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A commonly occurring genetic variant within the NPLOC4-TSPAN10-PDE6G gene cluster is associated with the risk of strabismus

Research output: Contribution to journalArticle

  • UK Biobank Eye and Vision Consortium
Original languageEnglish
Pages (from-to)723-737
Number of pages15
JournalHuman Genetics
Volume138
Issue number7
Early online date9 May 2019
DOIs
DateAccepted/In press - 20 Apr 2019
DateE-pub ahead of print - 9 May 2019
DatePublished (current) - 1 Jul 2019

Abstract

Strabismus refers to an abnormal alignment of the eyes leading to the loss of central binocular vision. Concomitant strabismus occurs when the angle of deviation is constant in all positions of gaze and often manifests in early childhood when it is considered to be a neurodevelopmental disorder of the visual system. As such, it is inherited as a complex genetic trait, affecting 2-4% of the population. A genome-wide association study (GWAS) for self-reported strabismus (1345 cases and 65,349 controls from UK Biobank) revealed a single genome-wide significant locus on chromosome 17q25. Approximately 20 variants across the NPLOC4-TSPAN10-PDE6G gene cluster and in almost perfect linkage disequilibrium (LD) were most strongly associated (lead variant: rs75078292, OR = 1.26, p = 2.24E-08). A recessive model provided a better fit to the data than an additive model. Association with strabismus was independent of refractive error, and the degree of association with strabismus was minimally attenuated after adjustment for amblyopia. The association with strabismus was replicated in an independent cohort of clinician-diagnosed children aged 7 years old (116 cases and 5084 controls; OR = 1.85, p = 0.009). The associated variants included 2 strong candidate causal variants predicted to have functional effects: rs6420484, which substitutes tyrosine for a conserved cysteine (C177Y) in the TSPAN10 gene, and a 4-bp deletion variant, rs397693108, predicted to cause a frameshift in TSPAN10. The population-attributable risk for the locus was approximately 8.4%, indicating an important role in conferring susceptibility to strabismus.

    Research areas

  • strabismus, amblyopia, denome-wide association study, uk biobank, ALSPAC

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via Springer Nature at https://link.springer.com/article/10.1007%2Fs00439-019-02022-8#citeas. Please refer to any applicable terms of use of the publisher.

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