GWAS in myopia: insights into disease and implications for the clinic

Abstract

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 IntroductionMyopia is already the commonest eye condition and its prevalence is increasing across the world (1-4). Although myopia is strongly associated with a number of environmental factors, the most important risk factor in determining whether an individual develops the trait is having a family history of myopia, suggesting a genetic predisposition. The heritability of a trait is an estimate of how much phenotypic variation in a population is due to genetic factors. The heritability of refractive error, using spherical equivalent as a quantitative trait, has been determined in a number of family and, more credibly, twin studies [ Figure 1].These indicate the heritability of myopia is high at around 70% (5-15). Myopia is a complex trait influenced by a complicated interplay of genetic and environmental factors. As with many complex traits there is a distribution of refractive error in the population, meaning the risk of ordinary or "simple" myopia developing is not determined by a classic Mendelian single gene mode of inheritance; there are likely many genes, each contributing a small effect to overall myopia risk. This may not be true for very high, familial or syndromeassociated forms of myopia, where a rare dominantly inherited mutation may be important in an individual family, but not important in the overall population risk. Up until the era of genome-wide association studies (GWAS), identification of disease-associated genes relied on family studies (using linkage analysis) or candidate gene studies. In myopia, these were singularly unsuccessful and prior 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Genome-wide association studies (GWAS)Genome-wide association studies (GWAS) are approaches that allow a vast array of markers scattered across an individual's DNA or genome to be rapidly tested for association with a disease or trait. These 'markers' are variations in the base pair of nucleotides at specific points along the genome, commonly known as SNPs (single-nucleotide polymorphisms), and give an indication of what nearby genes may be associated with the trait.In order for this analysis technique to be possible, all of the base pairs, namely adenine (A), guanine (G), thymine (T) or cytosine (C), forming the human DNA code had to be sequenced (ie. read and mapped). The human genome project, completed in 2003, was a major international scientific collaboration that identified all of the base pairs and genes that make up the human genome, approximately 20,500 genes in total (16, 17). This has enabled researchers to have access to a detailed resource on the structure, function and organization of the co...

Novel evidence for complement system activation in chick myopia and hyperopia models: a meta-analysis of transcriptome datasets

“…To date, debate surrounding the relevance of animal models to human myopia has primarily focused on similarities and differences in visual experience, refractive development and anatomy (for review see refs 4 , 64 – 68 ). Our findings contribute to an additional small but growing body of evidence for molecular similarities between humans and animal models 21 , 65 , 69 – 73 , made possible by the recent availability of large-scale refractive error GWAS 74 . The two induction time-points in our meta-analysis were roughly proportionally represented in the overlap with human GWAS candidate genes.…”

SWATH Based Quantitative Proteomics Reveals Significant Lipid Metabolism in Early Myopic Guinea Pig Retina

“…They oppose the action of kinases and phosphorylases and are involved in signal transduction, but have never been previously reported as changing in myopic tissues. In a previous study, PPP2R2 has been reported to be involved in the MAPK signaling pathway [ 98 ], and this pathway has a close relationship with myopia based on a clinical gene analysis [ 99 ] and a basic animal study [ 100 ]. Hence, our SWATH-based proteomic approach may yield more comprehensive proteins, including novel candidates, to the established pathways in myopia research.…”

73‐1: Invited Paper: Pediatric Device Use: Implications for Myopia Development

“…While the recent rise in myopia prevalence would seem to be much faster than accountable by genetic mutations, it has taken the application of recent advances in molecular biology in the form of Genome Wide Association Studies (GWAS), to overturn the traditional wisdom that myopia was largely genetic, based on observed trends within families and twin studies. Genetic variations are now thought to account for less than 12% of variations in refractive error, based on recent meta-analyses of GWAS investigations (7,8), suggesting environmental factors are at play.…”