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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56 Scopus citations

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), Article 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 = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

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

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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.

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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U2 - 10.1038/s41467-018-06705-0

DO - 10.1038/s41467-018-06705-0

M3 - Article

C2 - 30301978

AN - SCOPUS:85054566394

SN - 2041-1723

VL - 9

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 4171

ER -

A missense variant in SLC39A8 is associated with severe idiopathic scoliosis

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