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

Autor: Pirro G. Hysi, Jeremy A. Guggenheim, Denize Atan, Denis Plotnikov, Jugnoo S Rahi, Rupal L. Shah, Cathy Williams, Phillippa M. Cumberland, Jamille Rodrigues
Rok vydání: 2019
Předmět:
Male
Linkage disequilibrium
Visual acuity
genetic structures
Tetraspanins
Visual Acuity
Genome-wide association study
Cohort Studies
Mice
Neurodevelopmental disorder
Risk Factors
Child
10. No inequality
Genetics (clinical)
Original Investigation
Genetics
0303 health sciences
education.field_of_study
030305 genetics & heredity
Nuclear Proteins
Middle Aged
ALSPAC
3. Good health
Multigene Family
Female
medicine.symptom
Adult
Population
Locus (genetics)
Biology
Polymorphism
Single Nucleotide
Retina
Frameshift mutation
03 medical and health sciences
medicine
Animals
Humans
education
Strabismus
Aged
amblyopia
030304 developmental biology
Cyclic Nucleotide Phosphodiesterases
Type 6
uk biobank
medicine.disease
strabismus
eye diseases
Case-Control Studies
Mutation
Genome-Wide Association Study
denome-wide association study
Zdroj: 2019, ' A commonly occurring genetic variant within the NPLOC4-TSPAN10-PDE6G gene cluster is associated with the risk of strabismus ', Human Genetics, vol. 138, no. 7, pp. 723-737 . https://doi.org/10.1007/s00439-019-02022-8
Human Genetics
ISSN: 1432-1203
0340-6717
Popis: 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. Electronic supplementary material The online version of this article (10.1007/s00439-019-02022-8) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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