A missense variant in SLC39A8 is associated with severe idiopathic scoliosis

Gabe Haller, Kevin McCall, Supak Jenkitkasemwong, Brooke Sadler, Lilian Antunes, Momchil Nikolov, Julia Whittle, Zachary Upshaw, Jimann Shin, Erin Baschal, Carlos Cruchaga, Matthew Harms, Cathleen Raggio, Jose A. Morcuende, Philip Giampietro, Nancy H. Miller, Carol Wise, Ryan S. Gray, Lila Solnica-Krezel, Mitchell Knutson, Matthew B. Dobbs and Christina A. Gurnett ()
Additional contact information
Gabe Haller: Washington University
Kevin McCall: Washington University
Supak Jenkitkasemwong: University of Florida
Brooke Sadler: Washington University
Lilian Antunes: Washington University
Momchil Nikolov: Washington University
Julia Whittle: Washington University
Zachary Upshaw: Washington University
Jimann Shin: Washington University School of Medicine
Erin Baschal: University of Colorado
Carlos Cruchaga: Washington University
Matthew Harms: Columbia University
Cathleen Raggio: Hospital for Special Surgery
Jose A. Morcuende: University of Iowa
Philip Giampietro: Drexel University
Nancy H. Miller: University of Colorado
Carol Wise: Texas Scottish Rite Hospital for Children
Ryan S. Gray: The University of Texas at Austin
Lila Solnica-Krezel: Washington University School of Medicine
Mitchell Knutson: University of Florida
Matthew B. Dobbs: Washington University
Christina A. Gurnett: Washington University

Nature Communications, 2018, vol. 9, issue 1, 1-7

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06705-0

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