The myopic eye focuses images in front of the retina, resulting in blurred distant vision. Myopia is the most common form of refractive error and a major cause of moderate to severe visual impairment worldwide.1 Mild to moderate myopia, defined as a refractive error less than −6 diopters, can mostly be corrected by optical lenses or refractive surgeries. In contrast, high myopia, usually defined as a refractive error of −6 diopters or greater, is associated with an increased risk of blinding complications, such as retinal detachment, chorioretinal degeneration, and choroidal neovascularization, which require prompt intervention.2 High myopia contributes to 12% to 15% of the myopic population; whereas up to 70% of high myopic patients may develop serious ocular pathologies, and the risk increases with the severity of myopia.3 Thus, myopia, especially high myopia, has a great impact on public health care and socioeconomic well-being.
The occurrence of myopia is essentially related to the increase in axial length and the thinning of the posterior sclera, which may be due to both reduced collagen synthesis and increased collagen degradation.2,4 Animal studies in chicken, fish, tree shrews, marmosets, rhesus monkeys, and guinea pigs revealed that blurred vision caused by form deprivation or minus lens rearing resulted in myopic growth of the sclera.5 In humans, several environmental factors have been identified for myopia, such as less time spent on outdoor activities, higher education, near work, urban living environment, and off-axis refraction.6–10 Among these, less outdoor activity is a major risk factor for myopia,6,7,9,10 and increased outdoor activity has been effective in controlling myopia progression.11 In addition, genetic factors also play a role in myopia. In recent years, a number of genomic studies conducted in the Asia-Pacific region, where the occurrence of myopia is higher than in other parts of the world, have led to discoveries of important genetic information. To date, more than 20 chromosomal loci and more than 100 gene variants have been reported for myopia by linkage analyses, candidate gene or genome-wide association studies (GWAS), and whole-exome sequencing.12–14
So far, the exact mechanism of myopia is incomplete, and the difference in myopia prevalence across populations has yet to be fully explained. In the Asia-Pacific region, higher prevalence was found in Koreans, Japanese, and Chinese,15 with the prevalence up to 84% in school-aged children16 and 95% in university students17 compared with less than 30% in the Australian population of European ancestry.15 Such differences might be explained by the multifactorial basis of myopia8,18–20; the interactions between personal, environmental, and genetic factors; or the variations in study design and conduct. However, there is still a need to search for a more complete explanation.
This review is an attempt to summarize the major findings in myopia genetics with a focus on the differences in allelic frequencies of gene variants associated with myopia in different ethnic groups, especially in the Asia-Pacific region. The role of genetic predisposition, environmental factors, and their interactions in myopia pathogenesis will also be discussed.
Studies on identical twins21–24 and parent-siblings25 have revealed familial aggregation of myopia, indicating a major role of inheritance in refractive errors and related endophenotypes. Among 1224 white twin pairs in Australia, Dirani et al22 found that the heritability of spherical equivalent was 88% and 75% in men and women, respectively, and for axial length was 94% and 92%, respectively. In the Guangzhou Twin Eye Study, He’s group analyzed 459 Chinese twin pairs and found the heritability of anterior chamber depth to be 89% and angle opening distance to be 70%, with 25% and 13%, respectively, of shared genetic factors with axial length.23
In addition, both population-based cross-sectional and longitudinal studies in schoolchildren have provided evidence that support the genetic basis of myopia. Parental history of myopia is associated with higher likelihood of myopia,26 along with a rapid growth rate and myopic shift.27 Furthermore, even before the onset of juvenile myopia, children of myopic parents are prone to have longer eyes, resembling the elongated eye present in myopia.28 Genetic susceptibility plays a role in the initial shape and subsequent growth of the eye. On the other hand, because the correlation is not absolute between identical twins and the correlation weakens in ametropia, particularly in high myopia,29 refractive errors are not completely genetically determined and can involve the effects of other risk factors, such as intrauterine complications, living environment, and personal factors including near work and outdoor activities.24,25,30
In this review, although we focus on the genetics of nonsyndromic myopia, it should be noted that there is a group of patients experiencing syndromic myopia, namely, myopia associated with an ocular or systemic syndrome. These syndromes usually have stronger genetic determinants. Reported genes for myopia-related syndromes include (1) congenital night blindness [NYX (OMIM 300278),31,32CACNA1F (OMIM 300110),33,34GRM6 (OMIM 604096),35,36 and LRIT3 (OMIM 615004)]37; (2) Down syndrome (21 trisomy)38 and Hirschsprung disease [ZEB2 (OMIM 605802)]39; (3) homocystinuria [CBS (OMIM 613381)]40; (4) Marfan syndrome [FBN1 (OMIM 134797)]41,42; (5) retinitis pigmentosa [RP1 (OMIM 603937),43RP2 (OMIM 300757),44,45 and RPGR (OMIM 312610)]45; (6) Stickler syndrome type 1 [COL2A1 (OMIM 120140)]46 and type 2 [COL11A2 (OMIM 120280)]47; (7) Spondyloepiphyseal dysplasia congenita [COL2A1 (OMIM 120140)]48; and (8) juvenile glaucoma [MYOC (OMIM 137750)].49
In the past 2 decades, linkage analyses, candidate gene and genome-wide association studies (GWAS), and next-generation sequencing (NGS) studies have substantiated the gene mapping for nonsyndromic myopia. A number of genes and loci have been identified to be in linkage with or causative for myopia in familial cases, or associated with an increased risk of myopia in unrelated cases. In recent years, there have been a large number of studies conducted in the Asia-Pacific region, especially among the Japanese, Korean, and Chinese populations. The reported variants have been replicated to different extents in other ethnic populations, including Indians, Hispanics, and Whites.
To date, 24 chromosomal loci have been linked to myopia (Table 1). The 18p11.31 (MYP2)50 and 5p15.33-p15.2 (MYP16)51 linkage loci were identified in Hong Kong Chinese. Among the 24 loci, mutations in 6 genes have been reported as disease causing, including SCO2,52ZNF644,53CCDC111,54LRPAP1,55,56SLC39A5,57 and LEPREL1.58 Candidate gene studies have also suggested genetic association between myopia and some genes, such as TGFB59 and PAX6.60,61 However, the candidate gene approach is limited by the need of prior hypothesis and usually generates results that are not broadly replicable across different study populations.61
With the completion of the HapMap project, the development of genome-wide genotyping platforms, and advancements in programs for data analysis, GWAS has become a major method for the identification of susceptibility gene loci for common complex diseases, including myopia. So far, a total of 8 GWAS and 4 GWAS-based meta-analyses of myopia and refractive errors have been reported (Table 2). Among them, 6 GWAS and 2 meta-analyses identified approximately 40 single nucleotide polymorphisms (SNPs) within or near 31 genes/loci to be associated with high myopia,62–67 such as the BLID,62CTNND2,63MIPEP,65ZC3H11B,66VIPR2,67 and SNTB167,68 genes, and the 4q22-q27 locus.64 There are another 24 genes/loci for self-reported myopia.68 For refractive errors, 2 GWAS and 1 meta-analysis have revealed 29 associated SNPs in or near 27 genes/loci. Among them, RASGRF169,70 and GJD270,71 were reported in 2 GWAS for refractive errors. Notably, multiple genes/loci were identified for both myopia and refractive errors, including ANTXR2, KCNQ5, LAMA2, PRSS56, RASGRF1, RDH5, SHISA6, TJP2, TOX/CA8, and ZIC2.68,70 These findings reveal the shared genetic components in the molecular pathogenesis of refractive error and myopia. Of note, all GWAS on refractive errors and myopia required large sample sizes to identify small-effect SNPs, suggesting that no single gene plays a predominant role in the complex genetic basis of refractive errors and myopia.62,69,71 This is in contrast with earlier GWAS on age-related macular degeneration, which adopted small samples but successfully identified large-effect SNPs in CFH72 and ARMS2-HTRA1.73
The NGS technologies have provided a high-throughput sequence analysis platform. Whole-exome sequencing and targeted regional resequencing have become important tools for gene discovery for both familial53 and sporadic56 myopia and refractive errors. To date, NGS studies have identified causative mutations in 8 genes (ie, ZNF644, SCO2, CCDC111, SLC39A5, LEPREL1, RBP3, P4HA2, and OPN1LW) for familial high myopia52–54,57,74–77 and 6 genes (ie, CTSH, LEPREL1, SCO2, SLC39A5, ZNF644,56 and WNT7B)78 for sporadic myopia. More new genes for myopia can be anticipated when more myopic samples and pedigrees are involved in GWAS and NGS studies.
Based on the reported genes for refractive errors and myopia, several potential pathways have been highlighted by gene annotations, gene list enrichment,79 and gene network14 analyses. These included extracellular matrix remodeling (ANTXR2,68BMP2, BMP3,70 and LAMA2),68,70 neuronal signaling and development (GJD2, GRIA4, RASGRF1,70DLG2, KCNMA1, LRRC4C, RBFOX1, TJP2,68 and RBFOX1),68,70 eye and body growth (CHD7, SIX6, ZIC2,70BMP4, DLX1, ZBTB38,68 and PRSS56),68,70 retinoic acid synthesis in the retina or the visual cycle (RORB, CYP26A1,70 and RDH5/RGR),68,70 retinal ganglion cell projections (ZIC2 and ZMAT4),68 and ion transport, channel activity, and the maintenance of membrane potential (KCNQ5, CD55, CACNA1D, KCNJ2, CHRNG, and MYO1D).70 However, none of these genes or pathways has been thoroughly investigated in disease models of myopia. Therefore, studies are warranted to elaborate the role of these genes and pathways in the pathogenesis of myopia.
DIFFERENTIAL ALLELIC FREQUENCIES
It is challenging to establish a biological link between a gene variant and myopia and refractive errors. Additionally, it is difficult to interpret the drastic differences in the allelic frequencies and effect sizes of some myopia SNPs across different ethnic groups. Possible explanations include genetic drift, ethnic diversities in genetic components, population substructures, and the existence of ethnic-specific genetic variations and associations. Usually, large samples are required to provide sufficient power for detecting SNPs of mild to moderate effects. Therefore, the limited sample sizes in some studies could be a reason why an association was detected in some study populations but not in others, especially in candidate gene studies. In GWAS, effective measures have been taken to eliminate false-positive findings, such as the genomic control method,73 principal component analysis,80 replications in multiple cohorts recruited from different populations, and meta-analysis that accounts for intercohort heterogeneity. Therefore, while being a powerful platform for detecting associated variants for myopia, GWAS also provides an opportunity to identify variations of allelic diversities, in terms of allelic frequency and effect size, across different ethnic populations.
Most of the genes identified from GWAS for high myopia and related traits have been replicated in at least 1 independent population. These included the 4q25 locus81 and the RASGRF1,82,83B4GALNT2, BICC1, BMP2, BMP4, CD55, CYP26A1, EHBP1L1, GJD2, GRIA4, KCNQ5, LRRC4C, QKI, SFRP1, SH3GL2,83SHISA6, and ZIC282 genes. However, some genes or loci remain to be further replicated in other populations, including TOX,82,83RDH5,82,83PRSS56, LAMA2,83ZFHX1B,67SNTB1,67,68 and VIPR2.68 Importantly, many identified genes are heterogeneous in their associations across different ethnic groups or even within the same population. To illustrate such genetic diversities, the associations of myopia with the 11q24.1 (BLID and LOC399959) and CTNND2 loci, and of refractive errors with the 15q25 (RASGRF1 and TMED3) and 15q14 (GJD2 and ACTC1) loci, are summarized in Table 3.
The 11q24.1 locus was initially reported in Japanese for pathological myopia.62 Later, 3 replication studies were conducted in Chinese. Among them, 2 studies in Wenzhou and Guangzhou could not replicate the associations for any of the 19 tagging SNPs within the 11q24.1 locus,64,84 whereas Yu et al85 in Shanghai Chinese found SNPs rs577948 (allelic model, P = 0.029) and rs562052 (genotypic model, P = 0.028) to be marginally associated with high myopia. Of note, the A allele of rs577948 showed a protective effect against myopia in both the Wenzhou [odds ratio (OR) = 0.93] and Shanghai (OR = 0.78) cohorts, compared with a risk effect in the Guangzhou cohort (OR = 1.052) and Japanese cohort (OR = 1.37).
The CTNND2 gene was first identified for myopia in Singaporean Chinese.63 Later, Lu et al86 reported a significant association of CTNND2 rs6885224 with moderate to high myopia in Guangzhou Chinese, with the C allele conferring a protective effect (P ≤ 0.005; OR = 0.69) opposite to that in the initial GWAS (OR = 1.24).54 In a Shanghai Chinese cohort, Yu et al85did not detect a significant association of the 2 SNPs from the GWAS [ie, rs6885224 (P = 0.157) and rs12716080 (P = 0.111)] but reported a new SNP, rs1479617, to be marginally associated with myopia (P = 0.0126). Of note, the allelic frequencies of both the SNPs in Yu’s study were different from those in the Singaporean Chinese cohort63 and Guangzhou Chinese cohort (Table 3).86 However, the authors did not provide explanations for such differences.
The 15q25 (RASGRF1 and TMED3) and 15q14 (GJD2 and ACTC1) loci were initially identified for refractive errors by GWAS in white populations from the United Kingdom69 and the Netherlands,71 respectively. To replicate these findings, Schache et al tested multiple SNPs from the 2 GWAS in 1571 white individuals from the Blue Mountains Eye Study cohort in Australia. They found that only the 15q14 locus was replicable, with all tested SNPs showing comparable associations with that in the GWAS.71 In contrast, none of the SNPs at 15q25 showed a significant association with refractive errors.71 This again highlighted the difference in the association profiles of myopia and refractive errors among different study cohorts, even within the same ethnicity.
Such inconsistencies in the genetic associations could be due to variable sample sizes, variation in study designs, and diversity in the ethnic backgrounds of the study populations. Further replication studies are warranted to resolve these inconsistencies and determine the shared and population-specific variations.
ARE ETHNIC DIFFERENCES GENETIC OR ENVIRONMENTAL?
Ethnic differences also exist in the prevalence of myopia as observed in populations of different cultural affiliations, socioeconomic status, and geographical regions. Several lines of evidence from molecular genetic studies, epidemiological studies, and clinical trials have helped establish the role of both intrinsic and extrinsic components in the pathogenesis of myopia. As more genetic and environmental risk factors are identified for myopia, it is important to investigate how the genetic predisposition and environmental factors interact with one another to lead to the development of abnormal anatomical changes in myopic eyes.
Fan et al87 investigated the effects of education on the associations of 40 SNPs with refractive errors, axial length, and myopia among 8461 adults of Chinese, Malay, and Indian ancestry in Singapore. They found 3 loci—SHISA6-DNAH9 (rs2969180, P = 3.6E-6), GJD2 (rs524952, P = 1.68E-5), and ZMAT4-SFRP1 (rs2137277, P = 1.68E-4)—that exhibited a strong association with myopia in individuals with higher secondary or university education. However, the association at these loci was insignificant or of borderline significance in those with lower secondary education or below (P for interaction: 3.82E-3 to 4.78E-4).87 Moreover, this interactive effect between genetic predisposition and education was also demonstrated by Verhoeven et al88 in 2 independent population-based cohorts consisting of 5256 and 3938 individuals of European descent, respectively. Of note, the combined effect on the risk of myopia was much higher than the sum of these 2 individual effects [synergy index, 4.2; 95% confidence interval (CI), 1.9–9.5],88 suggesting an interaction rather than a simple additive effect. Similar interactions were also reported for axial length in the study by Fan et al.87
The biological effects of gene-gene and gene-environment interactions in the pathogenesis of myopia are largely unknown. Conducting an interaction study could be challenging because of difficulties in (1) the correct quantification of environmental factors and (2) the large sample sizes required to test for hundreds or even thousands of possible interactions with mild to moderate effects. Therefore, continuous efforts should be made to tackle these challenges via (1) establishing large population-based cohorts using standardized protocols and (2) building up international consortia for collaborative research.
Studies from the Asia-Pacific region have made essential contributions to the understanding of the genetic basis of myopia. Ethnic differences in allelic frequencies and association profiles are common, which should be clarified by further replication studies in various ethnic groups. Both genetic and environmental factors are important components of myopia etiology. Their interactions could have more substantial effects on the pathogenesis of myopia. With diversities in the disease burden, ethnic groups, cultural affiliations, socioeconomic status, and geographic patterns in the Asia-Pacific region, more intriguing discoveries should be anticipated in the near future under the joint efforts of multiple research institutes.
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They are ill discoverers that think there is no land, when they can see nothing but sea.
— Francis Bacon