Role of Genetics in Myopia
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Myopia, also known as short-sightedness, is a refractive error defined as an optical condition where parallel light rays entering the eye are focussed before the retina, resulting in a blurred image. Optical correction of this refractive error can be done with spectacles, contact lenses and surgical procedures such as photorefractive keratectomy. People with myopia are usually classified into two groups, low to moderate myopia (0.00D to -6.00D) or high/pathological myopia (greater than -6.00D). High myopia is also known as pathological myopia because it is often associated with sight threatening ocular conditions such as retinal detachment, macular degeneration, and glaucoma (Fredrick, 2002). Also systemic findings of many genetic syndromes such as Marfan and Stickler syndromes have myopia as consistent feature (Terri et al., 2004).
Throughout the world myopia is a common cause for visual disability particularly in underdeveloped countries where the health care is poor or even non-existent. Myopia currently affects over 1.5 billion worldwide and this is expected to increase to approximately 2.5 billion by the year 2020 (Dirani et al., 2006a). Prevalence varies between countries and ethnicities, reaching as high as 9 out of 10 people affected in some Asian populations such as Singapore and China (Chow et al., 1990; Wong et al., 2000). Epidemiological studies show that the prevalence of myopia is increasing and this is becoming a significant public health problem (Fredrick, 2002; Paluru et al., 2003; Saw et al., 1996). As well as needing resources for optical correction of myopia, the associated increased risk of vision loss has further economic and social implications for the population. Therefore extensive research is being carried out to understand the mechanisms and factors underlying myopia development in aim to reduce the incidence of myopia.
An emmetropic eye is one that has zero or negligible refractive error. Most babies are born hypermetropic (long-sighted) and emmetropisation is the process by which the eye goes through changes to reach emmetropia, this occurs within the first 5-8 years of life (Fredrick, 2002). The simple reason for the increasing prevalence of myopia may be due to changes in environment, especially modernisation of the underdeveloped world which is partly due to improved education infrastructure and the technological/internet revolution. This means people are now using their eyes for near tasks such as computing much more than before. Therefore this near visual experience may have some influence in the emmetropisation process, resulting in the eyes becoming myopic instead of emmetropic. However there are many studies, such as twin and family history studies that have also found a strong positive correlation between genetics and myopia (Hammond et al., 2001). Other studies have mapped particular genes that influence the onset of myopia or predispose an individual to becoming myopic. It seems there is some interaction between environment and genetics and how they influence the onset and progression of myopia but the relative contribution of each is not fully understood (Saw et al., 1996).
Identifying potential myopia disease genes will help us understand the pathophysiological mechanisms behind myopia development. The potential for this in the future would be the ability to identify individuals at risk from myopia and help develop preventative therapies (Tang et al., 2008). This dissertation will aim to explore the role of genetics in myopia and review the current genes that have been identified to be associated with myopia.
There are multiple ways to help identify genes associated with myopia, and researchers often employ a combination of techniques to further validate their findings. Genes are identified using genetic markers and genetic mapping techniques, these are explained further below.
A genetic marker is a gene or DNA sequence with a known location on a chromosome. It is usually described as a variation, which may be due to mutation or alteration in the genomic loci. This variation is what helps researchers identify genes associated with a particular trait like myopia. Genetic markers can be short DNA sequences, such as single nucleotide polymorphism (SNP), or long sequences such as microsatellites.
SNPs are polymorphic markers that are variations in the DNA sequence occurring when a single nucleotide in the genome differs between two members of the same species (Warthmann et al., 2007). For example people with myopia will have a common SNP compared to those without.
Microsatellites are short sections of DNA made up of repeating units containing 10-60 base pairs. Although microsatellites may have different or unknown repeating units, the repeating unit within the microsatellite is relatively constant (Dorland, 2007). The number of repeating units varies between individuals in a species i.e. they vary in length and these differences in DNA can be detected via capillary gel electrophoresis (Tang et al., 2008). Microsatellites have a high level of polymorphism that makes them another useful tool to help identify genetic markers. Genetic maps are made up of many microsatellites with known positions; this allows genes to be located relative to the microsatellites.
The aim of genetic mapping is to assign DNA fragments to chromosomes, which eventually accumulates to a complete genetic map for a condition. There are two methods for genetic mapping; linkage analysis and association study (Tang et al., 2008). Each method has its own advantages that help overcome different situations.
Linkage analysis is based on the link between loci (locations of genes). If two loci are inherited together on the same chromosome then they are said to be linked. Meiosis results in genes being recombined from parent chromosomes into a new combination in the offspring and this crossing over of DNA can cause alleles previously on the same chromosome to be separated. Therefore if two loci are closer together, the possibility of them being inherited together is greater i.e. there is a reduced chance of alleles being separated and therefore the offspring is more likely to inherit parental traits. Linkage studies aim to uncover genetic markers that are linked to disease genes with the potential to identify other genes as possible disease gene candidates (Terri et al., 2004).
Association studies (FIND BOOK REF)
An association study is another route to help identify susceptibility genes when studying a multifactorial disease like myopia. Association studies are different from linkage studies in that a common allele is associated with the disease where as linkage study allows different alleles to be associated with the disease in different families (Cordell et al., 2005). There are two separate approaches that an association study can take, it can either be population-based or family based. The main aim is to compare DNA samples from affected individuals against non-affected individuals similar to case-control studies. If the findings show a common allele in the affected individuals that is not found in the controls then it can be assumed that this allele is positively associated with a specific disease (Zhang et al., 2010).
Population-based association studies take a sample of people from the population and compares genetic markers between affected individuals (cases) and unaffected individuals (controls). The two groups must be unrelated (no blood relation) although the human population does share common ancestry and so it can be argued that the wider population is just an extended family (Tang et al., 2008; Cordell et al., 2005). Small genetic differences can be detected for complex traits using population-based studies and this can produce powerful results but there may be a confounding effect due to population stratification. Therefore a careful selection of cases and controls is required for a good quality association study.
Family-based association studies involve nuclear families consisting of affected offspring and their parents. It is presumed that the non-transmitted alleles from the parents act as internal controls and the transmitted alleles act as the cases. This means family-based studies eliminate any mismatching between cases and controls, therefore avoiding any chance association due to population stratification (Tang et al., 2008).
GENETIC INFLUENCE ON MYOPIA
Many studies have been conducted to help identify the exact role of genetics in myopia onset and progression. As myopia seems to be multifactorial, twin and family studies are performed to help differentiate between the genetic influence and other factors such as an environmental influence.
There are two types of twin pairs; monozygotic and dizygotic. Identical twins are known as monozygotic i.e. they originated from the same fertilised ovum, where as dyzgotic twins originate from two separately fertilised eggs therefore their DNA is not identical.
In 2001 a classic twin study was performed by Hammond et al. using 226 monozygotic and 280 dizygotic twin pairs from the UK, all female and aged between 49 and 19 years old. The study looked at heritability values of refractive error and found a much higher correlation in monozygotic twins compared to dizygotic twins; this can be seen in fig 1.
This suggests there is a strong genetic influence when inheriting refractive error since monozygotic twins have identical DNA and dyzogitc twins only share up to half their DNA. However heritability is population specific, and if this study was repeated for another population sample with a different gene pool or environment then similar results may not be seen (Hammond et al., 2001).
A more recent study carried out by Dirani et al. in 2006 was composed of 345 monozygotic and 267 dizygotic twin pairs aged between 18 and 88 years old. Twins were recruited from Australia both male and female. Again the study found similar results to above; a significantly higher correlation was found in the monozygotic than the dzygotic twin pairs. The study found that the high heritability can explained by additive and dominant genetic effects which suggests there are multiple genes involved in the aetiology of myopia (Dirani et al., 2006b).
Many other twin studies have also reported on the importance of genetic factors in myopia (Teikari et al., 1980; Hu, D., 1981; Miller, E. M., 1995; Dirani et al., 2008). This leads one to conclude that genetics plays an important role in myopia development. However twin studies do rely on a common assumption that all twins share a similar environment (Dirani et al., 2006a). This way the studies performed can assume all results are are relative with no significant environmental discrepency i.e. there is no confounding effect as long as the assumption holds true.
Although twin studies show good evidence of genetics influencing myopia, some argue they do not apply to the singleton population as twin studies rely on contestable assumptions (Hammond et al., 2001; Morgan et al., 2005). An alternative approach to studying the genetic influence is to conduct a familial study.
Familial studies concentrate on the heritability value of a condition being passed on from parents to their offspring. If there is a family history of particular condition then there is a greater probability that the children will inherit the same condition. For myopia, there is a higher risk of the children developing the condition if one or both parents have myopia compared to children without myopic parents (Zadnik et al., 1994). A study surveying 2888 children in China and Hong Kong found the prevalence of myopia to be 7.3% if neither parent was myopic, 26.2% if one parent was myopic and 45% if both parents were myopic, reinforcing the view of a strong genetic influence in myopia (Yap et al., 1993).
Although this seems like a genetic predisposition to myopia, there is a possible confounding effect since family members not only share common genes but also share a similar environment (Morgan et al., 2005; Sperduto et al., 1996). Therefore when comparing families' careful selection should be made to ensure a large difference in environmental circumstances does not exist between the families. If there is a difference in the environment then this should be factored into the results. Familial studies suggest that a gene-environment interaction exists but this conclusion must be used with an open-mind since parental myopia history can denote a genetic marker, a common lifestyle, or both (Saw at al., 2001; Young et al., 2007).
The classic Mendelian inheritance model has laws that state the inheritance of traits' is linked to single genes on chromosomes in the nucleus. There are four modes of Mendelian inheritance; autosomal dominant, autosomal recessive, X-linked dominant and X-linked recessive (Book ReF).
There are genetic differences between forms of high myopia and low myopia (Olmedo et al., 1992; Pintado et al., 1992). Some studies have found a Mendelian inheritance pattern for myopia, particularly for dominantly inherited simple high myopia (Guggenheim et al., 2000). Young et al. found an autosomal dominant pattern of inheritance identifying two loci for high myopia (Young et al., 1998a; Young et al., 1998b). A recent family-based study consisting of 162 Chinese nuclear families found an association and linkage between the myocilin gene (MYOC) polymorphisms and high myopia (Tang et al., 2007). Many other genetic linkage studies dealing with familial high myopia have also identified myopia loci with an autosomal dominant mode of inheritance (Naiglin et al., 2002; Paluru et al., 2003; Paluru et al., 2005; Zhang et al., 2005; Nallasamy et al., 2007).
However, similar studies have also found that myopia is likely to be influenced by multiple genes (Hammond et al., 2004; Wojciechowski et al., 2006) and other factors like environment (Morgan et al., 2005). This concept of a multifactorial disorder suggests that myopia does not conform to a single-gene Mendelian inheritance model (Ashton, 1985; Klein et al., 2005; Young et al., 2007). Therefore Mendelian inheritance patterns may only apply to simple high myopia i.e. low myopia and some forms of high myopia are comlex traits that do not conform to a Mendelian inheritance model.
Complex trait myopia
Myopia can be expressed as part of a syndrome, rarely as a monogenic form (typically high myopia) or most commonly as a complex disorder (Tang et al., 2008). A complex trait results from the interaction of multiple factors, each of which has a relatively small effect. Family studies show that myopia is more prevalent with a positive family history but it is not a single-gene defect and there may be an environmental influence. This multi-factorial inheritance suggests that the disorder is only expressed if a critical number of genes are inherited independently, and accompanied with an environmental influence i.e. near-work (Saw et al., 1996; Young et al., 2007).
Many low myopia loci have also been mapped using linkage analysis (Hammond et al., 2004; Wojciechowski et al., 2006; Klein et al., 2007). However, the genes influencing myopia onset and progression are still not fully understood and research has continued to help identify potential candidate genes that may have a critical role in myopia development.
Many genes are involved in eye development processes such as emmetropisation, and some of these have been suggested as candidate genes that make an individual more susceptible to develop myopia.
The PAX6 gene is part of the Pax family that are transcriptional regulators and have an important role in the developing eye. Mutations in the PAX6 gene have been implicated for the development of serious ocular conditions such as aniridia and congenital cataracts (Glaser et al., 1994; Hever et al., 2006). Varying the dosage of PAX6 gene in transgenic mice has been proved to influence eye size (Schedl et al., 1996). Therefore it is thought that polymorphisms in the PAX6 gene may be associated with developing a refractive error in humans.
Hammond et al. (2004) carried out a genomewide scan of 221 dyzygotic twins and found 5 SNPs with strong linkage to the PAX6 gene but no associtaion, suggesting that PAX6 may influence myopia development. Another study perfomed by Simpson et al. (2007) used 25 tag SNPs, which covered the PAX6 gene, and found no association between PAX6 and refractive error. However, more recent studies have suggested there is an association between the PAX6 gene and high myopia (Tsai et al., 2008; Han et al., 2009).
It seems an association may exist but due to the lack of evidence further investigation is required to fully understand the potential influence of the PAX6 gene in myopia development.
The transforming growth β-induced factor (TGIF) gene functions as a transcriptional repressor. Mutations in TGIF have been identfied in patients with holoprosencephaly; a common congenital forebrain development defect (Satoh et al., 2008).
Young et al. (1998) identified MYP2 locus on chromosome 18p11.31 to be associated with autosomal dominant high myopia. The TGIF gene has been mapped to be located within the MYP2 interval and therefore is considered as a candidate gene for MYP2-associated high myopia. However, studies investigating the relationship between TGIF and high myopia have not found any association (Scavello et al., 2004; Hasumi et al., 2006; Wang et al., 2009)
Although experimental science has found a strong expression of TGIF in mice during early stages of retinal development (Satoh et al., 2008), the exact role of TGIF in neural development is not fully understood. Further research is required to determine the underlying mechanisms and influence of TGIF in developmental processes.
The hepatocyte growth factor (HGF) has been found to be strongly linked to determining the eye size in mice i.e. causing myopia (Zhou et al., 1999). HGF has also been closely associated with biological mechanisms influencing axial myopia such as critical scleral remolding proteinases (Hamasuna et al., 1999; Gong et al., 2003). This makes HGF a potential candidate gene for myopia. A recent family-based study found a positive association between a HGF gene polymorphism and high myopia in the Han Chinese population (Han et al.,2006). However, another study by Wang et al. (2009) found little association between HGF and myopia.
It seems many candidate genes have been suggested to be associated with myopia, particularly with high myopia loci, but none of them have been proven to be clearly involved (Scavello et al., 2004; Young, T. L., 2004; Wang et al., 2009).
Normally in humans the eyes develop from neonatal hypermetropia to emmetropia in the early years of life (Fredrick, 2002). However, this same process in animal models can be disrupted by environmental factors. Experimental animal studies have shown that if an image is not allowed to be focussed on the retina, either by suturing eyelids or placing diffusers over the eye, then myopia will develop (Wallman et al., 1978; Raviola et al., 1985; Siegwart et al., 1998). In human infants naturally occuring diseases, such as congenital cataracts and periocular haemangiomas, cause similar vision deprivation. In eyes that are left untreated, axial elongation and myopia develops (Hoyt et al., 1981; Fredrick, 2002), however not all these patients develop myopia (Young et al., 2007). Therefore the emmetropisation process may be sensitive to envronmental factors but it is not solely influenced by them.
Myopia prevalence is increasing and becoming a more significant public health problem (Saw et al., 1996; Fredrick, 2002; Paluru et al., 2003). The use-abuse theory suggests that near work causes myopia, therefore people that are highly educated are more like to be myopic than others (Saw et al., 1996). However educational attainment is related to intellect which is strongly influenced by genes, therefore the use-abuse theory should not be solely considered as an environmental factor (Dirani et al., 2008b). Differences in myopia prevalence between the old and new generations also suggest that myopia is more likely to be influenced by environmental changes, such as increased near work like surfing the internet, rather than genetic changes.
However, even in these modern times with a high incidence of myopia, there are individuals that do not develop myopia. This supports the theory of influential interaction between genetics and environment factors i.e. some individuals are genetically predisposed that makes them more susceptible to develop myopia due to environmental risk factors, such as near work (Lyhne et al., 2001).
In this theory it is assumed that myopia results from both genetic and environmental factors. This means that in the parental generation, those that have 'myopia genes' may not develop myopia due to lack of exposure to environmental risk factors and those that have no 'myopia genes' but are exposed to the environmental risk may become myopic. Therefore this makes it very difficult to study the potential impact of this theory, particularly where there are large changes in the environment and prevalence of myopia between old and new generations (Morgan et al., 2005).
Saw et al. (2001) found that although a gene-environment interaction may exist for myopia, the association between near work and myopia is different for children with no, one or two myopic parents. The study found that children can be classified as high or low-risk depending on if parental myopia exists e.g. those with two myopic parents and high environmental exposure have a significatntly higher chance of developing myopia compared to those on the opposite scale. However, 'it is not known whether family history is a factor due mainly to inheritance or to common lifestyle, nor is it known how inheritance might interact with nearwork' (Goss, 2000).
In 2001 Lyhne et al. performed a study to investigate the genetic and environmental impact on myopia. The study found a strong heritability value for myopia but no significant environmental impact. Other studies have also explored the complex gene-environment theory but have not found any conclusive results (Zadnik et al., 1994; Saw et al., 2001).
Many studies looking at the potential interaction between genes and environment use a 'classic' quantitative method to analyse their results. This method does not take into account the potential influence of gene-environment interactions. Therefore to get a true quantitative estimation of interaction the model needs to include a very large population sample with reliable information on early life environmental encounters, such as study habits (Lyhne et al., 2001).
However, the environment may have a significant influence, especially when you compare the increasing prevalence of myopia with the modern world where there is better educational, increasing computer usage and mobile phones etc. The gene-environment interaction theory needs to be investigated further to help understand the relative influence of individual factors and how they work together.
It is generally accepted that myopia is a complex disease and its increasing prevalence is becoming a more significant public health problem; there is the social impact of visual disability and economic impact of treatment costs. This has instigated many research projects to help identify underlying mechanisms influencing myopia onset and progression. Current mapping techniques include linkage-analysis and association studies
Credibility of Mapping Techniques
Each has its own advantages and researchers tend to use a combination of mapping techniques to help identify myopia loci and study potential disease genes. Many myopia loci have been identified and candidate genes have been suggested, but no specific genes have been identified to cause myopia.
Results from family studies and twin studies have suggested there is a strong genetic influence in myopia development. However, the genes involved in complex or multi-factorial diseases are difficult to identify and their influence may be affected by unrelated genes and environment (Young, 2004). Therefore when selecting samples for studies care needs to be taken to ensure any discrepancies are kept to a minimum and taken into account when interpreting results.
Other factors such as environment have also been implicated in the development of myopia, especially when looking at results from animal studies. The main environmental risk factor is considered to be increasing near work but there are possibly other environmental aspects to also consider such as personality, social and cultural factors. Understanding each factor in association to myopia will help further understand the environmental influence and the extent of interaction between genes and environment.
This gives rise to the gene-environment theory which is very difficult to study. This is because myopia is a complex disease where several different influential factors may need to be taken into consideration when performing a study. Again much more investigative research is required to understand and add substance to this theory.
In 2003 the 13-year Human Genome Project was completed and identified approximately all the genes in the human DNA. Currently analysis of the data is continuing through many research projects. Further advancements in genetic research and technology will definitely benefit the human population and hopefully ongoing research will eventually give us a much better insight into the underlying mechanisms of myopia development. This will in turn help determine the relative influence between genetics and environment, and eventually help develop better therapies to manage myopia.
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