Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: the CREAM Consortium. Fan Q, Wojciechowski R, Kamran Ikram M, et al. Several genes for secondary syndromic myopia overlap with those for common myopia. The main goal of GWAS is to improve insight on the molecules involved in disease, and help identify disease mechanisms. Therefore, reducing miR-328 may be a potential strategy for preventing or treating myopia.61 Another study focused on miR-184. Morgan IG, Rose KA. Wojciechowski R, Congdon N, Bowie H, Munoz B, Gilbert D, West SK. Verhoeven, None; C.C.W. . The secondary syndromic myopias are generally monogenic and have a wide spectrum of clinical presentations. For myopia, a retina-to-sclera signaling cascade had been proposed for many years (see accompanying paper IMI Report on Experimental Models of Emmetropization and Myopia103), but knowledge on its molecular drivers was limited. 23andMe also replicated GJD2, RASGRF1, and RFBOX1 and identified 11 new loci: BMP3, BMP4, DLG2, DLX1, KCNMA1, LRRC4C, PABPCP2, PDE11A, RGR, ZBTB38, ZIC2.89 Of the 22 loci discovered by CREAM, 8 were replicated by 23andMe, and 16 of the 20 loci identified by 23andMe were confirmed by CREAM. 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 parameters.18,19 Correlations between corneal curvature and axial length were at least 64%,20 suggesting a considerable genetic overlap between the parameters. ZNF644.118,119 Although most genetic variants displayed an autosomal dominant hereditary pattern,108,112,118,119 X-linked heterozygous mutations were identified in ARR3, only in female family members.114 The functions of these novel genes include DNA transcription (CCDC111, ZNF644), mitochondrial function (NDUFAF7, SCO2), collagen synthesis (P4HA2), cell signaling (UNC5D, BSG), retina-specific signal transduction (ARR3), TGF-beta pathway (LOXL3, SLC39A5, LRPAP1), and degradation of proteins in lysosomes (CTSH). 3). Is nearsightedness genetic? What causes myopia - Medical News Today APLP2 regulates refractive error and myopia development in mice and humans. Table 4 summarizes all studies that reported statistically significant associations for myopia or ocular refraction. Focusing in on the complex genetics of myopia. A novel genetic variant of BMP2K contributes to high myopia. = 85,757; all European ancestry), and identified more than 100 novel loci for myopia.79 Because this study was intended for association analyses between traits, precise locus definitions, post-GWAS quality control, and replication were not performed. Han S, Chen P, Fan Q, et al. Xie et al.151 analyzed rs157907 A/G in miR-29a and rs10877885 C/T in let-7i in a severe myopia case-control study (Ncases = 254; Ncontrols = 300). Peet JA, Cotch M-F, Wojciechowski R, Bailey-Wilson JE, Stambolian D. Heritability and familial aggregation of refractive error in the Old Order Amish. Careers, Unable to load your collection due to an error. Annotated genes have a wide variety of functions, and all retinal layers appear to be sites of expression. Lopes MC, Andrew T, Carbonaro F, Spector TD, Hammond CJ. IMI 2021 Yearly Digest - PMC - National Center for Biotechnology Stambolian D, Ibay G, Reider L, et al. Comprehensive replication of the relationship between myopia-related genes and refractive errors in a large Japanese cohort. Li et al.73 studied 102 high myopia cases (defined as 8 D with retinopathy) and 335 controls in an ethnic Chinese population. Invest Ophthalmol Vis Sci. PAX6 gene associated with high myopia: a meta-analysis. A twin study on myopia in Chinese school children. Replication validity of genetic association studies. Association of high myopia with crystallin beta A4 (CRYBA4) gene polymorphisms in the linkage-identified MYP6 locus. HTRA1 promoter polymorphism in wet age-related macular degeneration. Zhou X, Ji F, An J, et al. IMI-Management and Investigation of High Myopia in Infants and Young Children. John Hopkins University. The genetic loci appear to play a role in synaptic transmission, cell-cell adhesion, calcium ion binding, cation channel activity, and the plasma membrane. Currently, three studies have been published on MR in refractive error and myopia. Animal models are often used as a first step before moving to humans, although epigenetic processes are not always conserved across species. Han W, Leung KH, Fung WY, et al. Detection of mutations in LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 in 298 families with early-onset high myopia by exome sequencing. Editorial: International Myopia Institute White Paper Series 2023 Guggenheim JA, Pong-Wong R, Haley CS, Gazzard G, Saw SM. Even so, polygenic risk scores, which are constructed by the sum of effect sizes of all risk variants per individual depending on their genotypes, were well able to distinguish individuals with hyperopia from those with myopia at the lower and higher deciles. Ciner E, Ibay G, Wojciechowski R, et al. Magda A Meester-Smoor; Several genes for secondary syndromic myopia overlap with those for common myopia. Wang B, Liu Y, Chen S, et al. Andrew T, Maniatis N, Carbonaro F, et al. sharing sensitive information, make sure youre on a federal Although sometimes highly effective, this approach is limited by its reliance on existing knowledge. Association of PAX6 polymorphisms with high myopia in Han Chinese nuclear families. Hammond CJ, Andrew T, Mak YT, Spector TD. Angi MR, Clementi M, Sardei C, Piattelli E, Bisantis C. Heritability of myopic refractive errors in identical and fraternal twins. A high genetic correlation between European and Asian individuals (>0.78) was found, implying that the genetic architecture of refractive error is quite similar for European and Asian individuals. Inclusion in an NLM database does not imply endorsement of, or agreement with, Study of association of PAX6 polymorphisms with susceptibility to high myopia in a Japanese population. They represent other changes of the helix structure, such as DNA methylation and histone modification,143 and these changes can regulate gene expression. Ku CS, Loy EY, Pawitan Y, Chia KS. Coordinated genetic scaling of the human eye: shared determination of axial eye length and corneal curvature. Founded by BHVI. Full-text available. Annotated genes have a wide variety of functions, and all retinal layers appear to be sites of expression. The role of microRNAs in myopia. 2019; 60: M89-M105. Because several studies had proposed that vitamin D has a protective effect against myopia,140142 the third MR study investigated the causality of low vitamin D concentrations on myopia. IMI - Myopia Genetics Report CREAM Consortium, Milly S. Tedja, Annechien E. G. Haarman, Magda A. Meester-Smoor, Jaakko Kaprio , Juho Wedenoja Institute for Molecular Medicine Finland IMI - Myopia Genetics Report M. Tedja, A. E. Haarman, +6 authors C. Klaver Published 1 February 2019 Biology Investigative Ophthalmology & Visual Science The knowledge on the genetic background of refractive error and myopia has expanded dramatically in the past few years. LOXL3,115 Liu H-P, Lin Y-J, Lin W-Y, et al. National Center for Biotechnology Information. We performed an extensive literature search and conducted informal discussions with key stakeholders. Education and myopia: assessing the direction of causality by mendelian randomisation. This Committee recommends expanding large-scale, in-depth genetic studies using complementary big data analytics, consideration of gene-environment effects by thorough measurement of environmental exposures, and focus on subgroups with extreme phenotypes and high familial occurrence. Overview of Secondary Syndromic Forms of Myopia: Ocular Syndromes Associated With Myopia. GWAS for myopia have been performed using myopia as a dichotomous outcome or refractive error as a quantitative trait. The G allele of the rs157907 locus was significantly associated with decreased risk of severe myopia (P = 0.04), launching the hypothesis that rs157907 A/G might regulate miR-29a expression levels. Estimating heritability and shared environmental effects for refractive error in twin and family studies. Crossref; PubMed; Scopus (102) Google Scholar; P value was calculated using the chi-square test or exact test (myopia parents) for categorical variables and the t test (GRS, age at inclusion, and age of stabilization) or Mann-Whitney U test (RE, AL, age of . Similar results were observed in data from the UK Biobank study (N = 67,798); MR was performed and causality of education was tested for myopic refractive error bi-directionally.139 Genetic variants for years of education from Social Science Genetic Association Consortium (SSGAC) and 23andMe studies were considered. The COL1A1 gene and high myopia susceptibility in Japanese. The genetic variant was located at the 3-UTR of PAX6, which is decreased in myopia. Lin H-J, Wan L, Tsai Y, Chen W-C, Tsai S-W, Tsai F-J. Wojciechowski R, Hysi PG. Tsai Y-Y, Chiang C-C, Lin H-J, Lin J-M, Wan L, Tsai F-J. Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG. A experiment using monocular form deprivation in a mouse model found that hypermethylation of CpG sites in the promoter/exon 1 of COL1A1 may underlie reduced collagen synthesis at the transcriptional level in myopic scleras.146 A human study analyzing myopic individuals found that methylation of the CpG sites of the CRYAA promotor leads to lower expression of CRYAA in human lens epithelial cells.147. Polygenic risk scores show overrepresentation of high myopia in the higher deciles of risk. High-throughput next-generation sequencing technologies and high-resolution genome-wide epigenetic profiling platforms are still under development, and accessibility of RNA expression in human ocular tissues145 is limited. Smith GD, Ebrahim S. Mendelian randomization: prospects, potentials, and limitations. Following two-stage replication in three independent cohorts, the most significantly associated variant (P = 8.95 1014) was identified in the vasoactive intestinal peptide receptor 2 (VIPR2) gene within the MYP4 locus, followed by three other variants within a linkage disequilibrium block in the syntrophin beta 1 (SNTB1) gene (P = 1.13 108 to 2.13 1011). Mishra A, Yazar S, Hewitt AW, et al. Xie M, Li Y, Wu J, Wu J. IMI - Myopia Genetics Report (CREAM Consortium) Tedja, Milly S.; Haarman, Annechien E. G.; Meester-Smoor, Magda A.; Kaprio, Jaakko; Mackey, David A.; Guggenheim, Jeremy A.; Hammond, Christopher J.; Verhoeven, Virginie J. M.; Klaver, Caroline C. W.; for the CREAM Consortium The researchers found a novel genetic variant in the coiled-coil domain containing 102B (CCDC102B) locus (P = 1.461010), which was subsequently replicated in an independent cohort (P=2.40106). Genomewide scan in Ashkenazi Jewish families demonstrates evidence of linkage of ocular refraction to a QTL on chromosome 1p36. This was surprising, as the studies used very different phenotyping methods. Genes are estimated to explain up to 80% of the variance in refractive error. The current genetic findings offer a world of new molecules involved in myopiagenesis. An integrated map of genetic variation from 1,092 human genomes. 1 author 2. The importance of genes and environment for ocular refraction and its determiners: a population based study among 2045 year old twins. Based on literature, heritability of myopia is probably between 60% and 80%. IMI - Myopia Genetics Report. - Abstract - Europe PMC A susceptibility locus for myopia in the normal population is linked to the PAX6 gene region on chromosome 11: a genomewide scan of dizygotic twins. Haarman, None; M.A. Editorial: International Myopia Institute White Paper Series 2023 Genetic variants on chromosome 1q41 influence ocular axial length and high myopia. Chen K-C, Hsi E, Hu C-Y, Chou W-W, Liang C-L, Juo S-HH. Fan Q, Guo X, Tideman JWL, et al. Correlations in refractive errors between siblings in the Singapore Cohort Study of Risk factors for myopia. CCDC102B confers risk of low vision and blindness in high myopia. Heritability statistics can be used to estimate the proportion of variation in a phenotypic trait of a population that is due to genetics, and further details can be found in the accompanying IMI - Myopia Genetics Report. Overview of SNPs and annotated genes found in the most recent GWAS meta-analysis.24 The x-axis displays the minor allele frequency of each SNP; y-axis displays the effect size of the individual SNP in diopters; We transformed the z-scores of the fixed effect meta-analysis between CREAM (refractive error) and 23andMe (age of diagnosis of myopia . 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. [PDF] IMI - Myopia Genetics Report | Semantic Scholar Exomes are interesting, as they directly contribute to protein translation, but they constitute only approximately 1% of the entire genome. A. PAX6 gene polymorphism is associated with genetic predisposition to extreme myopia. IMI Myopia Genetics Report - Myopia Institute A study investigating GxE interactions in children and the major environmental risk-factors, nearwork, time outdoors, and 39 SNPs derived from the CREAM meta-GWAS revealed nominal evidence of interaction with nearwork (top variant in ZMAT4).133,134. Lam DSC, Lee WS, Leung YF, et al. Another caveat not specific for this approach is that genetic variability across populations can make it difficult to distinguish normal variation from disease-associated variation.13 In addition, candidate gene studies are very prone to publication bias, and therefore published results are highly selected. Exact mechanisms by which these genes function in a retina-to-sclera signaling cascade and other potential pathways remain to be elucidated. The heritability of ocular traits. To date, WGS has not been conducted for myopia or refractive error, most likely due to the reasons mentioned above. Thank you to Nicole Liu for her professional assistance in this summary. Functional characterization of associated variants is simultaneously needed to bridge the knowledge gap between sequence variance and consequence for eye growth. As most of the phenotypic variance of refractive errors is still unexplained, larger sample sizes are required with deeper coverage of the genome. The conclusion from these studies was that education appears truly causally related to myopia, and effects calculated by the current observational studies may be underestimated. Nishizaki R, Ota M, Inoko H, et al. Klaver, Bayer (C), Novartis (C), Optos (C), Topcon (F), Thea Pharma (C), Joan E. Bailey-Wilson,1 Paul Nigel Baird,2 Amutha Barathi Veluchamy,35 Ginevra Biino,6 Kathryn P. Burdon,7 Harry Campbell,8 Li Jia Chen,9 Ching-Yu Cheng,1012 Emily Y. Chew,13 Jamie E. Craig,14 Phillippa M. Cumberland,15 Margaret M. Deangelis,16 Ccile Delcourt,17 Xiaohu Ding,18 Cornelia M. van Duijn,19 David M. Evans,2022 Qiao Fan,23 Maurizio Fossarello,24 Paul J. Foster,25 Puya Gharahkhani,26 Adriana I. Iglesias,19,27,28 Jeremy A. Guggenheim,29 Xiaobo Guo1,8,30 Annechien E. G. Haarman,19,28 Toomas Haller,31 Christopher J. Hammond,32 Xikun Han,26 Caroline Hayward,33 Mingguang He,2,18 Alex W. Hewitt,2,7,34 Quan Hoang,3,35 Pirro G. Hysi,32 Robert P. Igo Jr.,36 Sudha K. Iyengar,3638 Jost B. Jonas,39,40 Mika Khnen,41,42 Jaakko Kaprio,43,44 Anthony P. Khawaja,25,45 Caroline C. W. Klaver,19,28,46 Barbara E. Klein,47 Ronald Klein,47 Jonathan H. Lass,36,37 Kris Lee,47 Terho Lehtimki,48,49 Deyana Lewis,1 Qing Li,50 Shi-Ming Li,40 Leo-Pekka Lyytikinen,48,49 Stuart MacGregor,26 David A. Mackey,2,7,34 Nicholas G. Martin,51 Akira Meguro,52 Andres Metspalu,31 Candace Middlebrooks, Masahiro Miyake,53 Nobuhisa Mizuki,52 Anthony Musolf,1 Stefan Nickels,54 Konrad Oexle,55 Chi Pui Pang,9 Olavi Prssinen,56,57 Andrew D. Paterson,58 Norbert Pfeiffer,54 Ozren Polasek,59,60 Jugnoo S. Rahi,1,5,25,61 Olli Raitakari,62,63 Igor Rudan,8 Srujana Sahebjada,2 Seang-Mei Saw,64,65 Dwight Stambolian,66 Claire L. Simpson,1,67 E-Shyong Tai,65 Milly S. Tedja,19,28 J. Willem L. Tideman,19,28 Akitaka Tsujikawa,53 Virginie J. M. Verhoeven,19,27,28 Veronique Vitart,33 Ningli Wang,40 Juho Wedenoja,43,68 Wen Bin Wei,69 Cathy Williams,22 Katie M. Williams,32 James F. Wilson,8,33 Robert Wojciechowski1,70,71 Ya Xing Wang,40 Kenji Yamashiro,72 Jason C. S. Yam,9 Maurice K. H. Yap,73 Seyhan Yazar,34 Shea Ping Yip,74 Terri L. Young,47 Xiangtian Zhou75, 1Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States, 2Centre for Eye Research Australia, Ophthalmology, Department of Surgery, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia, 3Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, 4DUKE-NUS Medical School, Singapore, Singapore, 5Department of Ophthalmology, National University Health Systems, National University of Singapore, Singapore, 6Institute of Molecular Genetics, National Research Council of Italy, Pavia, Italy, 7Department of Ophthalmology, Menzies Institute of Medical Research, University of Tasmania, Hobart, Australia, 8Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom, 9Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital, Kowloon, Hong Kong, 10Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 11Ocular Epidemiology Research Group, Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, 12Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), DUKE-NUS Medical School, Singapore, 13Division of Epidemiology and Clinical Applications, National Eye Institute/National Institutes of Health, Bethesda, Maryland, United States, 14Department of Ophthalmology, Flinders University, Adelaide, Australia, 15Great Ormond Street Institute of Child Health, University College London, London, United Kingdom, 16Department of Ophthalmology and Visual Sciences, John Moran Eye Center, University of Utah, Salt Lake City, Utah, United States, 17Universit de Bordeaux, INSERM, Bordeaux Population Health Research Center, Team LEHA, UMR 1219, F-33000 Bordeaux, France, 18State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China, 19Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands, 20Translational Research Institute, University of Queensland Diamantina Institute, Brisbane, Queensland, Australia, 21MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom, 22Department of Population Health Sciences, Bristol Medical School, Bristol, United Kingdom, 23Centre for Quantitative Medicine, DUKE-National University of Singapore, Singapore, 24University Hospital San Giovanni di Dio,' Cagliari, Italy, 25NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, United Kingdom, 26Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia, 27Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands, 28Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands, 29School of Optometry & Vision Sciences, Cardiff University, Cardiff, United Kingdom, 30Department of Statistical Science, School of Mathematics, Sun Yat-Sen University, Guangzhou, China, 31Institute of Genomics, University of Tartu, Tartu, Estonia, 32Section of Academic Ophthalmology, School of Life Course Sciences, King's College London, London, United Kingdom, 33MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom, 34Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia, 35Department of Ophthalmology, Columbia University, New York, United States, 36Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, United States, 37Department of Ophthalmology and Visual Sciences, Case Western Reserve University and University Hospitals Eye Institute, Cleveland, Ohio, United States, 38Department of Genetics, Case Western Reserve University, Cleveland, Ohio, United States, 39Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Mannheim, Germany, 40Beijing Tongren Eye Center, Beijing Tongren Hospital, Beijing Institute of Ophthalmology, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Capital Medical University, Beijing, China, 41Department of Clinical Physiology, Tampere University Hospital and School of Medicine, University of Tampere, Tampere, Finland, 42Finnish Cardiovascular Research Center, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland, 43Department of Public Health, University of Helsinki, Helsinki, Finland, 44Institute for Molecular Medicine Finland FIMM, HiLIFE Unit, University of Helsinki, Helsinki, Finland, 45Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom, 46Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands, 47Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States, 48Department of Clinical Chemistry, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland, 49Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere, Tampere, Finland, 50National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, United States, 51Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia, 52Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan, 53Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan, 54Department of Ophthalmology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany, 55Institute of Neurogenomics, Helmholtz Zentrum Mnchen, German Research Centre for Environmental Health, Neuherberg, Germany, 56Department of Ophthalmology, Central Hospital of Central Finland, Jyvskyl, Finland, 57Gerontology Research Center, Faculty of Sport and Health Sciences, University of Jyvskyl, Jyvskyl, Finland, 58Program in Genetics and Genome Biology, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada, 60University of Split School of Medicine, Soltanska 2, Split, Croatia, 61Ulverscroft Vision Research Group, University College London, London, United Kingdom, 62Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland, 63Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland, 64Myopia Research Group, Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, 65Saw Swee Hock School of Public Health, National University Health Systems, National University of Singapore, Singapore, 66Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States, 67Department of Genetics, Genomics and Informatics, University of Tennessee Health Sciences Center, Memphis, Tennessee, United States, 68Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland, 69Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Ophthalmology & Visual Sciences Key Lab, Beijing Tongren Hospital, Capital Medical University, Beijing, China, 70Department of Epidemiology and Medicine, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States, 71Wilmer Eye Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States, 72Department of Ophthalmology, Otsu Red Cross Hospital, Nagara, Japan, 73Centre for Myopia Research, School of Optometry, The Hong Kong Polytechnic University, Hong Kong, 74Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, 75School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, China, National Library of Medicine