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 - 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.
UR - http://www.scopus.com/inward/record.url?scp=85054566394&partnerID=8YFLogxK
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 -