1.3
Gene-Environment Interactions
in the Aetiology of Myopia
Ian G. Morgan* and Kathryn A. Rose†
The term “gene-environment interactions” in statistical genetics refers to the possibility of different genotypes responding differentially to environmental exposures. Myopia is an etiologically heterogeneous disorder, in which there is a low prevalence of clearly genetic myopias, which are generally strongly familial, early in onset and severe. In the last few decades, there has been a marked increase in the prevalence of mild to moderate myopia, particularly in urban East Asia. This increase appears to be strongly associated with changing environmental exposures involving increasingly intensive education and less time spent outdoors. With analysis restricted to this form of acquired or school myopia, there is abundant evidence for environmental impacts, but only limited evidence for genetic contributions. Until the relevant genetic variation has been identified, scientific analysis of gene-environment interactions will not be possible. Currently, it is more parsimonious to interpret school myopia as a disorder caused by environmentally induced excessive axial elongation.
Introduction
After a period of flirtation with the idea that myopia was a predominantly genetic disorder (for the early references, see Curtin, 19851), myopia is now
*ARC Centre of Excellence in Vision Science, Research School of Biology, Australian National University, Canberra, Australia. E-mail: ian.morgan@anu.edu.au
†Discipline of Orthoptics, Faculty of Health Sciences, University of Sydney, Lidcombe, Australia.
45
46 I.G. Morgan and K.A. Rose
commonly regarded as a disorder in which both genes and environment are involved, and in which gene-environment interactions may be important.2 At one level, the first part of this statement is trivial, since gene expression must be involved in any biological process, including the development of myopia. Refractive development of the eye involves changes in the cellular composition and interactions of the cornea, lens, retina, choroid and sclera. These changes must involve changes in gene expression. At the same time, genes must operate in an environment, and thus genes and environment, acting together, are essential for the expression of any biological trait.
From an epidemiological perspective, however, the important question is not whether genes and environment are involved. They simply must be. The important question is about the relationship between variations in phenotype and variations in genotype and environmental factors. In this context, the term “gene-environment interactions” has a very specific meaning in statistical genetics. Martin3 has stated this quite neatly:
“Many people who should know better use the term GxE to denote that both genes and environment are important. Apart from the triviality of such a sentiment (what manifestation of life is not ultimately coded for by genes, and what life is not dependent on the supply of air, water, food from the environment?), a better term is “genotype-environment co-action). We should reserve for the term GxE its statistical sense of different genotypes responding differentially to the same environment; or viewed from the other end, some genotypes being more sensitive to changes in the environment than others….”
From this biological perspective, the cells and molecules involved in growth control pathways, which link detection of relevant variations in visual input at the retinal level to regulation of sclera extracellular matrix remodeling, must ultimately be encoded in the genome. Some of these pathways have now been extensively studied (for a comprehensive review see Ref. 4), and are also reviewed in other sections of this book. Expression of some genes in these pathways must change when visual inputs lead to changes in eye growth. But this is not evidence of gene-environment interactions. This is simply evidence of environmental impacts on gene expression.