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Non-additive (dominance) effects of genetic variants associated with refractive error and myopia

Pozarickij, Alfred, Williamson, Cathy and Guggenheim, Jeremy A. ORCID: 2020. Non-additive (dominance) effects of genetic variants associated with refractive error and myopia. Molecular Genetics and Genomics 295 , pp. 843-853. 10.1007/s00438-020-01666-w

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Optometry and Vision Sciences
Additional Information: UK Biobank and Vision Consortium listed in byline]
Publisher: Springer Nature
ISSN: 1617-4615
Funders: National Eye Research Centre grant SAC015; NIHR Senior Research Fellowship award SRF-2015-08-005
Date of First Compliant Deposit: 30 March 2020
Date of Acceptance: 16 March 2020
Last Modified: 03 May 2023 08:53

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