A missense variant in SLC39A8 is associated with severe idiopathic scoliosis. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Haller, Gabe; McCall, Kevin; Jenkitkasemwong, Supak; Sadler, Brooke; Antunes, Lilian; Nikolov, Momchil; Whittle, Julia; Upshaw, Zachary; Shin, Jimann; Baschal, Erin; Cruchaga, Carlos; Harms, Matthew; Raggio, Cathleen; Morcuende, Jose; Giampietro, Philip; Miller, Nancy; Wise, Carol; Gray, Ryan; Solnica-Krezel, Lila; Knutson, Mitchell; Dobbs, Matthew; Gurnett, Christina
• Is Part Of: Nature communications. Volume 9:Issue 1(2018)
• Page Start: 1
• Page End: 7
• Publication Date: 2018-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-018-06705-0
• Languages: English
• ISSNs: 2041-1723

Abstract

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 inSLC39A8 (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 combinedP = 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 theSLC39A8 p.Ala391Thr variant and vertebral abnormalities, impaired growth, and decreased motor activity inslc39a8 mutant zebrafish. Our results suggest the possibility that scoliosis may be amenable to dietary intervention. The majority of scoliosis is considered idiopathic with onset in adolescence (AIS) and has a genetic contribution. Here, the authors perform an exome wide association study of data from 457 severe AIS cases and 987 controls, and find a missense variant inSLC39A8 is associated with AIS.