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

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.

A multiethnic genome-wide analysis of 44,039 individuals identifies 41 new loci associated with central corneal thickness

“…Many of the CCT-associated loci identified in this study, are also associated with other eye conditions, particularly NPLOC4, CYP1B1, RBMS3, and PLEKHA1. NPLOC4 encodes the NPL4 homolog, ubiquitin recognition factor, and polymorphisms at this locus have been previously reported to be associated with myopia, age-related macular degeneration, eye color, and recently with corneal or refractive astigmatisms, strabismus and macular thickness [48][49][50][51][52][53] . Mutations in CYP1B1, which encodes a member of the cytochrome P450 superfamily of enzymes, involved in eye development 54 , are associated with primary congenital glaucoma 55,56 .…”

Recurrent Rare Copy Number Variants Increase Risk for Esotropia

“…None of the genes involved in the duplications suggest an obvious pathologic mechanism for strabismus, but study of their developmental expression patterns and functions may lead to further insights into strabismus. The genetic loci identified as strabismus risk factors through GWAS, WRB 21 and NPLOC4-TSPAN10-PDE6G, 22 similarly do not have obvious roles in strabismus pathology.…”

“…21 A second GWAS, using self-reported strabismus in the UK Biobank, identified a locus on chromosome 17q25, which extends across the NPLOC4-TSPAN10-PDE6G gene cluster. 22 This locus has been associated through GWAS with several eye conditions, including macular thickness, 23 astigmatism, 24 retinal microvascular size, 25 and myopia. 26 Genetic variation can result from DNA sequence differences, duplications or deletions of genomic elements (copy number variants [CNVs]), or complex genetic rearrangements.…”

Identification of Possible Risk Variants of Familial Strabismus Using Exome Sequencing Analysis

“…Genome-wide screening of common strabismus form reported three Mendelian loci (7p22.1, 4q28.3 and 7q31.2) [ 11 , 12 , 13 ]. The UK Biobank Eye and Vision Consortium, a genome-wide association study of 1345 cases and 65,349 controls, identified a NPLOC4 – TSPAN10 – PDE6G gene cluster as being associated with an increased risk of strabismus [ 14 ]. Common variants within intron 1 of the WRB (tryptophan rich basic protein) were shown to be significantly associated with esotropia and showed paternal transmission bias in paternal inheritance [ 15 ].…”