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

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 KnutsonMatthew B. Dobbs, Christina A. Gurnett

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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 × 10⁻⁷, 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.

Original language	English
Article number	4171
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06705-0
State	Published - Dec 1 2018

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Haller, G., McCall, K., Jenkitkasemwong, S., Sadler, B., Antunes, L., Nikolov, M., Whittle, J., Upshaw, Z., Shin, J., Baschal, E., Cruchaga, C., Harms, M., Raggio, C., Morcuende, J. A., Giampietro, P., Miller, N. H., Wise, C., Gray, R. S., Solnica-Krezel, L., ... Gurnett, C. A. (2018). A missense variant in SLC39A8 is associated with severe idiopathic scoliosis. Nature communications, 9(1), [4171]. https://doi.org/10.1038/s41467-018-06705-0

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title = "A missense variant in SLC39A8 is associated with severe idiopathic scoliosis",

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.",

author = "Gabe Haller and Kevin McCall and Supak Jenkitkasemwong and Brooke Sadler and Lilian Antunes and Momchil Nikolov and Julia Whittle and Zachary Upshaw and Jimann Shin and Erin Baschal and Carlos Cruchaga and Matthew Harms and Cathleen Raggio and Morcuende, {Jose A.} and Philip Giampietro and Miller, {Nancy H.} and Carol Wise and Gray, {Ryan S.} and Lila Solnica-Krezel and Mitchell Knutson and Dobbs, {Matthew B.} and Gurnett, {Christina A.}",

note = "Funding Information: Research reported in this publication was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases under Award Number R01AR067715, Eunice Kennedy Shriver National Institutes of Child Health and Human Development of the National Institutes of Health under the Award Number P01HD084387, the Marfan Foundation Faculty Grant award #81831, Washington University Institute of Clinical and Translational Sciences grant UL1 TR002345 from the National Center for Advancing Translational Sciences of the National Institutes of Health, Washington University Musculoskeletal Research Center (NIH/NIAMS P30 AR057235), the Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under Award Number U54 HD087011 to the Intellectual and Developmental Disabilities Research Center at Washington University. We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The Center is partially supported by NCI Cancer Center Support Grant #P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant# UL1RR024992 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This study was funded with support from University of Missouri Spinal Cord Injury Research Program, Shriners Hospital for Children, and the Children{\textquoteright}s Discovery Institute of Washington University and St Louis Children{\textquoteright}s Hospital, and Hope Center DNA/ RNA Purification Core at Washington University School of Medicine. Computations were performed using the facilities of the Washington University Center for High Performance Computing, which were partially funded by NIH grants 1S10RR022984-01A1, and 1S10OD018091-01. We thank patients and their families for their participation, as well as Drs Munish Gupta, Keith Bridwell, Mike Kelly, Scott Luhmann, Brian Kelly, Luke Zebala, Lawrence Lenke and Christi Abeln. Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-06705-0",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

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Haller, G, McCall, K, Jenkitkasemwong, S, Sadler, B, Antunes, L, Nikolov, M, Whittle, J, Upshaw, Z, Shin, J, Baschal, E, Cruchaga, C, Harms, M, Raggio, C, Morcuende, JA, Giampietro, P, Miller, NH, Wise, C, Gray, RS, Solnica-Krezel, L, Knutson, M, Dobbs, MB & Gurnett, CA 2018, 'A missense variant in SLC39A8 is associated with severe idiopathic scoliosis', Nature communications, vol. 9, no. 1, 4171. https://doi.org/10.1038/s41467-018-06705-0

TY - JOUR

T1 - A missense variant in SLC39A8 is associated with severe idiopathic scoliosis

AU - Haller, Gabe

AU - McCall, Kevin

AU - Jenkitkasemwong, Supak

AU - Sadler, Brooke

AU - Antunes, Lilian

AU - Nikolov, Momchil

AU - Whittle, Julia

AU - Upshaw, Zachary

AU - Shin, Jimann

AU - Baschal, Erin

AU - Cruchaga, Carlos

AU - Harms, Matthew

AU - Raggio, Cathleen

AU - Morcuende, Jose A.

AU - Giampietro, Philip

AU - Miller, Nancy H.

AU - Wise, Carol

AU - Gray, Ryan S.

AU - Solnica-Krezel, Lila

AU - Knutson, Mitchell

AU - Dobbs, Matthew B.

AU - Gurnett, Christina A.

N1 - Funding Information: Research reported in this publication was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases under Award Number R01AR067715, Eunice Kennedy Shriver National Institutes of Child Health and Human Development of the National Institutes of Health under the Award Number P01HD084387, the Marfan Foundation Faculty Grant award #81831, Washington University Institute of Clinical and Translational Sciences grant UL1 TR002345 from the National Center for Advancing Translational Sciences of the National Institutes of Health, Washington University Musculoskeletal Research Center (NIH/NIAMS P30 AR057235), the Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under Award Number U54 HD087011 to the Intellectual and Developmental Disabilities Research Center at Washington University. We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The Center is partially supported by NCI Cancer Center Support Grant #P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant# UL1RR024992 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This study was funded with support from University of Missouri Spinal Cord Injury Research Program, Shriners Hospital for Children, and the Children’s Discovery Institute of Washington University and St Louis Children’s Hospital, and Hope Center DNA/ RNA Purification Core at Washington University School of Medicine. Computations were performed using the facilities of the Washington University Center for High Performance Computing, which were partially funded by NIH grants 1S10RR022984-01A1, and 1S10OD018091-01. We thank patients and their families for their participation, as well as Drs Munish Gupta, Keith Bridwell, Mike Kelly, Scott Luhmann, Brian Kelly, Luke Zebala, Lawrence Lenke and Christi Abeln. Publisher Copyright: © 2018, The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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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DO - 10.1038/s41467-018-06705-0

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SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

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M1 - 4171

ER -

A missense variant in SLC39A8 is associated with severe idiopathic scoliosis

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