Year: 2018
Type: article
Study design: Observational Study
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.
Source: Nature Communications
Authors: 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
Institutions: Washington University in St. Louis, University of Florida, University of Colorado Denver, Columbia University, Hospital for Special Surgery, University of Iowa, Drexel University, Texas Scottish Rite Hospital for Children, The University of Texas Southwestern Medical Center, The University of Texas at Austin, Shriners Hospitals for Children - St. Louis
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Health and Human Services, University of Missouri, Institute of Clinical and Translational Sciences, Children's Discovery Institute, Marfan Foundation, Shriners Hospitals for Children, Alvin J. Siteman Cancer Center, Hope Center for Neurological Disorders, Georgia Clinical and Translational Science Alliance, National Institutes of Health, Intellectual and Developmental Disabilities Research Center, Musculoskeletal Research Center, Washington University in St. Louis, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine in St. Louis
Awards: G1078697686, G1114310655, G1148754291, G12431752, G1599388212, G1661677298, G1699415014, G1704182483, G1804656025, G1861184163, G2195970601, Familial idiopathic scoliosis: gene discovery and functional studies, G299873027, G3192412319, G3455473179, G3802757361, G4163933616, Core Center for Musculoskeletal Biology and Medicine, HIGH PERFORMANCE BIOMEDICAL IMAGING COMPUTER RESOURCES, G5153300018, G5165247642, G5191482376, WASHINGTON UNIVERSITY INTELLECTUAL AND DEVELOPMENTAL DISABILITIES RESEARCH CENTER, Training Program in Cellular and Molecular Biology, G6992116998, Washington University Intellectual and Developmental Disabilities Research Center, Genetic risk factors for severe scoliosis, G7860800203, Washington University Institute of Clinical and Translational Sciences (UL1), G8242737674, GPU COMPUTING RESOURCE TO ENABLE INNOVATION IN IMAGING AND NETWORK BIOLOGY, G8405709672, G8631229147, G9000206903, G9000239813, G9000319192, Washington University Institute of Clinical and Translational Sciences, Investigations of the molecular genetics and pathogenesis of scoliosis., Cancer Center Support Grant, Developmental Mechanisms of Human Idiopathic Scoliosis, G96856385
OpenAlex ID: W2895170936