A missense variant in SLC39A8 is associated with severe idiopathic scoliosis
| Autor: | Lilian Antunes, Jimann Shin, Brooke Sadler, Gabe Haller, Supak Jenkitkasemwong, Mitchell D. Knutson, Zachary Upshaw, Kevin McCall, Erin E. Baschal, Matthew B. Dobbs, Christina A. Gurnett, Cathleen L. Raggio, Ryan S. Gray, Matthew B. Harms, Nancy H. Miller, Philip F. Giampietro, Jose A. Morcuende, Carol Wise, Momchil Nikolov, Lila Solnica-Krezel, Carlos Cruchaga, Julia Whittle |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Movement Science Mutation Missense General Physics and Astronomy Scoliosis Polymorphism Single Nucleotide Gastroenterology Bone and Bones Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Polymorphism (computer science) Internal medicine Genetic variation medicine Animals Humans SNP Missense mutation Exome Genetic Predisposition to Disease lcsh:Science Cation Transport Proteins Genetic Association Studies Zebrafish Ions Multidisciplinary business.industry General Chemistry medicine.disease Minor allele frequency HEK293 Cells 030104 developmental biology Blood pressure Cohort lcsh:Q business |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-7 (2018) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. 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 in SLC39A8 is associated with AIS. |
| Databáze: | OpenAIRE |
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