Nature and nurture: the complex genetics of myopia and refractive error

Abstract

The refractive errors, myopia and hyperopia, are optical defects of the visual system that can cause blurred vision. Uncorrected refractive errors are the most common causes of visual impairment worldwide. It is estimated that 2.5 billion people will be affected by myopia alone within the next decade. Experimental, epidemiological and clinical research has shown that refractive development is influenced by both environmental and genetic factors. Animal models have showed that eye growth and refractive maturation during infancy are tightly regulated by visually guided mechanisms. Observational data in human populations provide compelling evidence that environmental influences and individual behavioral factors play crucial roles in myopia susceptibility. Nevertheless, the majority of the variance of refractive error within populations is thought to be because of hereditary factors. Genetic linkage studies have mapped two dozen loci, while association studies have implicated more than 25 different genes in refractive variation. Many of these genes are involved in common biological pathways known to mediate extracellular matrix (ECM) composition and regulate connective tissue remodeling. Other associated genomic regions suggest novel mechanisms in the etiology of human myopia, such as mitochondrial-mediated cell death or photoreceptor-mediated visual signal transmission. Taken together, observational and experimental studies have revealed the complex nature of human refractive variation, which likely involves variants in several genes and functional pathways. Multiway interactions between genes and/or environmental factors may also be important in determining individual risks of myopia, and may help explain the complex pattern of refractive error in human populations.

Figure 1

The anatomical basis of refractive errors. LEFT: Myopia or nearsightedness (top left): parallel light rays from distant objects (dashed lines) come to focus in front of the retina, causing blurred distance vision. Emmetropia or “normal” vision (middle left): incident light from distant objects are focused on the retina. Hyperopia or farsightedness (bottom left): images of distant objects are focused behind the retinal plane in an unaccommodating eye. Illustrations modified from: the National Eye Institute, National Institutes of Health (not copyrighted). TOP RIGHT: Histological section of the posterior eye. The retina is a neurosensory tissue that detects contrast, processes the signal locally through various spatial and temporal filters, and sends the pre-processed visual signals to the visual cortex via the retinal ganglion cells. When the retina is exposed to visual signal degradation during early ocular development, it detects contrast deterioration and releases neurotransmitters to signal eye growth. These signals pass though the retinal pigmented epithelium and the vascular choroid to reach the fibrous sclera which responds with scleral tissue remodeling and axial eye growth. BOTTOM RIGHT: Diagram illustrating the effects of form deprivation through neonatal lid fusion on various eye dimensions in rhesus monkey. The temporal halves of the eyes are juxtaposed. From Wiesel and Raviola (1977)(18), figure 2.

Figure 2

Prevalence of refractive errors among 15 year-olds in the Refractive Errors Study in Children (RESC). Red shows prevalence of myopia (spherical equivalent refraction ≤ -0.5 D in both eyes); green shows prevalence of hyperopia (spherical equivalent refraction ≥ +2.50 D in both eyes); grey shows prevalence of clinical emmetropia.

Figure 3

First-order biological interaction network for refraction-associated genes in table 2. Genes that do not interact directly with other gene products in the network are omitted. Official gene symbol, gene names and (alternative names): COLA1A=collagen, type I, alpha 1; COL2A1= collagen, type II, alpha 1; COL11A1=collagen, type XI, alpha 1; HGF= hepatocyte growth factor (hepapoietin A; scatter factor); MET= met proto-oncogene (hepatocyte growth factor receptor); MMP1=matrix metallopeptidase 1 (interstitial collagenase); MMP2=matrix metallopeptidase 2 (gelatinase A); MMP3=matrix metallopeptidase 3 (stromelysin 1, progelatinase); MMP9=matrix metallopeptidase 9 (gelatinase B, 92kDa gelatinase, 92kDa type IV collagenase); MMP13= matrix metallopeptidase 13 (collagenase 3); LUM=lumican; PAX6= paired box 6; TGFB1= transforming growth factor, beta 1; TGFB2= transforming growth factor, beta 2.