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

Abstract

Genome-wide association studies (GWAS) have revealed that the genetic contribution to certain complex diseases is welldescribed 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 (R 2 = 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.

Changes in chromatin accessibility landscape and histone H3 core acetylation during valproic acid-induced differentiation of embryonic stem cells

“…For example, Troponin T3 (Tnnt3) as well as the Coiled-Coil Domain Containing Protein 80 (CCdc80), Alpha-3-Catenin (Ctnna3), and the Polycomb Group Ring Finger Protein (Pcgf5) play critical roles in cardiac/myogenic cell lineages and are crucial for striated muscle contraction [ 42 – 46 ]. Additionally, Zinc Finger Matrin-Type 4 (Zmat4) and the Paternally Expressed Gene 10 (Peg10) are implicated in mammalian neurogenesis [ 47 , 48 ], suggesting that VPA treatment induces changes in chromatin accessibility that favor onset of cell differentiation. This notion is supported by the fact that VPA exposure led to a net loss of ATAC-seq peaks and hence decreased accessibility at 3923 loci (Fig.…”

The Roles of Optogenetics and Technology in Neurobiology: A Review

“…Special neurons in the retina react to light and transmit it to the brain to produce vision ( Pozarickij et al, 2020 ; Creeden et al, 2021 ; Liu H. et al, 2021 ; Yu et al, 2021 ; Elkhalifa et al, 2022 ). When neurons in the retina stop working properly, the eye can’t work properly.…”

Myopia Genetics and Heredity

“…Myopia development involves complicated gene-gene and geneenvironmental interactions that display high heterogeneity, with non-uniform, non-linear, and non-additive effects [129]. Establishing polygenic risk scores (PRS) with acceptable accuracy still requires a large amount of genetic, environmental, and ophthalmic data [141]. Nevertheless, a trio-based study of early-onset high myopia using next-generation sequencing and whole-exome sequencing (WES) suggested that de novo mutations of the BSG gene may play a causative role in myopia and may therefore serve as genetic predictors [142].…”

“…A study that screened the known variants associated with refractive error for nonadditivity (dominance) showed that non-additive effects had negligible impacts on the accuracy of a PRS for refractive error derived by using genome-wide significant GWAS variants [141]. In another recent genetic association study of 54,006 individuals, PRSs derived from a GWAS for high myopia were predictive of high myopia, low myopia, and hyperopia [151].…”