8
Hospital for Special Surgery, New York, NY, USA.
9
Department of Orthopaedics and Rehabilitation, University of Iowa, Iowa City, IA, USA.
10
Department of Pediatrics, Drexel University, Philadelphia, PA, USA.
11
Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX, USA.
12
Departments of Orthopaedic Surgery, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
13
McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
14
Department of Pediatrics, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.
15
Shriners Hospital for Children, St. Louis, MO, USA.
16
Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA. gurnettc@neuro.wustl.edu.
17
Department of Neurology, Washington University, St. Louis, MO, USA. gurnettc@neuro.wustl.edu.
18
Department of Pediatrics, Washington University, St. Louis, MO, USA. gurnettc@neuro.wustl.edu.

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.

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