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Hum Genet. 2019 Jul;138(7):723-737. doi: 10.1007/s00439-019-02022-8. Epub 2019 May 9.

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

Author information

1
School of Optometry and Vision Sciences, Cardiff University, Cardiff, CF24 4HQ, UK.
2
Population Health Sciences, Bristol Medical School, University of Bristol, 1-5 Whiteladies Road, Bristol, BS8 1NU, UK.
3
Life Course Epidemiology and Biostatistics Section, Institute of Child Health, University College London, London, WC1N 1EH, UK.
4
Ulverscroft Vision Research Group, University College London Institute of Child Health, London, WC1N 1EH, UK.
5
University College London Great Ormond Street Institute of Child Health, London, WC1N 3JH, UK.
6
National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology, London, WC1E 6BT, UK.
7
Department of Twin Research and Genetic Epidemiology, King's College London, St Thomas' Hospital, London, SE1 7EH, UK.
8
Population Health Sciences, Bristol Medical School, University of Bristol, 1-5 Whiteladies Road, Bristol, BS8 1NU, UK. cathy.williams@bristol.ac.uk.
9
School of Optometry and Vision Sciences, Cardiff University, Cardiff, CF24 4HQ, UK. GuggenheimJ1@cardiff.ac.uk.

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.

PMID:
31073882
DOI:
10.1007/s00439-019-02022-8
[Indexed for MEDLINE]

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