近视遗传学报告（英文版）.pdf

Special Issue IMI Myopia Genetics Report Milly S. Tedja, 1,2 Annechien E. G. Haarman, 1,2 Magda A. Meester-Smoor, 1,2 Jaakko Kaprio, 3,4 David A. Mackey, 57 Jeremy A. Guggenheim, 8 Christopher J. Hammond, 9 Virginie J. M. Verhoeven, 1,2,10 and Caroline C. W. Klaver 1,2,11 ; for the CREAM Consortium 1 Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands 2 Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands 3 Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland 4 Department of Public Health, University of Helsinki, Helsinki, Finland 5 Centre for Eye Research Australia, Ophthalmology, Department of Surgery, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia 6 Department of Ophthalmology, Menzies Institute of Medical Research, University of Tasmania, Hobart, Tasmania, Australia 7 Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia 8 School of Optometry and Vision Sciences, Cardiff University, Cardiff, United Kingdom 9 Section of Academic Ophthalmology, School of Life Course Sciences, Kings College London, London, United Kingdom 10 Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands 11 Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands Correspondence: Caroline C. W. Klaver, Erasmus Medical Center, Room Na-2808, P.O. Box 2040, 3000 CA, Rotterdam, the Netherlands; c.c.w.klavererasmusmc.nl. MST and AEGH contributed equally to the work presented here and should therefore be regarded as equivalent first authors. VJMV and CCWK contributed equally to the work presented here and should therefore be regarded as equivalent senior authors. See the appendix for the members of the CREAM Consortium. Submitted: October 12, 2018 Accepted: January 9, 2019 Citation: Tedja MS, Haarman AEG, Meester-Smoor MA, et al.; for the CREAM Consortium. IMI Myopia Genetics Report. Invest Ophthalmol Vis Sci. 2019;60:M89M105. doi/10.1167/iovs.18-25965 The knowledge on the genetic background of refractive error and myopia has expanded dramatically in the past few years. This white paper aims to provide a concise summary of current genetic findings and defines the direction where development is needed. We performed an extensive literature search and conducted informal discussions with key stakeholders. Specific topics reviewed included common refractive error, any and high myopia, and myopia related to syndromes. To date, almost 200 genetic loci have been identified for refractive error and myopia, and risk variants mostly carry low risk but are highly prevalent in the general population. Several genes for secondary syndromic myopia overlap with those for common myopia. Polygenic risk scores show overrepresentation of high myopia in the higher deciles of risk. Annotated genes have a wide variety of functions, and all retinal layers appear to be sites of expression. The current genetic findings offer a world of new molecules involved in myopiagenesis. As the missing heritability is still large, further genetic advances are needed. This Committee recommends expanding large-scale, in-depth genetic studies using complementary big data analytics, consideration of gene-environment effects by thorough measurement of environ- mental exposures, and focus on subgroups with extreme phenotypes and high familial occurrence. Functional characterization of associated variants is simultaneously needed to bridge the knowledge gap between sequence variance and consequence for eye growth. Keywords: myopia, refractive error, genetics, GWAS, GxE interactions 1. SUMMARY F or many years, it has been recognized that myopia is highly heritable, but only recently has significant progress been made in dissecting the genetic background. In particular genome-wide association studies (GWAS) have successfully identified many common genetic variants associated with myopia and refractive error. It is clear that the trait is complex, with many genetic variants of small effect that are expressed in all retinal layers, often with a known function in neurotrans- mission or extracellular matrix. Exact mechanisms by which these genes function in a retina-to-sclera signaling cascade and other potential pathways remain to be elucidated. The prediction of myopia from genetic risk scores is improving, but whether this knowledge will affect clinical practice is yet unknown. This Committee recommends expanding large-scale genetic studies to further identify the molecular mechanisms through which environmental influences cause myopia (gene- by-environment effects), with an ultimate view to develop targeted treatments. 2. KEY POINTS 1. Refractive errors including myopia are caused by a complex interplay between many common genetic factors and environmental factors (near work, outdoor exposure). 2. Early linkage studies and candidate gene studies have identified up to 50 loci and genes, but findings remained mostly unverified in replication studies. Copyright 2019 The Authors iovs.arvojournals j ISSN: 1552-5783 M89 This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from iovs.arvojournals on 03/01/2019 3. Large consortia performing GWAS enabled identifica- tion of common genetic variants associated with refractive error and myopia. 4. The Consortium for Refractive Error and Myopia (CREAM) and 23andMe published findings from GWAS separately, and later combined studies in a GWAS meta- analysis, identifying 161 common variants for refrac- tive error but explaining only approximately 8% of the phenotypic variance of this trait. 5. Polygenic risk scores based on these variants indicate that persons at high genetic risk have an up to 40 times increased risk of myopia compared with persons at low genetic risk. 6. The genetic loci appear to play a role in synaptic transmission, cell-cell adhesion, calcium ion binding, cation channel activity, and the plasma membrane. Many are light-dependent and related to cell-cycle and growth pathways. 7. Pathway analysis confirms the hypothesis for a light- induced retina-to-sclera signaling pathway for myopia development. 8. Genome-environment-wide interaction studies (GE- WIS) assessing variant 3 education interaction effects identified nine other loci. Evidence for statistical interaction was also found; those at profound genetic risk with higher education appeared particularly susceptible to developing myopia. 9. As most of the phenotypic variance of refractive errors is still unexplained, larger sample sizes are required with deeper coverage of the genome. 10. The ultimate aim of genetic studies is to discern the molecular signaling cascade and open up new avenues for intervention. 3. INTRODUCTION Although myopia is strongly determined by environmental factors, the trait has long been known to run in families, suggesting a genetic predisposition. The heritability of refractive error, using spherical equivalent as a quantitative trait, has been determined in a number of families and twin studies. 18 The estimates resulting from these studies calculat- ed heritabilities from 15% to 98%. 5,710 However, it is important to note that this does not necessarily imply that most refractive error is genetic; familial clustering also can be determined by other factors. 11 Like many other traits, common myopia has a complex etiology that is influenced by an interplay of genetic and environmental factors. 12 The current evidence, as summarized in this review, indicates that it is likely to be caused by many genes, each contributing a small effect to the overall myopia risk. The evidence for this has been confirmed by large GWAS. 15,7,13,14 Several high, secondary syndromic forms of myopia, such as Marfan, Stickler, and Donnai-Barrow, form the exception, as they inherit predominantly in a Mendelian fashion with one single, highly penetrant, causal gene. 15 This white paper aims to address the recent developments in genetic dissection of common refractive errors, in particular myopia. Up until the era of GWAS, identification of disease- associated genes relied on studies using linkage analysis in families or investigating variants in candidate genes. In myopia, these were singularly unsuccessful, and before 2009, there were no genes known for common myopia occurring in the general population. However, with the advent of GWAS, many refractive error genes associated with myopia have been identified, providing potential new insights into the molecular machinery underlying myopia, and perhaps promising leads for future therapies. 4. HERITABILITY Eighty years ago, Sir Duke-Elder was one of the first to recognize a hereditary tendency to myopia. 16 Since then, evidence for familial aggregation has been delivered by various familial clustering, twin, and offspring studies, 14 and a genetic predisposition became more widely recognized. Strikingly, the estimates of myopia heritability vary widely among studies, with values as low as 10% 9,10 found in a parent-offspring study in Eskimos, to as high as 98% in a study of female twin pairs 5,7,8 (Table 1). Differences in study design and method of analysis may account for this, but it is also conceivable that the phenotypic variance determined by heritable factors is high in settings in which environmental triggers are limited, and low where they are abundant. Based on literature, heritability of myopia is probably between 60% and 80%. Variation in corneal curvature and axial length contribute to the degree of myopia. 17 Twin studies also estimated a high heritability for most of the individual biometric parame- ters. 18,19 Correlations between corneal curvature and axial length were at least 64%, 20 suggesting a considerable genetic overlap between the parameters. Studies addressing the inheritance structure of myopia and its endophenotypes identified several models, mostly a combination of additive genetic and environmental ef- fects. 6,18,21,22 Genome-wide complex trait analysis, using high-density genome-wide single-nucleotide polymorphism (SNP) genotype information, was performed in young children from the Avon Longitudinal Study of Parents and Children (ALSPAC), and results suggested that common SNPs explained approximately 35% of the variation in refractive error between unrelated subjects. 23 SNP heritability calculated by linkage disequilibrium score regression in the CREAM Consortium was 21% in European individuals but only 5% in Asian individuals, which could be due to the low representation of this ancestry. 24 In conclusion, the genetic component of myopia and ocular biometry is well recognized, but its magnitude varies in studies depending on the population being studied, the study design, and the methodology. It is important to note that the recent global rise of myopia prevalence is unlikely to be due to genetic factors, but the degree of myopia may still be under genetic control. 25 5. LINKAGE STUDIES A number of linkage studies for myopia were performed in families and high-risk groups before the GWAS era (Fig. 1). 26 Linkage studies have searched for cosegregation of genetic TABLE 1. Heritability Estimates of Refractive Error Subjects Study Heritability Estimate (6SE or 95% CI) Monozygous and dizygous twin pairs Dirani et al. 2006 6 0.88 6 0.02 (men) (SE) Hammond et al. 2001 21 0.86 (0.830.89) Lyhne et al. 2001 7 0.890.94 (0.820.96) Sibling pair Guggenheim et al. 2007 152 0.90 (0.621.12) Peet et al. 2007 153 0.69 (0.580.85) Full pedigree Klein et al. 2009 19 0.62 6 0.13 Parent-offspring pair Lim et al. 2014 154 0.30 (0.270.33) IMI Myopia Genetics Report IOVS j Special Issue j Vol. 60 j No. 3 j M90 Downloaded from iovs.arvojournals on 03/01/2019 markers (such as cytosine-adenine CA repeats) with the trait through pedigrees, and has been successfully applied for many Mendelian disorders. 27 In families with an autosomal dominant inheritance pattern of myopia, this approach helped to identify several independent loci for (high) myopia: MYP 1 to 20, 26,2830 as well as several other loci. 3136 Fine-mapping of several of these loci led to candidate genes, such as the IGF1 gene located in the MYP3 locus. 12 Although validation of the same markers failed in these candidate genes, other variants appeared associated with common myopia, suggesting genetic overlap between Mendelian and complex myopia. 37 Linkage studies using a complex inheritance design found five additional loci. 3842 With the development of new approaches for gene finding, linkage analysis with CA-markers became unfashionable. Nevertheless, segregation and linkage analysis of a variant or region in pedigrees is still a common procedure for fine- mapping or dissection of disease haplotypes. 6. SECONDARY SYNDROMIC MYOPIA Myopia can accompany other systemic or ocular abnormalities. The secondary syndromic myopias are generally monogenic and have a wide spectrum of clinical presentations. Table 2 summarizes the known syndromic conditions that present with myopia, and Table 3 summarizes the known ocular conditions. 43 Among these disorders are many mental retarda- tion syndromes, such as Angelman (Online Mendelian Inher- itance in Man database OMIM #105830), Bardet-Biedl (OMIM #209900), and Cohen (OMIM #216550) and Pitt-Hopkins syndrome (OMIM #610954). Myopia also can be a character- istic feature in heritable connective tissue disorders, such as Marfan (OMIM #154700), Stickler (OMIM #108300, #604841, #614134, #614284), and Weill-Marchesani syndrome (OMIM #277600, #608328, #614819, #613195), and several types of Ehlers-Danlos syndrome (OMIM #225400, #601776). A number of inherited retinal dystrophies also present with myopia, most strikingly X-linked retinitis pigmentosa caused by mutations in the RPGR-gene (retinal G proteincoupled receptor) (see Ref. 44 for common gene acronyms) and congenital stationary night blindness. 45 Other eye disorders accompanied by myopia are ocular albinism (OMIM #300500) and Wagner vitreoretinopathy (OMIM #143200). Most genes causing syndromic forms of myopia have not (yet) been implicated in common forms of myopia, except for collagen type II alpha 1 chain (COL2A1) 46,47 and fibrilin 1 (FBN1). 24,48 However, a recent study screened polymorphisms located in and around genes known to cause rare syndromic myopia, and found them to be overrepresented in GWASs on refractive error and myopia. 49 This implies that although rare, pathogenic mutations in these genes have a profound impact on the eye; more benign polymorphisms may have only subtle effects on ocular biometry and refractive error. 7. CANDIDATE GENE STUDIES Candidate genes are generally selected based on their known biological, physiological, or functional relevance to the disease. Although sometimes highly effective, this