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A missense variant in SLC39A8 is associated with severe idiopathic scoliosis

Author

Listed:
  • Gabe Haller

    (Washington University)

  • Kevin McCall

    (Washington University)

  • Supak Jenkitkasemwong

    (University of Florida)

  • Brooke Sadler

    (Washington University)

  • Lilian Antunes

    (Washington University)

  • Momchil Nikolov

    (Washington University)

  • Julia Whittle

    (Washington University)

  • Zachary Upshaw

    (Washington University)

  • Jimann Shin

    (Washington University School of Medicine)

  • Erin Baschal

    (University of Colorado)

  • Carlos Cruchaga

    (Washington University)

  • Matthew Harms

    (Columbia University)

  • Cathleen Raggio

    (Hospital for Special Surgery)

  • Jose A. Morcuende

    (University of Iowa)

  • Philip Giampietro

    (Drexel University)

  • Nancy H. Miller

    (University of Colorado)

  • Carol Wise

    (Texas Scottish Rite Hospital for Children
    University of Texas Southwestern Medical Center at Dallas
    University of Texas Southwestern Medical Center at Dallas)

  • Ryan S. Gray

    (The University of Texas at Austin)

  • Lila Solnica-Krezel

    (Washington University School of Medicine)

  • Mitchell Knutson

    (University of Florida)

  • Matthew B. Dobbs

    (Washington University
    Shriners Hospital for Children)

  • Christina A. Gurnett

    (Washington University
    Washington University
    Washington University)

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.

Suggested Citation

  • Gabe Haller & Kevin McCall & Supak Jenkitkasemwong & Brooke Sadler & Lilian Antunes & Momchil Nikolov & Julia Whittle & Zachary Upshaw & Jimann Shin & Erin Baschal & Carlos Cruchaga & Matthew Harms & , 2018. "A missense variant in SLC39A8 is associated with severe idiopathic scoliosis," Nature Communications, Nature, vol. 9(1), pages 1-7, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06705-0
    DOI: 10.1038/s41467-018-06705-0
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    Cited by:

    1. Liina Nagirnaja & Alexandra M. Lopes & Wu-Lin Charng & Brian Miller & Rytis Stakaitis & Ieva Golubickaite & Alexandra Stendahl & Tianpengcheng Luan & Corinna Friedrich & Eisa Mahyari & Eloise Fadial &, 2022. "Diverse monogenic subforms of human spermatogenic failure," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Gianmarco Mignogna & Caitlin E. Carey & Robbee Wedow & Nikolas Baya & Mattia Cordioli & Nicola Pirastu & Rino Bellocco & Kathryn Fiuza Malerbi & Michel G. Nivard & Benjamin M. Neale & Raymond K. Walte, 2023. "Patterns of item nonresponse behaviour to survey questionnaires are systematic and associated with genetic loci," Nature Human Behaviour, Nature, vol. 7(8), pages 1371-1387, August.
    3. Eun-Kyung Choi & Thekkelnaycke M. Rajendiran & Tanu Soni & Jin-Ho Park & Luisa Aring & Chithra K. Muraleedharan & Vicky Garcia-Hernandez & Nobuhiko Kamada & Linda C. Samuelson & Asma Nusrat & Shigeki , 2024. "The manganese transporter SLC39A8 links alkaline ceramidase 1 to inflammatory bowel disease," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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