Update on the Epidemiology and Genetics of Myopic Refractive Error

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Update on the epidemiology and genetics of myopic refractive error

Justin C Sherwin & David A Mackey

To cite this article: Justin C Sherwin & David A Mackey (2013) Update on the epidemiology and genetics of myopic refractive error, Expert Review of Ophthalmology, 8:1, 63-87, DOI: 10.1586/ eop.12.81 To link to this article: https://doi.org/10.1586/eop.12.81

Published online: 09 Jan 2014.

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1746-9899 Justin C Sherwin1,2 and While myopia is an increasingly common refractive error worldwide, its prevalence is greatest David A Mackey*1 in urbanized regions in east Asia. Myopia is a complex multifactorial ocular disorder governed by both genetic and environmental factors and possibly their interplay. Evidence for a genetic 1Lions Eye Institute, University 1746-9902 of Western Australia, Centre for role in myopia has been derived from studies of syndromal myopia, familial correlation studies Ophthalmology and Visual Science, and linkage analyses. More recently, candidate gene and genome-wide association studies have 2 Verdun St, Nedlands, 6009, Perth, been utilized. However, a high proportion of the heritability of myopia remains unexplained. WA, Australia 2Department of Public Health and Most genetic discoveries have been for high myopia, with the search for genes underpinning Primary Care, Institute of Public Health, myopia of lesser severity yielding fewer positive associations. This may soon change with the University of Cambridge, Cambridge, use of next-generation sequencing, as well as the use of epigenetics and proteomic approaches. UK *Author for correspondence: [email protected] Keywords: complex disease • genetics • heritability • myopia • refractive error • SNP • syndrome

Refraction & its components and south Asia, as well as high-income econo- Four ocular structures contribute to the refrac- mies [1] . Myopia is the most common refractive tive apparatus of the human eye: cornea, lens, error globally, and it is estimated that there are and aqueous and vitreous humors. Incoming 1.44 billion people affected, equal to 22.6% of light rays are refracted onto the retina, which the world’s population [2]. The prevalence of then transmits an impulse along the optic nerve correction for myopia is lowest in areas of sub- to the brain for processing. Refractive error Saharan Africa and south Asia (including India, arises when the eye is unable to perform this Pakistan and Bangladesh) [2]. Myopia prevalence accurately. Most commonly, refractive error has been increasing worldwide throughout the arises due to excessive axial length (AL), and 20th century, especially in some populations less frequently, because the main refractive struc- in east Asia, where it is also associated with an ture of the eye – the cornea and lens – lack the increased prevalence of high myopia [3,4]. The required refractive power. Blurred vision ensues. reasons underlying this increase are not entirely Myopia (‘short-sightedness’) results when light is understood. focused in front of the retina rather than on the Uncorrected refractive error (URE) represents retina. Astigmatism may occur in conjunction the most common cause of visual impairment with myopia. Without correction, myopia causes worldwide and the second leading cause of blind- distant objects to appear blurred but near objects ness [5]. URE does not always correlate positively are viewed clearly. Blurred vision may be associ- with myopia severity [6], as it is a reflection of ated with squinting and eye rubbing, which may the available health system’s capacity to provide prompt a vision assessment. refractive services to a population. Therefore, in Using a country-level analysis, refractive low- and middle-income countries, the propor- error was responsible for 27.7 million disability- tion of individuals with refractive error who are adjusted life years worldwide in 2004, which was uncorrected may be higher than in high-income the highest of any eye disease and remained the countries. URE is a leading cause of visual highest of any eye disease separately across low/ impairment in urban China, where over 70% medium- and high-income countries [1] . The of 15-year-olds have myopia [7], and in adults burden of refractive errors predominantly affects in sub-Saharan Africa, where the prevalence of the World Bank regions of east Asia and Pacific, myopia and other refractive error is far less [8].

A systematic review identified social factors (including socio of atropine drops for controlling myopic progression is hopeful economic status, isolation and education), treatment/service fac- and has been shown to be superior to placebo for children with tors (rural domicile, access among minority groups and access to mild-to-moderate myopia in several recent meta-analyses [19–21] . health insurance) and individual factors (including psychological However, owing to several common adverse effects (including near factors) as being associated with URE [9]. It has been shown blur, light sensitivity, dermatitis and allergic conjunctivitis), the that uncorrected myopia is associated with poorer overall visual uptake of this intervention has been sluggish. This may change, function and having difficulty with specific activities including as a recent RCT demonstrated doses as low as 0.01% may be reading street signs, recognizing friends and watching television better tolerated without limiting clinical efficacy [22]. Increasing [10] . However, separate research found that lower quality-of-life time outdoors may be a suitable intervention to prevent myopia (QoL) scores were associated with myopia irrespective of correc- and its progression [23] but ongoing RCTs must first be assessed tion status [11] . In children and younger adults, myopia has little and prescribing a lifestyle intervention has inherent challenges. or no impact on general health, but a positive relationship exists It is important to acknowledge that correction of refractive between increasing severity of myopia and poorer vision-specific error by means of spectacles, refractive surgery or otherwise does functioning; myopia may cause visual deficits that transcend not negate the elevated risk of pathology associated with severe decreased visual acuity [12] . myopia. In the majority of affected individuals with early-onset Although mild myopia has a relatively uncomplicated and nonsyndromic high myopia, loss of vision during working life is benign natural history, the potential for sight loss in patients with minimal [24]. Nevertheless, high myopia remains a major cause severe (high) myopia is substantial, with the risk increasing with of blindness and visual impairment in older adults [25,26]. Novel worsening degree of myopic refractive error. High myopia may be treatments that may improve the visual outcome of those affected associated with sight-threatening cataract, open-angle glaucoma, with myopic sequalae such as choroidal neovascularization, a maculopathy and choroidal neovascularization, peripheral retinal major cause of visual loss in high myopia, are being developed [15] . changes (such as lattice degeneration), retinal holes and tears, as well as retinal detachment [13–15] . In adults, severe myopia may Epidemiology of myopia affect more adversely on QoL than myopia of lesser severity [16] . Refraction across the lifespan Pathology associated with higher degrees of myopia is chronic, Refraction is dynamic throughout a lifespan. Newborns are usu- progressive and more prevalent with increasing age; this may ally hyperopic; over the first few years after birth the prevalence of account for the minimal impact on QoL of myopia in children. myopia increases in conjunction with axial elongation, thinning As myopia is often present during the majority of one’s lifespan, of the lens and flattening of the cornea[13] . There is no simple this may explain why refractive error is a greater contributor to relationship between lens thickness and lens power. The crystal- the overall global burden of eye disease than chronic, age-related line lens continues to become thinner and although it starts to eye diseases such as cataract and macular degeneration [1] . thicken early in the second decade of life, it continues to lose The economic consequences of myopia at a population level power [27,28]. Children with longer AL, vitreous chamber depth are extensive. Assuming myopic individuals receive appropriate and thinner crystalline lenses are more likely to develop myopia refraction and correction, the global burden of myopia has been [29]. Myopic eye growth associated with an increased AL induces estimated at approximately US$45 billion [2]. However, this esti- the lens to compensate by becoming much thinner [28]. In adults mate does not take into account the difference in spectacle price above 40 years of age, increasing age is often associated with a according to region, intercountry differences in health systems, hyperopic shift, unless nuclear sclerosis/cataract is present, which the cost of alternative forms of myopic correction (e.g., refractive leads to a late-aged myopic shift [30,31]. There is also evidence that surgery), or the direct and indirect cost of treatments for conse- suggests that a hyperopic shift can start in earlier years [32]. quences of pathological (high) myopia. At a country level, the mean annual direct cost of myopia for Singapore school children Prevalence of myopia was US$148 per child, with greater costs associated with the use of The highest prevalence estimates for myopia are for young contact lenses, higher family income and paternal education [17] . adults in east Asia, with estimates encroaching 90% in some urbanized and highly educated populations [33]. Using pooled Management of myopia data and a standardized definition of myopia (standard error Myopia may be corrected with spectacles, contact lenses, ortho [SE]: ≤-1.0 D), the crude prevalence of myopia in adults aged keratology or surgical means including laser refractive surgery and ≥40 years in USA, western Europe and Australia was 25.4, 26.6 intraocular lens implantation. Correction of myopia can result in and 16.4%, respectively [34]. In adults aged ≥40 years in east Asia, ocular morbidity, including keratitis secondary to contact lens the prevalence tends to be higher than in other ethnic popula- wear and corneal scarring and persistent corneal haze following tions, but the disparity is less marked than in younger cohorts refractive surgery. At present, there is no widely used intervention (Table 1). It is noteworthy that in many studies, participants were to prevent myopia from occurring or progressing. Randomized often excluded from refraction analyses because of reduced vision controlled trials (RCTs) of several interventions to prevent myopic and/or if pseudophakic. Adult-onset myopia is not uncommon progression, including bifocal lenses, progressive additional lenses [35], although it does not usually progress to the same extent as and contact lenses have failed to show major promise [18]. The use myopia that arises in childhood. Data from population-based

64 Expert Rev. Ophthalmol. 8(1), (2013) Update on the epidemiology & genetics of myopic refractive error Review

Table 1. Prevalence of myopia in selected population-based studies. Study (year), location Age (years) Analyzed Eligible (%) Myopia Prevalence, % (95% CI) Ref. (n) (D) (SE) Andhra Pradesh Study (2009), South ≥40 2522 85.4 ≤-0.5 34.6 (33.1–36.1) † [36] India Baltimore Eye Study (1997), USA 50–80+ 5028 79.2 ≤-0.5 28.0 (white), 27.6 (black)† [217] Barbados Eye Study (1999) 40–84 4036 84 ≤-0.5 21.9 (20.6–23.2) [38] Beaver Dam Eye Study (1994), USA 43–86 4533 83.2 ≤-0.5 26.2‡ [218] Beijing Eye Study (2005), China ≥40 4319 83.4 ≤-0.5 22.9 (21.7–24.2) [45] Blue Mountains Eye Study (1999), 49–97 3650 82.4 ≤-0.5 14.0 [40] Australia Botucatu Eye Study (2009), Brazil 1–92 2454 81.8 ≤-0.5 29.7 (24.9–35.0 [30–39 years]), [219] 21 (15.8–27.3 [70+ years]) Central Australian Ocular Health 30+ 1653 67 [40+] ≤-0.5 11.1, 10.1 [40+] [220] (2010), Australia Handan Eye Study (2009), China ≥30 6491 85.9 ≤-0.5 26.7 (25.6–27.8) [46] (north) Hyderabad (1999), India All ages 2321 92.0 ≤-0.5 4.44 (2.14–6.75 [≤15 years]†), [221] 19.39 (16.54–22.24 [>15 years]†) Liwan Eye Study (2009), China ≥50 1269 75.3 ≤-0.5 32.3 (27.8–34.6) [222] (south) Mashhad Eye Study (2011), Iran All ages 2813 70.4 ≤-0.5 3.64 (2.19–5.09 [≤15 years]), [223] 22.36 (20.06–24.66 [>15 years]) Melbourne Visual Impairment Project 40–80+ 4506 83 (urban); ≤-0.5 17.0 (15.8–18.0) [63] (1999), Australia 91 (rural) National Eye Survey (2004), ≥30 11,189 90.9 ≤-0.5 23.8 (23.8, 23.8)† [224] Bangladesh National Eye Survey (2011), Nigeria ≥40 13,599 89.9 ≤-0.5 16.2 (15.2–17.1) [44] Nord-Trondelag (2002), Norway 20–25; 40–45 3137 (all) NS ≤-0.5 35 (20–25); 33 (40–45) [225] Segovia Eye Study (2009), Spain 40–49 417 89 ≤-0.5 25.4 (21.5–29.8) [226] Shihpai Eye Study (2003), Taiwan ≥65 1108 66.6 ≤-0.5 19.4 (16.7–22.1)† [39] Singapore Indian Eye Study (2011) ≥40 2805 75.6 ≤-0.5 28.0 (25.8–30.2)‡ [42] Singapore Malay Eye Study (2008) 40–80 2974 78.7 ≤-0.5 30.5 (30.2–30.7)‡ [227] Tajimi Study (2008), Japan ≥40 2829 78.1 ≤0.5 41.5 (41.1–41.9)† [228] Tanjong Pagar Study (2000), ≥40 1113 71.8 ≤-0.5 38.7 (35.5–42.1)‡ [47] Singapore †Age and gender-adjusted prevalence estimate. ‡Age-adjusted prevalence estimate. D: Diopter; NS: Not stated; SE: Spherical equivalent. studies in adults do not support a consistently higher prevalence especially of Chinese ethnicity, may possess an inherent sus- of myopia for either males or females [36–40]. High myopia affects ceptibility to myopia compared with western populations [48]. approximately 1–4% of adults aged ≥40 years [41–46], but is higher Multiethnic studies of refractive error highlight inter-ethnic in some studies of east Asian adults [47] and in younger east Asian differences in the prevalence of refractive error. In Singaporean populations [3,4]. Furthermore, the growth rate of high myopia males aged 15–25 years, the prevalence of myopia was 48.5% in in young adults clearly exceeds that of ‘any myopia’ in parts of Chinese, 34.7% in Eurasians (mostly white Caucasian), 30.4% east Asia [3]. in Indians and 24.5% in Malays [49]. In a group of American The prevalence of myopia in children and young adults varies school children aged 5–17 years, the prevalence of myopia was according to ethnicity, which could represent inter-ethnic genetic highest amongst Asians (19.8%) followed by Hispanics (14.5%), and/or environmental variation. Data from population-based African–Americans (8.6%) and whites (5.2%) [50]. Inter-ethnic studies performed in children propose that Asian populations, differences persisted even following adjustment for age and sex. www.expert-reviews.com 65 Review Sherwin & Mackey

The Refractive Error Study in Children (RESC) examined the cohort effect has also been suggested in Sweden where a decreased prevalence of refractive error in children aged 5–15 years in eight spherical equivalent (more myopic refraction) in 65- to 74-year- locations using a standardized protocol and diagnostic criteria. olds was observed over time [62]. Further evidence of a cohort Across RESC locations in subjects aged 15 years, the prevalence effect has been demonstrated in Australian population-based of myopia ranged from less than 1% (0.79%) in rural Nepal [51] studies [31,63]. There is also evidence of a myopic shift in indig- to nearly 80% (79.9%) in Guangzhou, China [7]. Such differences enous Australians over time [64]. Mutti and Zadnik concluded in myopia prevalence usually reflect differences in the respective that while most studies have indicated a reduced prevalence of population distributions of AL [52]. myopia and shortened AL with increasing age in older adults, Significant insight into the etiology of myopia can be gained by this is better explained by an intrinsic age-related decrease in studying the correlation with migration [53]. Myopia prevalence an individual’s myopia over time rather than a cohort effect [65]. is higher among second- or later generation Indian immigrants Results from cross-sectional surveys of younger adults at dif- in Singapore than the first-generation immigrants, suggesting ferent time points provide further evidence of cohort effects in that country-specific environmental factors may contribute to the refraction. In a study of 421,116 Singaporean military conscripts increasing prevalence of myopia in Asia [54]. Rose et al. compared aged 15–25 years, the estimated prevalence of myopia increased the prevalence and associations of myopia of children of Chinese from 26.3% in 1974–1984 to 43.3% in 1987–1991 [66]. A fur- ethnicity in both Singapore and Sydney [55]. They found a much ther study has been undertaken involving 15,086 new male lower prevalence in Sydney (3.3 vs 29.1%), with the Sydney chil- Singaporean military conscripts aged 16–26 years in 1996 and a dren spending much more time outdoors per week (mean: 13.75 vs repeat survey of 29,170 similarly aged males in 2009–2010 [67]. 3.05 h). Reduced time spent outdoors compared with Caucasians Overall myopia prevalence increased from 79.3 to 81.3% between was also shown in a clinic-based sample of Chinese–Canadian 1996 and 2009, with a concomitant increase in prevalence of high children with a high prevalence of myopia (64.1% at 12 years of myopia (13.1–14.8%). In Taiwan, the mean refraction in 4686 age) [56]. freshmen was -4.25 ± 2.74 D in 1988 and -4.93 ± 2.82 D in 2005 among 3709 freshman [4]. Similarly, in a series of cross-sectional Incidence & progression of myopia surveys of 919,929 Israeli Army conscripts, the overall prevalence Several studies in children and adults have investigated longi- of myopia increased from 20.3% in 1990 to 28.3% in 2002 [68]. tudinal changes in refraction. The annual incidence of myopia Notably in east Asia, the population distribution of refractive in Hong Kong was 144.1 cases per 1000 primary school chil- error has undergone a myopic shift in only a few generations. Even dren per annum and was significantly associated with increasing those children without myopic parents will likely become myopic, age [57]. The annual mean change in refraction was greater in some severely. The large and rapid increase in myopia prevalence myopes compared with nonmyopes [57]. An earlier study from in recent birth cohorts of east Asian origin and elsewhere where Hong Kong showed the incidence of myopia at age 7–8 years and large differences in environmental pressures have been observed, 11–12 years to be 9% and 18–20%, respectively [58]. In Singapore, coupled with the lower heritability estimates and parent–offspring the 3-year cumulative incidence rates were 47.7 and 32.4% for correlations obtained from parent and sibling–offspring correla- 7- and 9-year-old children, respectively [29]. tions in such populations, supports an important and major role In the Barbados Eye Study (BES), the overall 9-year incidence for environmental factors influencing myopia [33,69–71] . in adults aged ≥40 years was 12.0% for myopia (2.0% moderate- high myopia) and 29.5% for hypermetropia [59]. The degree of AL: the major endophenotype of refractive error shift in refraction in older adults was age associated, and it can AL is composed of the sum of anterior and vitreous chamber be shown that a myopic shift is more apparent in older adults depths and lens thickness. In emmetropic, pretreated eyes AL does beginning at approximately 60–70 years of age, which may be not correlate with myopia susceptibility; in a study of chicks it was due to increasing lenticular nuclear sclerosis [60,61] . At 10 years shown that the correlation between genetic variants controlling of follow-up in the Blue Mountains Eye Study (BMES), the susceptibility to visually induced myopia and variants controlling gender-adjusted changes in refraction were 0.40, 0.33, -0.02 and normal eye size was negligible [72]. However, when looking at a -0.65 diopters (D) in persons with baseline ages 49–54, 55–64, whole population containing both emmetropes and ametropes, 65–74 and ≥75 years, respectively [31] . In the Beaver Dam Eye increasing AL is associated with an increasingly myopic refrac- Study (BDES) there was a mean change of +0.48, +0.03 and tion, suggesting that factors leading to an increasing AL may -0.19 D for persons aged 43–59, 60–69 and ≥70 years at the share homology with those contributing to myopia and a myopic baseline examination, respectively [60]. refraction [73,74]. AL reaches its fastest rate of growth in the year prior to myo- Cohort effects on refraction pia onset before growing at a much slower pace following onset In the BDES, participants born in more recent years were more [75]. In Caucasian children before myopia onset, children with likely to have myopia than those born in earlier years [60]. Here it myopic parents display a longer AL than children with no posi- was shown that the mean refractions in persons 55–59 years at an tive family history, even after adjustment for environmental examination were +0.20, -0.13 and -0.50 D for those born in the covariates [76]. Notably, parental history of myopia influenced the years 1928–1932, 1933–1937 and 1938–1942, respectively [60]. A eye’s growth rate rather than size in a study of Chinese children

66 Expert Rev. Ophthalmol. 8(1), (2013) Update on the epidemiology & genetics of myopic refractive error Review

[77]. Peripheral hyperopia may stimulate the axial elongation in Diet myopia [78]. Greatly increased AL is characteristic of individu- Studies of the relationship between diet and refraction have been als with high myopia, and the degree of AL correlates strongly limited by small sample sizes and imprecise methods of dietary with high myopia severity [79]. In some adults with high myopia, assessment. No dietary factor appears relevant in myopia devel- the AL continues to increase, especially in those who develop opment or its progression. Malnutrition does not appear to be posterior staphyloma [80]. One benefit of using AL in analyses is associated with refractive error [93]. Children with vegetarian diets that it remains relatively constant following cataract or refractive had an increased prevalence of refractive errors compared with surgery, which is not true for refractive readings. omnivorous children [94], but reasons to account for this are not AL does not represent a perfect surrogate for refraction. Male clear. Using food records, Edwards found statistically significant sex is associated with a longer AL than female sex [81,82], which differences in energy intake, protein, fat, vitamins B1, B2 and may reflect differences in stature, but this does not translate C, phosphorus, iron and cholesterol between 24 children who into a higher prevalence of myopia [42,83,84]. Furthermore, the became myopic between 7 and 10 years of age and 68 controls [95]. inter-ethnic variation in height with resulting longer ALs does However, there were no differences in height or weight of cases not simply translate into a higher prevalence of myopia in and controls, and the study was not population-based. No dietary taller populations. For example, the prevalence of myopia in factors for myopia, as assessed by food-frequency questionnaire, the Dutch adult population [34], widely believed to be among were identified in a cross-sectional sample of 851 Chinese school the tallest population in the world, is much less than in the students aged 12.81 ± 0.83 years and, although some dietary adult Chinese [47]. components (cholesterol and fat) were associated with AL, multiple testing was not accounted for in analyses [96]. Several stud- Environmental, socioeconomic & lifestyle risk factors of ies have shown that being breastfed as an infant is associated myopia with increased hyperopic refraction [97,98], but this finding is not Environmental and lifestyle factors have strongly influenced the consistently replicated [99]. rapid increases in the prevalence of myopia over time in some populations [42,71] . Using a lifecourse epidemiological approach, Diabetes & glycemia several novel putative risk factors were identified from the 1958 The relationship between diabetes, acute and chronic changes British Birth Cohort Study, which support the overall global in glycemia and refractive error is complex. Acutely transient increase in myopia prevalence. These factors include increas- changes of refraction due to hyperglycemia could lead to either a ing maternal age, increasing rates of intrauterine growth retar- myopic or hyperopic shift, depending on whether changes occur dation, persistence of smoking during pregnancy, changing in the refractive indices or in the lens. Hyperglycemia-associated socioeconomic status and reduced rates of breastfeeding [85]. changes in the lens nucleus and cortex often lead to transient myopia and hyperopia, respectively; corneal edema often also Socioeconomic factors ensues [100] . In the cross-sectional Handan Eye Study and Los In ethnically homogenous populations, people growing up in an Angeles Latino Eye Study (LALES), diabetes was significantly urban environment have a higher risk of myopia than people from associated with myopia [41,46]. These results have not been well rural regions [45,86–88]. This incongruity may reflect differences in supported by longitudinal studies. Diabetes was not associated educational level and socioeconomic class rather than the effect with incident myopia in a 5-year follow-up study of the BMES of the environment itself. Other explanations may relate to long- [101] . The 9-year follow-up of the BES showed that diabetes was distance viewing, differences in light intensity and optical field, not significantly associated with any myopia, but was predictive and changes in levels of physical and outdoor activity [33]. of moderate-to-severe myopia (spherical equivalent ≤-3 D) [59]. One of the strongest environmental determinants of myopia is Furthermore, the BDES found that people with diabetes even educational attainment. Prevalence of myopia increases and over- underwent a hyperopic shift over time [60]. In a cross-sectional all mean spherical error decreases (becomes more myopic) with study of subjects with Type 2 diabetes in an urban Indian popula- increasing years of formal education [89,90]. Educational attain- tion aged ≥40 years, poor glycemic control was associated with ment is associated with higher income and decreased unemploy- myopia [102] . In a Danish population, increasing HbA1c was asso- ment [91], factors that are also associated with refractive error. In ciated with an increased odds of myopia, and risk of myopic shift an adult Japanese population, risk of myopia is higher in profes- was increased with HbA1c ≥8.8 compared with HbA1c <8.8, sional occupations with higher incomes and higher educational suggesting that myopia may be associated with chronic hypergly- attainment [37]. In the 1958 British Birth Cohort study, the asso- cemia [103] . By contrast, other studies have found that hypergly- ciation between social class and myopia was significantly attenu- cemia and elevated HbA1c have been associated with a hyperopic ated in the later life-stage models, thereby suggesting social class refraction [104,105]. was mediated through other relevant childhood factors, which may include education, growth and reduced time spent outdoors Smoking & alcohol [85]. It is important to acknowledge that educational attainment Parental smoking is independently associated with reduced myo- is also influenced by genetic factors and should not be regarded pia and increased hyperopic refraction [106] . For adults, higher as merely environmental [92]. frequency of personal smoking is independently associated with www.expert-reviews.com 67 Review Sherwin & Mackey

hyperopic refraction [107] . In a population-based cross-sectional underway, will shed further important insights. Why being out- study of 6491 adults aged 30–99 years in China, smoking was side is protective is incompletely understood, although exposure protectively associated with myopia, following adjustment for age, to natural light outdoors represents a possible mechanism. This diabetes, reading and family history of myopia [46]. In the Beijing has been supported by a protective association of myopia with Eye Study, subjects who consumed alcohol had less myopic refrac- increasing conjunctival ultraviolet autofluorescence[127] , a novel tion than those who did not, but this association was attenuated biomarker of time spent outdoors [128,129]. following adjustment for possible confounders [108] . Near work Anthropometric measures Traditionally, time spent doing activities involving near work has The finding that body stature is associated with myopia is uncon- been regarded as an important risk factor for myopia, although vincing. Although in some studies myopes were significantly taller animal data and epidemiological data are inconsistent [130] . Some than nonmyopes [109,110], many studies found only a weak or neg- studies have demonstrated that increased time spent on activities ligible association [111,112]. In the Genes in Myopia study, following involving near vision is associated with myopia in primary school adjustment for age, gender, educational attainment and ocular children [131] . Further, myopia is associated with proxy measures biometric characteristics, height was not associated with myopic of near work in adults [85,132], but reverse causality is likely. In refraction [113] . In a study of 106,926 consecutive Israeli male any case, there appears to be little difference in near work activ- military recruits aged 17–19 years, myopia was not associated ity between and after development of myopia compared with with taller height, and indeed an association in the opposite direc- emmetropia, suggesting other factors may be more important tion was found [114] . Because genetic coregulation exists between [133] . A number of studies have found that television watching stature and AL, taller people have longer eyes [115], yet because is not associated with myopia in children [122,134,135]. Television the same genes also appear to control other ocular component viewing habits also do not appear to differ before and after the dimensions [116] the eyes still end up emmetropic in general. onset of myopia [133] . Myopia has also been associated with low birthweight for ges- tational age [85]. The relationship between myopia and BMI is Genetic etiology of myopia absent [117] or negligible [114] . Elsewhere in Asian populations, Approach to gene finding in myopia a higher BMI has been associated with hyperopic refraction in Ocular and systemic syndromes associated with myopia, and children [110] and adults [107] . results from familial aggregation studies, heritability estimates, segregation analyses, linkage studies and, more recently, genome- Physical & sporting activity wide association studies (GWAS) provide weight to a genetic basis In a 2-year prospective study of Caucasian Danish medi- of myopia. Inter-ethnic differences in refractive error support cal students, duration of physical activity was associated with a genetic etiology further (see section ‘Prevalence of myopia’). a myopic refraction (0.175 D per hour of physical activity per Elucidating the genetic determinants of a disease involves several day; p = 0.015) after multivariate adjustment [118]. Adult physi- steps [136] . Until recently, the main approach to identify suscep- cal activity levels do not appear to show the same association tible chromosomal regions associated with disease was linkage [119] . Using objective measurements of physical activity, 12-year- analysis of related individuals (either using parametric or nonpar- old children with myopia spent less time in moderate–vigorous ametric approaches), followed by gene localization and sequencing physical activity than other children, and also increased time techniques. Candidate gene and GWAS can be performed on in sedentary behavior, even following adjustment for social and unrelated individuals with no specific hypothesis about which behavioral confounders [120] . Playing sports is inversely associ- single-nucleotide polymorphism (SNP) may be involved, thus ated with myopia [121,122], but not indoor sports [123], suggesting necessitating large sample sizes and strict p-value thresholds to exposure to an outdoor environment may be more important than determine statistically associations between gene variants and the exercise component. myopia. Once a possible causal gene variant is identified, functional studies can be conducted to identify the consequence(s) of Time spent outdoors changes in gene expression. The current available evidence favors time spent outdoors, rather than time spent in physical activity, as being protective against Animal studies myopia. A systematic review and meta-analysis has demonstrated Samples of ocular tissue that might be of interest in myopia a small but significant association between reduced time outdoors research, such as the retina and sclera, cannot be obtained from and myopia in children and young adults in observational studies living humans thus animal models are required. There are several [23]. Time spent outdoors is protective against incident myopia ways of inducing myopia experimentally: form deprivation (eyelid independently of physical activity level [124], and before becom- suturing or placing opaque lenses in the anterior eye causing axial ing myopic, children spend less time outdoors than those who do elongation and myopia), lens-induced optical defocus (exposure not become myopic [125] . Accordingly, findings from a small RCT to optical defocus via plus- or minus-powered lenses leading to [126] have been encouraging, and several other RCTs investigating compensatory changes in AL and refraction) and restricted visual the effect of time spent outdoors, of which several are currently environment conditions. Knockout, breeding experiments and

68 Expert Rev. Ophthalmol. 8(1), (2013) Update on the epidemiology & genetics of myopic refractive error Review quantitative-trait loci models in mice and chickens have identified variation in twin pairs compared with other family relation- genes involved in eye size and refractive regulation [137] . Animal ships may explain why heritability estimates from twin studies studies have demonstrated an active emmetropization mechanism are higher than from other study designs. Within a population, that normally ensures coherence between AL and optical power of heritability is not always constant, and may be altered by changes the eye [138] . Failure of emmetropization could arise from irregular in measurement methods and environmental factors, as well as expression of genes in the retina, retinal pigment epithelium, lens, effects of migration, selection and inbreeding [144] . choroid and/or sclera, resulting in axial elongation and myopia. A meta-analysis found that the pooled heritability estimate of both refractive error (six studies) and AL (seven studies) was 0.71 Familial aggregation analysis (71%), even though there was very high interstudy heterogeneity Given that families share environments, difficulty exists in dif- [146] . However, as the study designs contributing heritability meas- ferentiating the degree of familial clustering that is due to shared urements were different, the interpretation of such findings is genes and shared environments. The intrapair correlation coef- unclear even with a random-effects model. In that study [146], the ficient for spherical equivalent is significantly higher in mono individual heritability estimates for refractive error were broad, zygotic than dizygotic twins [35]. Several studies, encompassing ranging from 0.2 to 0.91, with the highest estimates derived several ethnic groups, have indicated an increased risk of myopia from twin studies. Most large studies, using quantitative data in offspring when either one or both parents are myopic compared and structural equation techniques, showed that refractive error with when both parents are nonmyopic [139,140] . The estimated is largely genetic in origin (heritability >50%). A high heritability recurrence risk for siblings of individuals with myopia (λs) var- of other refractive error endophenotypes, including AL, anterior ies between 1.5 and 3.0 for low myopia and several-fold higher chamber depth and corneal curvature, has also been demonstrated for high myopia [141] . This increased risk persists even after con- [146,147]. Investigation of myopia endophenotypes may provide a trolling for environmental risk factors [121] . In a cross-sectional useful strategy for unraveling the genetic risk factors of myopia study of individuals aged 17–45 years in Singapore, the odds [148] . Classical twin studies are potentially biased towards finding ratio (OR) for having mild/moderate myopia was between 2.5 a genetic basis of disease or trait as heritability estimates are often and 3.7, and for high myopia was 5.5; there was also a strong inflated due to the failure to model shared environmental effects, association between family history of myopia and having a longer following on from the assumption that any excess correlation AL (p < 0.001) [142] . In a study of Singaporean preschool chil- in MZ twins compared with DZ twins only represents genetic dren, subjects with two myopic parents were more likely to be effects. This may explain why heritability estimates from twin myopic and to have a more myopic refraction than children with- studies tend to be higher than those obtained from family-based out myopic parents [143]. Children with myopic parents may be designs [147] . Even when researchers attempt to model shared predisposed to myopia because of inheriting factors associated environmental effects, studies are often underpowered to detect with a longer AL [76]. them [149].

Heritability studies Segregation analyses The genetic contribution to a trait/disease can be divided into Segregation analysis, that is, using maximum likelihood analysis an additive (A) genetic variance component and a nonadditive to estimate transmission probabilities of the observed data, is a (D) genetic variance component – dominance and epistasis valuable statistical method to determine the way complex dis- (where the effects of one gene are modified by one or several orders such as myopia are inherited. Multiple different inherit- other genes). Heritability can be defined as the proportion of ance modes for myopia have been proposed, including recessive, variance of a disease or trait due to additive genetic factors. dominant and X-linked forms, providing further evidence of dis- Determination of heritability can be through either regression/ ease heterogeneity. Findings from 602 pedigrees encompassing correlation methods or variance component equations/structural 2138 BDES participants revealed that a multifactorial mode of equation modeling using modern computer software packages. inheritance was the most parsimonious [150], a finding that has Novel estimation methods of heritability analysis can employ been shown elsewhere [151] . high-density genetic marker technologies [144] . In twin studies, the most reported approximation of heritability using regression Syndromal myopia methods (Falconer’s formula) represents twice the difference in There are many ocular and systemic syndromes that are associ- the correlation of monozygotic (MZ) and dizygotic (DZ) twin ated with myopia (Table 2). In syndromal myopia, the degree of pairs; to be valid it needs to satisfy the assumptions of a classical myopia is usually severe and characterized by an early age of onset twin study [145] . If a genetic basis for a disease or trait exists, MZ and clearly recognized familial pattern. A search of OMIM [301] twins should be more similar as they share 100% of their genetic and PubMed databases performed in November 2012 revealed material, as opposed to DZ twins who on average share only 50%. more than 250 individual syndromes in which myopia has been Other assumptions of twin studies include the equal environ- described. The probability that the myopia results from the under- ment assumption, trait normality, homoscedasticity (equality) lying genetic mutation is elevated in cases when the myopia is of trait, variances between zygosity groups and accurate zygosity severe, the myopia is highly penetrant and when the gene(s) classification. Reduced variation in the range of environmental involved has a plausible role in refraction. Furthermore, most www.expert-reviews.com 69 Review Sherwin & Mackey

Table 2. Syndromes associated with high myopia. Name Frequency Gene(s) involved Mode of inheritance MIM ID Systemic syndrome Alport syndrome One in 50,000 newborns COL4A3, COL4A4, 80%: X-linked Several COL4A5 Cohen syndrome Fewer than 1000 worldwide COH1 (VPS13B) Autosomal recessive 216550 Congenital Rare: 175 cases reported in scientific COL2A1 Autosomal dominant 183900 spondoepiphyseal literature dysplasia Cornelia De Lange Possibly affects one in NIPBL (50–60% of cases), Most cases are sporadic 12247 (type 1); syndrome 10,000–30,000 newborns DXS423E, CSPG6, RAD21 300590 (type 2); 610759 (type 3); 614701(type 4) Danon disease Rare: exact prevalence unknown LAMP2 X-linked dominant 300257 Ehlers Danlos syndrome Combined (all types) one in 5000, There are more than ten Several different types Several with hypermobility and classic forms types. Genes include: more common ADAMTS2, COL1A1, COL1A2, COL3A1, COL5A1 and COL5A2 Homocystinuria Most common form affects at least CBS, MTHFR, MTR, MTRR Autosomal recessive Several one in 200,000–335,000 people and MMADHC genes inheritance worldwide, and more common in some countries (e.g., Qatar) Kniest syndrome Rare: exact incidence is unknown COL2A1 Autosomal dominant 156550 Knobloch syndrome Rare COL18A1 (type 1); Autosomal recessive 267750 (type 1); ADAMS18 (type 2) 608454 (type 2) Marfan syndrome One in 5000 FBN1 Autosomal recessive has 154700 been confirmed in some instances. Approximately 25% arise from new mutations Marshall syndrome Unknown COL11A1 Autosomal dominant 154780 McCune–Albright Between one in 100,000 and one in GNAS Not inherited. Random 174800 syndrome 1,000,000 worldwide mutation that occurs early in development (mosaicism) Noonan syndrome One in 1000 to one in 2500 people PTPN11, SOS1, KRAS, Autosomal dominant Several types NRAS and BRAF genes Pitt–Hopkins syndrome Rare: at least 50 people worldwide TCF4 Autosomal dominant 610954 Potocki–Shaffer Rare ALX4 Proximal 11p deletion 601224 syndrome syndrome Rubinstein–Taybi One in 100,000 to one in 125,000 When identified (half Autosomal dominant 180849 (type 1); syndrome newborns people no mutation) in pattern 613684 (type 2) CREBBP or EB300 or deletion on chromosome 16 Schwartz–Jampel Rare SHSPG2 or LIFR Either autosomal 255800 (type 1); syndrome (Type 2; also dominant or heterozygote 601559 (type 2) known as Stuve– manifestation Widemann syndrome MIM 151443) Data from OMIM [301] and the National Organization for Rare Disorders [302]. MIM: Mendelian inheritance in man; NA: Not applicable.

70 Expert Rev. Ophthalmol. 8(1), (2013) Update on the epidemiology & genetics of myopic refractive error Review

Table 2. Syndromes associated with high myopia (cont.). Name Frequency Gene(s) involved Mode of inheritance MIM ID Shprintzen–Goldberg Rare FBN1 Unknown: familial 182212 syndrome inheritance is rare Smith–Magenis At least one in 25,000 individuals Deletion on chromosome Typically not inherited 182290 syndrome 17 associated with RAI1 gene Stickler syndrome One in 7500–9000 newborns COL2A1, COL9A1, Autosomal dominant Several COL11A1 and COL11A2 inheritance Weill–Marchesani Rare; estimated prevalence ADAMTS10 and FBN1 Autosomal dominant or 277600 (type 1); syndrome approximately one in 100,000 autosomal recessive 608328 (type 2) Ocular syndrome Achromatopsia 3 Rare CNGB3 Autosomal recessive 262300 Brittle cornea syndrome Unknown Mutations in ZNF469 Autosomal recessive 614161 (type 1) or PRDM5 (type 2) (type 21); 614170 (type 2) Choroideremia One in 50,000 to one in 100,000 CHM X-linked recessive 303100 people Coloboma One in 10,000 PAX2, PAX6 Autosomal dominant and 120200 autosomal recessive both proposed Cone–rod dystrophy One in 2500–7000 Several Several types Several types (retinitis pigmentosa) Familial exudative Prevalence is unknown FZD4, LRP5 and NDP Autosomal dominant 133780 vitreoretinopathy genes Myelinated nerve fibers Unknown None identified Possibly autosomal 159500 dominant Wagner syndrome Rare: approximately 50 families VCAN Autosomal dominant 143200 identified worldwide X-linked retinitis Rare RP2 X-linked 312600 pigmentosa 2 X-linked Bornholm eye Rare: higher in Danish ancestry NA X-linked 300843 disease X-linked congenital Unknown NYX and CACNA1F X-linked 31500 stationary night blindness Data from OMIM [301] and the National Organization for Rare Disorders [302]. MIM: Mendelian inheritance in man; NA: Not applicable. cases of high myopia are not associated with a syndrome. In a Marfan syndrome [155] . Identification of mutations involved community-based UK population of children with high myo- with syndromic myopia led many researchers to hypothesize that pia who were identified from optometric and orthoptic practice these genes would be involved in cases of nonsyndromic myopia records, 56% had no associated ocular or systemic condition [152], [138] . Thereafter, a candidate gene approach could be employed. less than in a US study [153] . Polymorphisms in the collagen type 2 α 1 (COL2A1) gene, muta- Many mutations leading to syndromes that are associated with tions of which are associated with Stickler syndrome [156], have myopia are in connective tissues or extracellular matrix (ECM) been associated with nonsyndromic myopia [157] . components. This is unsurprising as the majority of the sclera is composed of collagen, and the growth and remodeling of the Linkage studies sclera is increasingly recognized as playing an important role in The role of genetic factors is likely to be stronger in cases of non- human refraction [154] . Numerous inherited syndromes are associ- syndromic high myopia of early onset in contrast to cases of low/ ated with high myopia and abnormal vitreous that predisposes to moderate myopia in which the environmental influence is likely rhegmatogenous retinal detachment: Stickler’s syndrome, Wagner to be more apparent [158] . Indeed, many of the loci found for disease and erosive vitreoretinopathy, Knobloch syndrome and myopia apply to high myopia only; 20 loci for myopia (MYP1-3; www.expert-reviews.com 71 Review Sherwin & Mackey

Table 3. List of genetic loci for myopia/refractive error. Study (year) Locus MIM ID Location Inheritance Pattern Myopia severity Age of onset Ref. Schwartz et al. MYP1 310460 Xq28 X-linked recessive High: -6.75 to -11.25 D Early: 1.5–5 years [229] (1990) Young et al. MYP2 160700 18p11.31 Autosomal dominant High: -6 to -21 D Early: 6.8 years [230] (1998) (mean) Young et al. MYP3 603221 12q21-q23 Autosomal dominant High: -6.25 to -15 D Early: 5.9 years [230] (1998) Average SE: -9.47 D (mean) Paluru et al. MYP5 608474 17q21-q22 Autosomal dominant High: -5.5 to -50 D Early: 8.9 years [231] (2003) Average SE: -13.925 D (mean) Stambolian et al. MYP6 608908 22q12 NA Mild-to-moderate: NA [232] (2004) -1.00 D or lower Hammond et al. MYP7 609256 11p13 NA -12.12 to +7.25 D NA [233] (2004) Mean SE: +0.39 D Hammond et al. MYP8 609257 3q26 NA -12.12 to +7.25 D NA [233,234] (2004); Andrew Mean SE: +0.39 D et al. (2008) Range: -20 to +8.75 D Hammond et al. MYP9 609258 4q12 NA -12.12 to +7.25 D NA [233] (2004) Mean SE: +0.39 D Hammond et al. MYP10 609259 8p23 NA -12.12 to +7.25 D NA [233] (2004) Mean SE: +0.39 D Zhang et al. MYP11 609994 4q22-q27 Autosomal dominant High: -5 to -20 D Early: before school [235] (2005) age Paluru et al. MYP12 609995 2q37.1 Autosomal dominant High: -7.25 to -27 D Early: before [236] (2005) Mean SE: -14.46 D 12 years of age Zhang et al. MYP13 300613 Xq23-q25 X-linked recessive High: -6 to -20 D Early: before school [237] (2006) age Wojciechowski MYP14 610320 1p36 NA Moderate-to-high: NA [238] et al. (2006) -3.46 D (average) Nallasamy et al. MYP15 612717 10q21.1 Autosomal dominant High: -7.04 D (average) Early: 6–16 years [239] (2007) Lam et al. (2008) MYP16 612554 5p15.33-p15.2 Autosomal dominant High: -7.13 to -16.86 D NA [240] (range of averages) Naiglin et al. MYP17, 608367 7q15 Autosomal dominant High: -13.05 D (average) NA [159,160] (2002), Paget formerly et al. (2008) MYP4 Yang et al. (2009) MYP18† 255500 14q22.1-q24.2 Autosomal recessive High: -13.5 D (average Early childhood [241] right eye) Ma et al. (2010) MYP19 † 613969 5p13.3-p15.1 Autosomal dominant High: -11.59 D (average) Early: average age [242] of myopia diagnosis 6.9 years (range: 4 –11 years) Shi et al. (2011) MYP20† 614166 13q12.12 Autosomal dominant High: -10.64 D (average NA [243] right eye) Shi et al. (2011) MYP21† 614167 1p22.2 Autosomal dominant High: -7.51 to -11.49 D Early: 3–4 years [161] caused by heterozygous (right eye) mutation in the ZNF644 gene †Not yet formally recognized by HUGO Gene Nomenclature Committee. MIM: Mendelian Inheritance in Man; NA: Not applicable.

MYP5-21) are currently listed on OMIM (Table 3) [301] . MYP4 was evidence of linkage to 7q36 even though they used the same fami- originally used for the locus on 7q36, but Paget et al. [159] found no lies as Naiglin et al. [160] . Instead, they found significant linkage

72 Expert Rev. Ophthalmol. 8(1), (2013) Update on the epidemiology & genetics of myopic refractive error Review

to 7p15, now referred to as MPY17 [159] . Most of these loci have evidence supporting a common pathway is weak. When a myopia been found through linkage analyses in highly myopic probands susceptibility locus is identified, genes lying within that locus can with multiple affected relatives, and corroborative findings from be sequenced, but this approach does not always result in success- replication studies have been limited. Most of these loci have ful gene finding [169,170] . Next-generation sequencing strategies displayed an autosomal dominant inheritance pattern, but other may improve changes of gene discovery in gene regions of interest. forms of inheritance have included autosomal recessive (MYP18) The interplay between different biological classes of refraction- and X-linked forms (MYP1 and MYP13). One locus, MYP21, associated genes, including generic binding proteins, transcription represents a mutation in the zinc finger protein 644 isoform 1 factors, metalloproteinases and receptors, may be important [137] . (ZNF644) gene, located on chromosome 1p22.2 [161] . Shi et al. By adopting a candidate gene approach, several positive asso- discovered heterozygosity for a 2091A>G transition in exon 3 of ciations have been identified, especially with genes involved in the ZNF644 gene in a Han-Chinese family with high myopia, ECM growth and remodeling (Table 4). In this group of genes, leading to an ile587val (I587V) substitution [161] . ZNF644 was positive associations have been found for genes encoding collagens expressed in human liver, placenta, retina and retinal pigment [157,171], proteoglycans [172,173], matrix metalloproteinases [174,175], epithelium, the only tissues examined. Subsequently, two novel and growth factors and their receptors [176–180] . The vitamin D single-nucleotide variants in ZNF644 (c.725C>T, c.821A>T) receptor (VDR) gene is another example of a candidate gene. It in two high-grade myopia individuals (one Caucasian and one is plausible that people who develop myopia have lower levels African–American) were identified in a US cohort of individuals or function of vitamin D as this nutrient is important for eye with high myopia [162] . growth in animal models [181] . Polymorphisms within the VDR Not all myopia susceptibility loci are formally recognized by gene appear to be associated with low-to-moderate myopia in HUGO but may be in due course. Researchers in the BDES iden- white individuals [182], whereas a polymorphism in the VDR gene tified two novel regions of suggestive linkage on chromosome 1q start codon (Fok1) has been associated with high myopia [183] . and 7p [163] . Ciner et al. conducted linkage analysis on 96 fami- These associations have not been found in recent GWAS. lies containing 493 African–American individuals in the Myopia It has become apparent that most of the (nonhigh myopia) Family Study (mean SE: -2.87 D) [164] . They found significant candidate gene associations reported previously represent poor linkage at 47 centimorgans (cM) on chromosome 7 (logarithm quality, false-positive findings. These studies are typified by small of the odds [LOD] score: 5.87; p = 0.00005). There were also sample sizes and unfeasibly large SNP effect sizes. In addition, three regions on chromosomes 2p, 3p and 10p showing suggestive even where candidate gene studies have been replicated, the rep- evidence of linkage (LOD >2; p < 0.005) for ocular refraction. lication often relates to different markers from those identified Using an additional 36 white families in addition to the African– originally, with the originally associated variants not being repli- American families, a suggestive linkage at chromosome 20 was cated. In cases of high myopia, where one would expect a stronger found, which became more significant when the scores were com- genetic role, replication of initial associations has also been rare. bined for both groups [165] . Using refractive error as a continuous For example, the rs1635529 polymorphism in the COL2A1 gene variable, two additional potential myopia susceptibility loci at has been associated with myopia in several Caucasian datasets 6q13-16.1 and 5q35.1-35.2 for myopia were found [166] . [157], but was not replicated in a Chinese population with high Li et al. performed whole-genome linkage scans for high myopia, myopia [184] . This may suggest that this SNP is only associated using 1210 samples from five independent sites [167]. In addition with only one ethnicity. However, lack of replication has also to replicating several previously identified loci, they found a novel been seen in studies of populations of the same ethnicity. Four region q34.11 on chromosome 9 (max LOD: 2.07 at rs913275). allele SNPs were previously associated with high myopia (alleles Sequencing of entire coding regions and intron–exon boundaries of rs2229336 in TGIF [185], rs3759223 in lumican [186], rs1982073 can be performed after genome-wide linkage analysis. In Bedouin in TGFB1 [185] and rs3735520 in HGF [178]) in Chinese people kindred with autosomal recessive high myopia, genome-wide link- living in southeast China. However, none of these four were rep- age analysis mapped the disease gene to 3q28 (LOD score of 11.5 licated in a study of 288 Chinese subjects with high myopia and at marker D3S1314). Six genes lying in the locus were subse- 208 controls [187], or other populations [188–192] . Another notable quently sequenced and a single mutation (c. 1523G>T) in exon example has been PAX6, for which there have been many failed 10 of LEPREL1 was identified that encodes prolyl 3-hydroxylase 2 attempts at replication (see Table 4). (PRHS2) which is involved in the hydroxylation of collagens [168]. GWAS of myopia Candidate gene studies Because myopia is a complex disease in which multiple genes may Candidate genes are chosen for several reasons: presence within contribute small effects on phenotype, case-controlled and family- a myopia susceptibility locus, relevant structure and/or function based association studies represent a powerful approach to iden- or previously identified as having a critical role in refraction in tify its associated genetic risk factors. In GWAS, myopia can be animal studies. Only a few genes have been consistently replicated expressed as a binary trait (any degree of myopia or a category of in myopia. Some candidate genes have been positively associated myopia severity; e.g., high myopia) at various SE or spherical error with both high and lesser severe forms of myopia [157], thus sug- cutoffs, or alternatively, refraction or an endophenotype of myopia gesting that common pathways underpin both forms, although (e.g., AL) can be used as quantitative traits. The number of GWAS www.expert-reviews.com 73 Review Sherwin & Mackey

Table 4. Selected candidate genes and their association with myopia in studies of humans. Gene Gene name Chromosomal MIM ID Studies with a Studies with no Reason for symbol location positive association being association candidate

BDNF Brain derived 11p14.1 113505 Mutti et al. (2007) [157] Associated with neurotrophic factor syndromic myopia

BMP2 Bone morphogenetic 20p12.3 112261 Liu et al. (2009) [244] Function protein 2

CHRM1 Cholinergic receptor, 11q12.3 118510 Lin et al. (2009) [245] Function muscarinic 1

COL1A1 Collaged type 1 α 1 17q21.31–q22 120150 Inamori et al. Liang et al. (2007) [246] Function (2007) [171]

COL2A1 Collagen type 2 α 1 12q13.11–q13.2 120140 Mutti et al. Wang et al. (2012) [184] Associated with (2007) [157] syndromic myopia

COL11A1 Collagen type 11 α 1 1p21.1 120280 Yip et al. (2011) [247] Function

COL18A1 Collagen type 18 α 1 21q22.3 120328 Mutti et al. (2007) [157]; Associated with Yip et al. (2011) [247] syndromic myopia

CRYBA4 Crystallin β A4 22q11.2–q13.1 123631 Ho et al. (2012) [248] Near MYP6 locus

DCN Decorin 12q21.33 125255 Yip et al. (2011) [249]; Proteoglycan Wang et al. (2006) [186] gene

DSPG3/EPYC Dermatan sulfate 12q21.33 601657 Chen et al. (2009) [172]; Function proteoglycan 3/ Wang et al. (2006) [186]; epiphycan Wang et al. (2009) [250]; Yip et al. (2011) [249]

EGR1 Early growth response 1 5q31.2 128990 Li et al. (2008) [251] Function

FBN1 Fibrillin 1 15q21.1 134797 Yip et al. (2011) [247] Associated with syndromic myopia

FGF-2 FGF-2 4q27–q28 134920 Mutti et al. (2007) [157]; Associated with Lin et al. (2009) [252] syndromic myopia FMOD Fibromodulin 1q32.1 600245 Majava et al. Paluru et al. (2004) Function (2007) [173] [253]; Lin et al. (2009) [252]

HGF HGF 7q21.11 142409 Han et al. (2006) [178]; Wang et al. (2009) [187] Animal studies Veerappan et al. (2010) [177]; Yanovitch et al. (2009) [179]

IGF1 IGF-1 12q22–q24.1 147440 Mak et al. (2012) [176]; Rydzanicz et al. Function Metlapally et al. (2011) [254] (2010) [180]

IGFBP3 IGF-binding protein 3 7p12.3 146732 Mak et al. (2012) [176] Function

IGFBP4 IGF-binding protein 4 17q21.2 146733 Mak et al. (2012) [176] Function

LAMA1 Laminin α 1 18p11.31– 150430 Zhao et al. Sasaki et al. (2007) [256] Function p11.23 (2011) [255]

LUM Lumican 12q21.33 600616 Majava et al. (2007) Dai et al. (2012) [257]; Function [173]; Chen et al. Paluru et al. (2004) [253]; (2009) [172] Wang et al. (2006) [186] MIM: Mendelian Inheritance in Man.

74 Expert Rev. Ophthalmol. 8(1), (2013) Update on the epidemiology & genetics of myopic refractive error Review

Table 4. Selected candidate genes and their association with myopia in studies of humans (cont.). Gene Gene name Chromosomal MIM ID Studies with a Studies with no Reason for symbol location positive association being association candidate CMET Met pro-oncogene 7q31.2 164860 Yanovitch et al. Schache et al. 2009 Function (hepatocyte growth 2009 [179]; Han et al. [258]; Wang et al. factor receptor) 2006 [178] 2009 [187] MMP1 Matrix 11q22.2 120353 Wojciechowski et al. Nakanishi et al. (2011) Function metalloproteinase 1 (2010) [174] [259] MMP2 Matrix 16q12.2 120360 Wojciechowski et al. Nakanishi et al. (2011) Function metalloproteinase 2 (2010) [174] [259]; Leung et al. (2011) [260]

MMP3 Matrix 11q22.2 185250 Hall et al. (2009) [175] Nakanishi et al. (2011) Function metalloproteinase 3 [259]; Liang et al. (2006) [261]

MMP9 Matrix 20q13.12 120361 Hall et al. (2009) [175] Wojciechowski et al. Function metalloproteinase 9 (2010) [174]

MYOC Myocilin 1q24.3 601652 Vatavuk et al. Dai et al. (2012) [257]; Within MYOC (2009) [262] Zayats et al. (2009) [263] locus OPTC Opticin 1q31-32 605127 Majava et al. (2007) Function [173]; Wang et al. (2009) [250]

PAX6 Paired box gene 6 11p13 607108 Hammond et al. Mutti et al. (2007) [157]; Associated with (2006) [233]; Han Dai et al. (2012) [257]; syndromic myopia et al. (2009) [264]; Simpson et al. within MYP7 Hewitt et al. (2007) (2007) [268] locus [265]; Liang et al. (2011) [266]; Tsai et al. (2008) [267]

PLOD1 Procollagen–lysine, 1p36.22 153454 Yip et al. (2011) [247] Associated with 2-oxoglutarate syndromic myopia 5-dioygenase RARA Retinoic acid receptor-α 17q21.2 180240 Veerappan et al. Function (2009) [269]

SERPINI2 Serine protease inhibitor 3p26.1 605587 Hysi et al. (2012) [270] Identified through member 2 previous linkage SOX2 Sry-Box 2 3q26.33 184429 Simpson et al. (2007) Function/ [268] identified through linkage

TGIF TGF-β-induced factor 18p11.31 602630 Lam et al. (2003) [185] Hasumi et al. Within MYP2 (2006) [189]; Pertile et al. locus (2008) [188]; Scavello et al. (2004) [192]; Wang et al. (2009) [187] TGFB1 TGF-β1 19q13.2 190180 Hayashi et al. (2007) Function [190]; Wang et al. (2009) [187] TGFB2 TGF-β2 1q41 190220 Lam et al. (2003) Function [185]; Lin et al. (2009) [252]

TIMP1 Tissue inhibitor of Xp11.23 305370 Liang et al. (2006) [261]; Function metalloproteinase 1 Wojciechowski et al. (2010) [174] MIM: Mendelian Inheritance in Man.

www.expert-reviews.com 75 Review Sherwin & Mackey

TIMP2 Tissue inhibitor of 17q25 188825 Leung et al. (2011) [260]; Function metalloproteinase 2 Wojciechowski et al. (2010) [174]

TIMP3 Tissue inhibitor of 22q12.1–q13.2 188826 Leung et al. (2011) [260]; Function metalloproteinase 3 Wojciechowski et al. (2010) [174] TIMP4 Tissue inhibitor of 3q25 601915 Wojciechowski et al. Function metalloproteinase 4 (2010) [174]

UMODL1 Uromodulin-like 1 21q22.3 613859 Zhu et al. (2012 ) [271] Previous linkage to loci VDR Vitamin D receptor 12q13.11 601769 Mutti et al. (2011) Function [182]; Annamaneni et al. (2011) [183] MIM: Mendelian Inheritance in Man. being performed for complex diseases has increased exponentially analyses. Most loci identified from GWAS have only been for in recent years, with an accompanying reduction in cost of the high myopia, with limited findings being successfully replicated. SNP-containing chips. The absence of successful replication of Furthermore, some variants are home to chromosomal regions, previously identified SNPs may reveal a type 1 error. In this type including noncoding regions, without a plausible candidate gene. of study, the relative risk of a causal SNP (commonly presented Most GWAS have investigated subjects with high myopia as an OR) is usually modest in contrast to findings from linkage (Table 5) but some success has been achieved when looking at

Table 5. Genome-wide association studies and myopia/refractive error. Study Primary Replication Ethnicity Phenotype Gene symbol Location Marker(s) Ref. (year) group group Fan et al. Singapore NA Chinese and High myopia ZC3H11B 1q41 rs4373767 [79] (2012) Malay and axial length Hysi et al. Netherlands UK, Australia. Caucasian Ocular GJD2, ACTC1 15q14 rs634990 [194] (2010) Replicated in refraction Japanese [272] Li et al. Singapore Japanese other Singaporean High myopia CTNND2 5p15 rs12716080; [199] (2011) Chinese group Chinese rs6885224 [200] Li et al. China NA. This was Han Chinese High myopia No known genes in 4q25 rs10034228 [274] (2011) replicated [273] region, but expressed sequence tags exist Nakinishi Japan NA Japanese High myopia BLID LOC399959 11q24.1 rs577948 [210] et al. (2009) Shi et al. China NA Han Chinese High myopia Locus contains three 13q12.12 rs9318086. [243] (2011) genes (MIPEP, Five other C1QTNF9B-AS1 and SNPs also C1QTNF9B) significant Solouki et al. UK Australia, The Caucasian Ocular RASGRF1 15q25.1 rs939658, [195] (2010) Netherlands. refraction rs8027411 Replicated in Japanese [272] An unpublished GWAS recently found 19 significant (p < 5 × 10-8) associations with myopia, 17 of which were novel [197]. Most of the associations (13; 68.4%) were located within or near genes known to be associated with eye development, neuronal development and signaling, the retinal visual cycle of the retina and general eye morphology: DLG2, KCNMA1, KCNQ5, LAMA2, LRRC4C, PRSS56, RBFOX1, RDH5, RGR, SFRP1, TJP2, ZBTB38 and ZIC2. NA: Not applicable; SNP: Single-nucleotide polymorphism.

76 Expert Rev. Ophthalmol. 8(1), (2013) Update on the epidemiology & genetics of myopic refractive error Review

subjects with less severe refractive error. The Consortium of twin compared with family-based studies [146] could be explained Refractive Error and Myopia recently published their first findings by gene–environment interaction. In addition, the sharp rise in [193] . This group included 31 cohorts with a total of 55,177 indi- the prevalence of predominantly mild-to-moderate myopia in viduals of Caucasian (81.5%) and Asian (18.5%) ancestry. They only a few decades in east Asia argues for a strong environmen- performed a fixed-effect meta-analysis of 14 SNPs on 15q14 and tal component that is associated with changes in environmental five SNPs on 15q25; these regions were previously identified as exposures that are associated with urbanization, such as increas- being associated with human refraction in GWAS [194,195]. Within ing level of educational and decreasing time spent outdoors [53]. this consortium, all of the SNPs at chromosome 15q14 were sig- In urban China, the prevalence of myopia considerably higher in nificantly replicated, with the top SNP at rs634990 [193] . An 15-year-old children than in parents (78.4 vs 19.8%) but children increased relative risk of myopia versus hyperopia was identified with myopic parents carried an even greater risk of myopia [203]. in homozygotes of the rs634990 risk allele (OR: 1.88; 95% CI: Evidence to support an inherited basis of school myopia, and to 1.64–2.16; p < 0.001) and for heterozygotes (OR: 1.33; 95% CI: support an inherited susceptibility to environmental risk factors 1.19–1.49; p < 0.001). However, a significant association between of myopia, is weak [33]. In countries with a high prevalence of myopia and SNPs at locus 15q25 was not found. The 15q14 locus myopia, a high proportion of high myopia may be acquired [4]. lies close to two genes: gap junction protein Δ 2 (GJD2) and Morgan and Rose have identified three questions that need to actin α cardiac muscle 1, both of which may have possible roles be asked when investigating the possibility of gene–environment in myopia development. GJD2 encodes the connexin 36 protein interaction in myopia [158]: and is expressed in the retina where it is involved in transmission • Do genetic differences contribute to phenotypic variations in and processing of visual signals [196] . Actin α cardiac muscle 1 myopia? may play a role in scleral remodeling [197] . Recently, a very large GWAS study, which used questionnaire-based ascertained data • Do environmental exposures contribute to phenotypic on myopia status, was performed in 43,360 Europeans [198] . The variations in myopia? results from the largest myopia GWAS to date were compelling: • Is there evidence of differential sensitivity of the different -8 19 significant (p-value: <5 × 10 ) associations with myopia were genotypes characterized to environmental changes? elucidated, 17 out of which were novel, which explained 2.7% of the total variance of myopia. Most of the associations (13; 68.4%) Overall, the evidence supporting gene–environment interac- were located within or near genes known to be associated with tion in acquired myopia in humans is weak, with the strongest eye development, neuronal development and signaling, the retinal evidence attributed to changes in environmental pressures leading visual cycle of the retina and general eye morphology: DLG2, to aberrant emmetropization [158] . Support from a recent animal KCNMA1, KCNQ5, LAMA2, LRRC4C, PRSS56, RBFOX1, study has provided an important insight into gene–environment RDH5, RGR, SFRP1, TJP2, ZBTB38 and ZIC2. interaction. In a study of outbred White Leghorn chicks [204], after In a meta-analysis of two genome-wide datasets of Singapore two rounds of selective breeding for high and low susceptibility Chinese subjects, Li et al. identified two variants (rs12716080 in response to 4 days of form deprivation, an established animal and rs6885224) in CTNND2 on 5p15 for high myopia [199] , one model for myopia [205], chicks in the high-susceptibility groups of which (rs6885224) was successfully replicated in a Japanese developed approximately twice the myopia as the low-suscepti- population in the same study [199] and another Chinese population bility group. There was also a significant difference between the [200]. CTNND2 is a neuronal-specific protein that is involved in groups in AL, with additive genetic effects explaining approxi- retinal development and whose function may be regulated by mately half of the interanimal variation. These results support a paired box gene 6 (PAX6) [201] . Positive GWAS findings have also role for gene–environment interaction in myopia by showing that been found for myopia endophenotypes. These include variants susceptibility to environmentally induced myopia in chickens is in FKBP12-rapamycin complex-associated protein (FRAP1) on strongly genetic in origin. As form deprivation during early life chromosome 1p36.2 and PDGF receptor α on chromosome 4q12 has been shown to occur in humans [206], results from this work associated with corneal curvature variation [202], and variants in suggest a potentially major role for gene–environment interaction 1q41 influencing differences in AL[79] . in human myopia. Most evidence supporting a gene–environment interaction Gene–environment interaction in cases of acquired myopia in humans have used surrogates of Myopia is a complex ocular disorder, in which several genes are genotype, namely parental myopia and ethnicity. Evidence for a likely to act in concert to control eye growth; the expression of gene–environment interaction is supported by a differential effect these genes may be modified by environmental factors. Some of outdoor activity and risk of myopia according to levels of family cases of myopia are clearly familial. In these instances, myopia is history of myopia [125] . However, the relationship between paren- typically early in onset and severe, and a pattern of inheritance tal myopia and measures of education or near work is more equiv- can be identified among family members. In others, the mode of ocal [121,207] . Furthermore, some modifiable environmental risk inheritance is heterogeneous. One common misconception is that factors, including educational attainment, are strongly influenced a high heritability is incompatible with rapid changes in preva- by genetic factors [92]. Recently, an association between SNPs lence [70]. The higher heritability estimates for refractive error in close to an MMP gene cluster and refractive error was identified www.expert-reviews.com 77 Review Sherwin & Mackey

after stratifying by educational attainment [208]; this may repre- affords the opportunity of analyzing DNA samples from patients sent a gene–environment interaction. As more genetic associations as an adjunct to clinical diagnosis, prognosis and counseling [211], are being discovered in cases of mild-to-moderate myopia, this and enrolling patients in clinical trials of therapeutic agents. will provide a better opportunity to investigate gene–environment interactions. Furthermore, the possibility of multiple and Five-year view varied gene–gene interactions contributing to refractive pheno- Ophthalmic genetics is evolving rapidly and we will understand types is high, and exploring this will require advanced statistical much more about the etiology of myopic refractive error over techniques in conjunction with extremely large sample sizes to the next 5 years. Much will be achieved with the advent of new permit sufficient power. It will be also necessary to collect data on technology. The emergence of GWAS that have underpinned the environmental factors in future GWAS studies, as most current discovery of variants associated with low/moderate and, more studies have limited environmental data, which could account for commonly, high myopia has been a major advance. Increasingly, the dearth of literature on gene–environment interaction. collaboration between research groups is required for the discovery, validation and meta-analysis of genetic discoveries from Expert commentary GWAS. Such collaborations also vastly increase the sample sizes Myopia is a common, complex ocular disorder that is prevalent available – crucial for ensuring sufficient power for finding rare across all ethnicities in varying proportions. In parts of east Asia, variants, copy number variants, SNPs of modest effect and evi- the number of children and young adults with myopia far exceeds dence of gene–gene interaction. Chromosomal regions that have the number without. This was not the case in previous genera- been previously identified for myopia through linkage analysis tions. We now have populations in which myopia is essentially will be amenable to new-generation sequencing, thus obviating universal in young adults [4] and this represents a major public the requirement for comprehensive SNP analysis [212]. health concern. All of these rapid changes have occurred in the Epigenetics seeks to understand heritable changes in gene context of increased urbanization and strong pressures to attain expression that cannot be attributed to changes in primary DNA high levels of education. A concomitant increase has been seen for nucleotide sequence. From this angle, it may be possible to fur- high myopia, which carries an elevated risk of sight-threatening ther elucidate the etiology of complex non-Mendelian disease and sequalae. Understanding the factors leading to high myopia and to assist in developing therapeutic interventions [213]. One key axial elongation are pivotal in this regard. Correction rates for mechanism involves methylation of cytosine–phosphate–guanine individuals with high myopia is high [6], but those with high myo- sites. It is likely that epigenetic effects play an important role in pia should have regular long-term follow-up for surveillance of the etiology of myopic refractive error, and will be instrumental associated pathology. Genetic discoveries for less severe but more in exploring possible gene–environment interactions [214]. Now prevalent myopia have been less successful, but steady progress the role of such studies remains largely undefined. An example has been made in recent years. of an epigenetic approach to myopia research has demonstrated Experimental, epidemiological and clinical studies indicate that that hypermethlyation of cytosine–phosphate–guanine sites pro- refraction is influenced by both environmental and genetic factors moter/exon 1 of the COL1A1 gene may be associated with reduced and, possibly, their interaction [209]. The majority of the intra-pop- collagen synthesis in myopic scleras [215]. ulation variance of refractive error within populations (heritabil- Proteomic approaches could potentially use aqueous or vitreous ity) is attributed to hereditary factors, and evidence supporting a humor, tears or serum to identify biomarkers of myopia. Duan genetic etiology for high myopia is compelling. Several syndromes, et al. performed a proteomic analysis by comparing the protein both ocular and systemic, are associated with high myopia and composition of the aqueous humor of highly myopic eyes to non- are commonly attributed to mutations in genes coding for ECM myopic eyes with cataract [216]. Interestingly, total protein concen- proteins or connective tissue components that are expressed in the tration in the aqueous humor of highly myopic eyes was signifi- eye (commonly the sclera). Many high myopia susceptibility loci cantly greater than in controls. Analysis linked the higher protein have now been mapped and display different forms of inheritance. concentration to albumin, transthyretin and a vitamin D-binding Some causative gene mutations have now been identified[161,168] , protein; these proteins may represent biomarkers that are involved allowing a closer insight into the pathogenesis. in axial elongation. One limitation of proteomic analysis is the The advent of GWAS has been instrumental in unraveling the potential confounding effect of concurrent medical and/or surgi- genetic complexity of myopia, and numerous unique susceptibility cal treatments, as they may also influence protein composition of variants have been identified. Without a doubt, several additional the tissues under investigation. variants will be identified in the ensuing years. Fortuitously, GWAS permit the identification of potential novel pathways involved in Financial & competing interests disclosure refraction such as mitochondrial-induced apoptosis [210] and pho- The authors have no relevant affiliations or financial involvement with any toreceptor-mediated signal transduction [195] . On the downside, organization or entity with a financial interest in or financial conflict with few GWAS findings have been replicated and it appears that vari- the subject matter or materials discussed in the manuscript. This includes ants in several genes interact with each other, and possibly with employment, consultancies, honoraria, stock ownership or options, expert environmental and lifestyle factors, to influence refractive error. testimony, grants or patents received or pending, or royalties. Elucidating the genetic causes of chronic diseases such as myopia No writing assistance was utilized in the production of this manuscript.

78 Expert Rev. Ophthalmol. 8(1), (2013) Update on the epidemiology & genetics of myopic refractive error Review

Key issues • Myopia is a complex and heterogeneous ocular disorder. • Some individuals develop myopia through inheriting a single gene mutation, whereas in others myopia is probably due to the action of multiple genetic and/or environmental actions. • Most recent success in understanding the genetic etiology of nonsyndromic myopic refractive error has been in high myopia. • More than 20 susceptibility loci have been mapped for myopia; genome-wide association studies and candidate gene studies have implicated several gene variants. • Several of the genes associated with myopia code for an extracellular matrix component, consistent with its role in influencing eye structure and development. • Myopia is strongly associated with level of education in the context of increasing urbanization and reduction in time spent outdoors, but support-linking myopia to increased near work is less convincing. • Evidence from studies in humans supporting a gene–environment interaction is not strong, but evidence from animal studies is stronger.

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