Abstract
Genome-wide association studies (GWAS) have revealed that the genetic contribution to certain complex diseases is well-described by Fisher’s infinitesimal model in which a vast number of polymorphisms each confer a small effect. Under Fisher’s model, variants have additive effects both across loci and within loci. However, the latter assumption is at odds with the common observation of dominant or recessive rare alleles responsible for monogenic disorders. Here, we searched for evidence of non-additive (dominant or recessive) effects for GWAS variants known to confer susceptibility to the highly heritable quantitative trait, refractive error. Of 146 GWAS variants examined in a discovery sample of 228,423 individuals whose refractive error phenotype was inferred from their age-of-onset of spectacle wear, only 8 had even nominal evidence (p < 0.05) of non-additive effects. In a replication sample of 73,577 individuals who underwent direct assessment of refractive error, 1 of these 8 variants had robust independent evidence of non-additive effects (rs7829127 within ZMAT4, p = 4.76E−05) while a further 2 had suggestive evidence (rs35337422 in RD3L, p = 7.21E−03 and rs12193446 in LAMA2, p = 2.57E−02). Accounting for non-additive effects had minimal impact on the accuracy of a polygenic risk score for refractive error (R2 = 6.04% vs. 6.01%). Our findings demonstrate that very few GWAS variants for refractive error show evidence of a departure from an additive mode of action and that accounting for non-additive risk variants offers little scope to improve the accuracy of polygenic risk scores for myopia.
Highlights
Myopia is an increasingly common disorder usually caused by excessive expansion and elongation of the eye during childhood (Morgan et al 2012)
In addition to the above analysis of variants known to be associated with refractive error, we carried out a full Genome-wide association studies (GWAS) analysis in the discovery sample to systematically search for variants with non-additive effects (Supplementary Note 3)
There was compelling evidence that rs7829127 had dominant/recessive effects on refractive error
Summary
Myopia (nearsightedness) is an increasingly common disorder usually caused by excessive expansion and elongation of the eye during childhood (Morgan et al 2012). The expansion in size of myopic eyes is accompanied by thinning and stretching of the retina, choroid and sclera, which is associated with a heightened risk of sight-threatening impairments such as myopic maculopathy, retinal detachment and glaucoma (Ohno-Matsui 2016). The increasing prevalence of the condition coupled with its associated pathological complications has resulted in myopia becoming a leading cause of blindness and visual impairment, especially in parts of Asia (Fricke et al 2018). Refractive error is a continuous trait quantifying how accurately the eye focuses an image of distant objects on the retina. Myopia represents the negative arm of the refractive error distribution and hyperopia (farsightedness) the positive arm.
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