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; Christina A Gurnett

doi:10.1038/s41467-018-06705-0

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A missense variant in SLC39A8 is associated with severe idiopathic scoliosis

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Open access

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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, …

Nature communications, Vol.9(1), pp.4171-7

10/09/2018

DOI: 10.1038/s41467-018-06705-0

PMCID: PMC6177404

PMID: 30301978

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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 , 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 , 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.

Bone and Bones - pathology

Genetic Predisposition to Disease

Movement

Scoliosis - genetics

Genetic Association Studies

Humans

Ions

Mutation, Missense - genetics

Zebrafish - genetics

Exome - genetics

Animals

HEK293 Cells

Polymorphism, Single Nucleotide - genetics

Cation Transport Proteins - genetics

Cation Transport Proteins - deficiency

Details

Title: Subtitle: A missense variant in SLC39A8 is associated with severe idiopathic scoliosis
Creators: Gabe Haller - Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA
Kevin McCall - Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA
Supak Jenkitkasemwong - Food Science and Human Nutrition Department, University of Florida, Gainesville, FL, USA
Brooke Sadler - Department of Neurology, Washington University, St. Louis, MO, USA
Lilian Antunes - Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA
Momchil Nikolov - Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA
Julia Whittle - Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA
Zachary Upshaw - Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA
Jimann Shin - Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA
Erin Baschal - Department of Orthopaedic Surgery, University of Colorado, Denver, CO, USA
Carlos Cruchaga - Department of Psychiatry, Washington University, St. Louis, MO, USA
Matthew Harms - Department of Neurology, Columbia University, New York, NY, USA
Cathleen Raggio - Hospital for Special Surgery, New York, NY, USA
Jose A Morcuende - Department of Orthopaedics and Rehabilitation, University of Iowa, Iowa City, IA, USA
Philip Giampietro - Department of Pediatrics, Drexel University, Philadelphia, PA, USA
Nancy H Miller - Department of Orthopaedic Surgery, University of Colorado, Denver, CO, USA
Carol Wise - McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
Ryan S Gray - Department of Pediatrics, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
Lila Solnica-Krezel - Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA
Mitchell Knutson - Food Science and Human Nutrition Department, University of Florida, Gainesville, FL, USA
Matthew B Dobbs - Shriners Hospital for Children, St. Louis, MO, USA
Christina A Gurnett - Department of Pediatrics, Washington University, St. Louis, MO, USA. gurnettc@neuro.wustl.edu
Resource Type: Journal article
Publication Details: Nature communications, Vol.9(1), pp.4171-7
DOI: 10.1038/s41467-018-06705-0
PMID: 30301978
PMCID: PMC6177404
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Publisher: England
Grant note: R01 AR067715 / NIAMS NIH HHS U54 HD087011 / NICHD NIH HHS T32 GM007067 / NIGMS NIH HHS R01 AR072009 / NIAMS NIH HHS P01 HD084387 / NICHD NIH HHS P01HD084387 / U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) UL1 TR002345 / NCATS NIH HHS R01AR067715 / U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) P30 HD062171 / NICHD NIH HHS R01 AR068292 / NIAMS NIH HHS
Language: English
Date published: 10/09/2018
Academic Unit: Stead Family Department of Pediatrics; Orthopedics and Rehabilitation
Record Identifier: 9984040492502771

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