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1. Meta-analysis of gene–environment-wide association scans accounting for education level identifies additional loci for refractive error

Author

Qiao Fan, Virginie J. M. Verhoeven, Robert Wojciechowski, Veluchamy A. Barathi, Pirro G. Hysi, Jeremy A. Guggenheim, René Höhn, Veronique Vitart, Anthony P. Khawaja, Kenji Yamashiro, S Mohsen Hosseini, Terho Lehtimäki, Yi Lu, Toomas Haller, Jing Xie, Cécile Delcourt, Mario Pirastu, Juho Wedenoja, Puya Gharahkhani, Cristina Venturini, Masahiro Miyake, Alex W. Hewitt, Xiaobo Guo, Johanna Mazur, Jenifer E. Huffman, Katie M. Williams, Ozren Polasek, Harry Campbell, Igor Rudan, Zoran Vatavuk, James F. Wilson, Peter K. Joshi, George McMahon, Beate St Pourcain, David M. Evans, Claire L. Simpson, Tae-Hwi Schwantes-An, Robert P. Igo, Alireza Mirshahi, Audrey Cougnard-Gregoire, Céline Bellenguez, Maria Blettner, Olli Raitakari, Mika Kähönen, Ilkka Seppälä, Tanja Zeller, Thomas Meitinger, Janina S. Ried, Christian Gieger, Laura Portas, Elisabeth M. van Leeuwen, Najaf Amin, André G. Uitterlinden, Fernando Rivadeneira, Albert Hofman, Johannes R. Vingerling, Ya Xing Wang, Xu Wang, Eileen Tai-Hui Boh, M. Kamran Ikram, Charumathi Sabanayagam, Preeti Gupta, Vincent Tan, Lei Zhou, Candice E. H. Ho, Wan’e Lim, Roger W. Beuerman, Rosalynn Siantar, E-Shyong Tai, Eranga Vithana, Evelin Mihailov, Chiea-Chuen Khor, Caroline Hayward, Robert N. Luben, Paul J. Foster, Barbara E. K. Klein, Ronald Klein, Hoi-Suen Wong, Paul Mitchell, Andres Metspalu, Tin Aung, Terri L. Young, Mingguang He, Olavi Pärssinen, Cornelia M. van Duijn, Jie Jin Wang, Cathy Williams, Jost B. Jonas, Yik-Ying Teo, David A. Mackey, Konrad Oexle, Nagahisa Yoshimura, Andrew D. Paterson, Norbert Pfeiffer, Tien-Yin Wong, Paul N. Baird, Dwight Stambolian, Joan E. Bailey Wilson, Ching-Yu Cheng, Christopher J. Hammond, Caroline C. W. Klaver, Seang-Mei Saw, and Consortium for Refractive Error and Myopia (CREAM)

Subjects
Science
Abstract

This report by the Consortium for Refractive Error and Myopia uses gene-environment-wide interaction study (GEWIS) to identify genetic loci that affect environmental influence in myopia development, and identifies ethnic specific genetic loci that attribute to eye refractive errors.

Published
2016
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2. APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans.

Author

Andrei V Tkatchenko, Tatiana V Tkatchenko, Jeremy A Guggenheim, Virginie J M Verhoeven, Pirro G Hysi, Robert Wojciechowski, Pawan Kumar Singh, Ashok Kumar, Gopal Thinakaran, Consortium for Refractive Error and Myopia (CREAM), and Cathy Williams

Subjects
Genetics, QH426-470
Abstract

Myopia is the most common vision disorder and the leading cause of visual impairment worldwide. However, gene variants identified to date explain less than 10% of the variance in refractive error, leaving the majority of heritability unexplained ("missing heritability"). Previously, we reported that expression of APLP2 was strongly associated with myopia in a primate model. Here, we found that low-frequency variants near the 5'-end of APLP2 were associated with refractive error in a prospective UK birth cohort (n = 3,819 children; top SNP rs188663068, p = 5.0 × 10-4) and a CREAM consortium panel (n = 45,756 adults; top SNP rs7127037, p = 6.6 × 10-3). These variants showed evidence of differential effect on childhood longitudinal refractive error trajectories depending on time spent reading (gene x time spent reading x age interaction, p = 4.0 × 10-3). Furthermore, Aplp2 knockout mice developed high degrees of hyperopia (+11.5 ± 2.2 D, p < 1.0 × 10-4) compared to both heterozygous (-0.8 ± 2.0 D, p < 1.0 × 10-4) and wild-type (+0.3 ± 2.2 D, p < 1.0 × 10-4) littermates and exhibited a dose-dependent reduction in susceptibility to environmentally induced myopia (F(2, 33) = 191.0, p < 1.0 × 10-4). This phenotype was associated with reduced contrast sensitivity (F(12, 120) = 3.6, p = 1.5 × 10-4) and changes in the electrophysiological properties of retinal amacrine cells, which expressed Aplp2. This work identifies APLP2 as one of the "missing" myopia genes, demonstrating the importance of a low-frequency gene variant in the development of human myopia. It also demonstrates an important role for APLP2 in refractive development in mice and humans, suggesting a high level of evolutionary conservation of the signaling pathways underlying refractive eye development.

Published
2015
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3. Genome-wide meta-analysis of myopia and hyperopia provides evidence for replication of 11 loci.

Author

Claire L Simpson, Robert Wojciechowski, Konrad Oexle, Federico Murgia, Laura Portas, Xiaohui Li, Virginie J M Verhoeven, Veronique Vitart, Maria Schache, S Mohsen Hosseini, Pirro G Hysi, Leslie J Raffel, Mary Frances Cotch, Emily Chew, Barbara E K Klein, Ronald Klein, Tien Yin Wong, Cornelia M van Duijn, Paul Mitchell, Seang Mei Saw, Maurizio Fossarello, Jie Jin Wang, DCCT/EDIC Research Group, Ozren Polašek, Harry Campbell, Igor Rudan, Ben A Oostra, André G Uitterlinden, Albert Hofman, Fernando Rivadeneira, Najaf Amin, Lennart C Karssen, Johannes R Vingerling, Angela Döring, Thomas Bettecken, Goran Bencic, Christian Gieger, H-Erich Wichmann, James F Wilson, Cristina Venturini, Brian Fleck, Phillippa M Cumberland, Jugnoo S Rahi, Chris J Hammond, Caroline Hayward, Alan F Wright, Andrew D Paterson, Paul N Baird, Caroline C W Klaver, Jerome I Rotter, Mario Pirastu, Thomas Meitinger, Joan E Bailey-Wilson, and Dwight Stambolian

Subjects
Medicine, Science
Abstract

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10(-8)), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10(-11)) and 8q12 (minimum p value 1.82×10(-11)) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

Published
2014
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5. A new polygenic score for refractive error improves detection of children at risk of high myopia but not the prediction of those at risk of myopic macular degeneration

Author

Rosie Clark, Samantha Sze-Yee Lee, Ran Du, Yining Wang, Sander C.M. Kneepkens, Jason Charng, Yu Huang, Michael L. Hunter, Chen Jiang, J.Willem L. Tideman, Ronald B. Melles, Caroline C.W. Klaver, David A. Mackey, Cathy Williams, Hélène Choquet, Kyoko Ohno-Matsui, Jeremy A. Guggenheim, Joan E. Bailey-Wilson, Paul N. Baird, Veluchamy A. Barathi, Ginevra Biino, Kathryn P. Burdon, Harry Campbell, Li Jia Chen, Ching-Yu Cheng, Emily Y. Chew, Jamie E. Craig, Margaret M. Deangelis, Cécile Delcourt, Xiaohu Ding, Qiao Fan, Maurizio Fossarello, Paul J. Foster, Puya Gharahkhani, Xiaobo Guo, Annechien E.G. Haarman, Toomas Haller, Christopher J. Hammond, Xikun Han, Caroline Hayward, Mingguang He, Alex W. Hewitt, Quan Hoang, Pirro G. Hysi, Adriana I. Iglesias, Robert P. Igo, Sudha K. Iyengar, Jost B. Jonas, Mika Kähönen, Jaakko Kaprio, Anthony P. Khawaja, Barbara E. Klein, Jonathan H. Lass, Kris Lee, Terho Lehtimäki, Deyana Lewis, Qing Li, Shi-Ming Li, Leo-Pekka Lyytikäinen, Stuart MacGregor, Nicholas G. Martin, Akira Meguro, Andres Metspalu, Candace Middlebrooks, Masahiro Miyake, Nobuhisa Mizuki, Anthony Musolf, Stefan Nickels, Konrad Oexle, Chi Pui Pang, Olavi Pärssinen, Andrew D. Paterson, Norbert Pfeiffer, Ozren Polasek, Jugnoo S. Rahi, Olli Raitakari, Igor Rudan, Srujana Sahebjada, Seang-Mei Saw, Claire L. Simpson, Dwight Stambolian, E-Shyong Tai, Milly S. Tedja, J. Willem L. Tideman, Akitaka Tsujikawa, Cornelia M. van Duijn, Virginie J.M. Verhoeven, Veronique Vitart, Ningli Wang, Ya Xing Wang, Juho Wedenoja, Wen Bin Wei, Katie M. Williams, James F. Wilson, Robert Wojciechowski, Jason C.S. Yam, Kenji Yamashiro, Maurice K.H. Yap, Seyhan Yazar, Shea Ping Yip, Terri L. Young, Xiangtian Zhou, Naomi Allen, Tariq Aslam, Denize Atan, Sarah Barman, Jenny Barrett, Paul Bishop, Graeme Black, Catey Bunce, Roxana Carare, Usha Chakravarthy, Michelle Chan, Sharon Chua, Valentina Cipriani, Alexander Day, Parul Desai, Bal Dhillon, Andrew Dick, Alexander Doney, Cathy Egan, Sarah Ennis, Paul Foster, Marcus Fruttiger, John Gallacher, David Garway-Heath, Jane Gibson, Dan Gore, Jeremy Guggenheim, Chris Hammond, Alison Hardcastle, Simon Harding, Ruth Hogg, Pirro Hysi, Pearse A. Keane, Peng Tee Khaw, Anthony Khawaja, Gerassimos Lascaratos, Thomas Littlejohns, Andrew Lotery, Phil Luthert, Tom MacGillivray, Sarah Mackie, Bernadette McGuinness, Gareth McKay, Martin McKibbin, Danny Mitry, Tony Moore, James Morgan, Zaynah Muthy, Eoin O'Sullivan, Chris Owen, Praveen Patel, Euan Paterson, Tunde Peto, Axel Petzold, Nikolas Pontikos, Jugnoo Rahi, Alicja Rudnicka, Jay Self, Panagiotis Sergouniotis, Sobha Sivaprasad, David Steel, Irene Stratton, Nicholas Strouthidis, Cathie Sudlow, Robyn Tapp, Caroline Thaung, Dhanes Thomas, Emanuele Trucco, Adnan Tufail, Stephen Vernon, Ananth Viswanathan, Katie Williams, Jayne Woodside, Max Yates, Jennifer Yip, Yalin Zheng, Neurology, Ophthalmology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Neuroinfection & -inflammation, Epidemiology, Clinical Genetics, and Erasmus MC other

Subjects
All institutes and research themes of the Radboud University Medical Center, General Medicine, General Biochemistry, Genetics and Molecular Biology, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12]
Abstract

Contains fulltext : 292919.pdf (Publisher’s version ) (Open Access) BACKGROUND: High myopia (HM), defined as a spherical equivalent refractive error (SER) ≤ -6.00 diopters (D), is a leading cause of sight impairment, through myopic macular degeneration (MMD). We aimed to derive an improved polygenic score (PGS) for predicting children at risk of HM and to test if a PGS is predictive of MMD after accounting for SER. METHODS: The PGS was derived from genome-wide association studies in participants of UK Biobank, CREAM Consortium, and Genetic Epidemiology Research on Adult Health and Aging. MMD severity was quantified by a deep learning algorithm. Prediction of HM was quantified as the area under the receiver operating curve (AUROC). Prediction of severe MMD was assessed by logistic regression. FINDINGS: In independent samples of European, African, South Asian and East Asian ancestry, the PGS explained 19% (95% confidence interval 17-21%), 2% (1-3%), 8% (7-10%) and 6% (3-9%) of the variation in SER, respectively. The AUROC for HM in these samples was 0.78 (0.75-0.81), 0.58 (0.53-0.64), 0.71 (0.69-0.74) and 0.67 (0.62-0.72), respectively. The PGS was not associated with the risk of MMD after accounting for SER: OR = 1.07 (0.92-1.24). INTERPRETATION: Performance of the PGS approached the level required for clinical utility in Europeans but not in other ancestries. A PGS for refractive error was not predictive of MMD risk once SER was accounted for. FUNDING: Supported by the Welsh Government and Fight for Sight (24WG201).

Published
2023

6. Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia

Author

Eric Jorgenson, Mark James Simcoe, Alex W. Hewitt, Omar A. Mahroo, Anthony P Khawaja, Pirro G. Hysi, Paul J. Foster, Virginie J. M. Verhoeven, UK Eye, Jie Yin, David A. Mackey, Ayellet V. Segrè, Christopher J Hammond, Milly S. Tedja, Peng T. Khaw, Richard A. Stone, Jugnoo S Rahi, Hélène Choquet, Jeremy A. Guggenheim, Karina Patasova, Phillippa M. Cumberland, Khanh K. Thai, Caroline C W Klaver, Ronald B. Melles, Robert Wojciechowski, Nicholas J. Wareham, Myopia, Veronique Vitart, Stuart MacGregor, Ophthalmology, Epidemiology, and Clinical Genetics

Subjects
Adult, Male, Refractive error, genetic structures, Genome-wide association study, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Article, White People, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 03 medical and health sciences, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Myopia, Genetics, medicine, Humans, Genetic Predisposition to Disease, Gene, Aged, 030304 developmental biology, Genetic association, 0303 health sciences, Genetic heterogeneity, Middle Aged, Heritability, Refractive Errors, medicine.disease, eye diseases, 3. Good health, Abnormal eye, Meta-analysis, Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Refractive errors, in particular myopia, are a leading cause of morbidity and disability world-wide. Genetic investigation can improve understanding of the molecular mechanisms underlying abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies involving 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (AUC=0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes participating in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may make possible predicting refractive error and the development of personalized myopia prevention strategies in the future., Reporting summary Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Published
2020

7. New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics

Author

Louis R. Pasquale, Jia Yu Koh, Aniket Mishra, Ananth C. Viswanathan, Mani Baskaran, Jie Jin Wang, Jonathan L. Haines, Angela J. Cree, Henriët Springelkamp, Puya Gharahkhani, Seyhan Yazar, Gabriel Cuellar-Partida, Herma C. van der Linde, Hans G Lemij, Thibaud Boutin, Yik Ying Teo, Stuart MacGregor, Jae H. Kang, Li Zheng, Leonieke M E van Koolwijk, Janey L. Wiggs, Qiao Fan, Cornelia M. van Duijn, Rob Willemsen, René Höhn, Stefan Nickels, Tien Yin Wong, Najaf Amin, Shamira A. Perera, Lisa S. Kearns, Pirro G. Hysi, Roger C. W. Wolfs, Jost B. Jonas, Robert Luben, Tiger Zhou, André G. Uitterlinden, Wanting Zhao, Elisabeth M. van Leeuwen, Wishal D. Ramdas, Cristina Venturini, Caroline C W Klaver, Xueling Sim, Sven J. van der Lee, Tin Aung, Jiemin Liao, Karl J. Lackner, Andrew J. Lotery, Adriana I Iglesias, Albert Hofman, Ben A. Oostra, Fernando Rivadeneira, Paul J. Foster, Eranga N. Vithana, Nomdo M. Jansonius, Jamie E Craig, E. Shyong Tai, Veronique Vitart, Ching-Yu Cheng, Ekaterina Yonova-Doing, Robert Wojciechowski, Chiea Chuen Khor, Kathryn P. Burdon, Anthony P Khawaja, Christopher J Hammond, Jane Gibson, Norbert Pfeiffer, Tanja Zeller, Johannes R. Vingerling, Emmanuelle Souzeau, Ya Xing Wang, Grant W. Montgomery, David A. Mackey, Philipp S. Wild, Paul Mitchell, Terri L. Young, Alex W. Hewitt, Paulus T. V. M. de Jong, Paul G. Sanfilippo, Abhishek Nag, Yih Chung Tham, Christian P. Müller, Jessica N. Cooke Bailey, James F. Wilson, Perceptual and Cognitive Neuroscience (PCN), Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Culture, Organization and Management, Epidemiology, Ophthalmology, Internal Medicine, Clinical Genetics, Neurology, MUMC+: MA UECM Oogartsen ZL (9), MUMC+: MA UECM Oogartsen MUMC (9), RS: FHML non-thematic output, and Netherlands Institute for Neuroscience (NIN)

Subjects
0301 basic medicine, Male, Intraocular pressure, genetic structures, Optic disk, Glaucoma, PROTEIN, Genome-wide association study, IDENTIFIES 5, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Optic neuropathy, Optic Nerve Diseases, PROSTATE, Genetics (clinical), RISK, Association Studies Articles, COMMON VARIANTS, General Medicine, Middle Aged, CANCER, 3. Good health, medicine.anatomical_structure, Optic nerve, Female, Glaucoma, Open-Angle, Optic disc, Cyclin-Dependent Kinase Inhibitor p21, medicine.medical_specialty, Open angle glaucoma, SUSCEPTIBILITY LOCI, Optic Disk, 610 Medicine & health, Biology, 03 medical and health sciences, Tonometry, Ocular, Ophthalmology, Genetics, medicine, Humans, GENOME-WIDE ASSOCIATION, Molecular Biology, Intraocular Pressure, Homeodomain Proteins, P53, Genome, Human, POPULATION-BASED EPIDEMIOLOGY, Zebrafish Proteins, medicine.disease, eye diseases, 030104 developmental biology, sense organs, Genome-Wide Association Study
Abstract

Item does not contain fulltext Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

Published
2017

8. Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma

Author

Janey L. Wiggs, UK Biobank Eye, Jessica N. Cooke Bailey, Jonathan L. Haines, Ching-Yu Cheng, Pirro G. Hysi, Mark James Simcoe, Anthony P Khawaja, Paul J. Foster, Christopher J Hammond, Peng T. Khaw, Louis R. Pasquale, Yeunjoo E. Song, Robert A. Scott, Robert Wojciechowski, Nicholas J. Wareham, Robert P. Igo, Khawaja, Anthony P [0000-0001-6802-8585], Cooke Bailey, Jessica N [0000-0002-4001-8702], Simcoe, Mark [0000-0003-2432-0810], Pasquale, Louis R [0000-0002-5835-3496], Haines, Jonathan L [0000-0002-4351-4728], Foster, Paul J [0000-0002-4755-177X], Wiggs, Janey L [0000-0003-1890-3278], Hammond, Chris J [0000-0002-3227-2620], Hysi, Pirro G [0000-0001-5752-2510], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Adult, Male, Intraocular pressure, Open angle glaucoma, genetic structures, Glaucoma, Genome-wide association study, Disease, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Genetics, medicine, Humans, Genetic Predisposition to Disease, Risk factor, Intraocular Pressure, Aged, Middle Aged, medicine.disease, eye diseases, 3. Good health, 030104 developmental biology, Genetic Loci, Cohort, 030221 ophthalmology & optometry, Female, sense organs, Glaucoma, Open-Angle, Cohort study, Genome-Wide Association Study
Abstract

Glaucoma is the leading cause of irreversible blindness globally 1 . Despite its gravity, the disease is frequently undiagnosed in the community 2 . Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG)3,4. Here we present a meta-analysis of 139,555 European participants, which identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were nominally associated with glaucoma in an independent cohort, 14 of which were significant at a Bonferroni-corrected threshold. Regression-based glaucoma-prediction models had an area under the receiver operating characteristic curve (AUROC) of 0.76 in US NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from the UK Biobank. Genetic-prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk.

Published
2018

9. Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium

Author

Paul Mitchell, Arne Schillert, Tanja Zeller, Beate St Pourcain, Yi Lu, Christopher J Hammond, Nicholas G. Martin, René Höhn, Veluchamy A Barathi, Terri L. Young, Johannes R. Vingerling, Mario Pirastu, Veronique Vitart, André G. Uitterlinden, Virginie J. M. Verhoeven, Federico Murgia, Xin Zhou, Pirro G. Hysi, Christian Gieger, Jeremy A. Guggenheim, Robert Wojciechowski, Paul G. Sanfilippo, Alireza Mirshahi, Caroline Hayward, Terho Lehtimäki, Phillippa M. Cumberland, Caroline C W Klaver, Konrad Oexle, Tin Aung, Alan F. Wright, Eranga N. Vithana, Paul N. Baird, Qiao Fan, Ching-Yu Cheng, Andrew D. Paterson, Joan E. Bailey-Wilson, Thomas Meitinger, Mohammad Kamran Ikram, Janina S. Ried, Youchan Shin, Albert Hofman, David A. Mackey, Lennart C. Karssen, James F. Wilson, George McMahon, Najaf Amin, Ben A. Oostra, Brian W Fleck, Tien Yin Wong, Olavi Pärssinen, Cathy Williams, Kari-Matti Mäkelä, Kumari Neelam, Rosalynn Siantar, Yik Ying Teo, Alex W. Hewitt, Hoi Suen Wong, Olli T. Raitakari, Seyhan Yazar, Barbara E.K. Klein, Janice Lam, Shea Ping Yip, Ekaterina Yonova-Doing, Chiea Chuen Khor, Maurice Yap, David M. Evans, Harry Campbell, Goran Benčić, Jost B. Jonas, Yingfeng Zheng, Cristina Venturini, Claire L. Simpson, S. Mohsen Hosseini, Dwight Stambolian, E. Shyong Tai, Fernando Rivadeneira, Juho Wedenoja, John P. Kemp, Stuart MacGregor, Qing Li, Cornelia M. van Duijn, Ozren Polasek, Mika Kähönen, Ya Xing Wang, Kate Northstone, Jugnoo S Rahi, Seang-Mei Saw, Karl J. Lackner, Nicholas J. Timpson, Ophthalmology, Erasmus MC other, Epidemiology, Internal Medicine, Clinical Genetics, Department of Public Health, and Silmäklinikka

Subjects
Male, Refractive error, BLUE MOUNTAINS EYE, CORNEAL ASTIGMATISM, Spherical equivalent, Genome-wide association study, astigmatism, gene, SNP, DISEASE, Cohort Studies, 0302 clinical medicine, Statistics, Genetics(clinical), Neural Cell Adhesion Molecules, POPULATION, Genetics (clinical), Original Investigation, Genetics, 0303 health sciences, education.field_of_study, Age Factors, High Mobility Group Proteins, Middle Aged, 3142 Public health care science, environmental and occupational health, 3. Good health, Female, OPEN-ANGLE GLAUCOMA, Adult, Genetic Markers, EXPERIMENTALLY-INDUCED MYOPIA, Keratoconus, SUSCEPTIBILITY LOCI, Cell Adhesion Molecules, Neuronal, education, Population, Nerve Tissue Proteins, Astigmatism, Biology, White People, 03 medical and health sciences, AGE, Asian People, MAJOR LOCUS, medicine, Humans, 3125 Otorhinolaryngology, ophthalmology, 030304 developmental biology, Genetic association, Calcium-Binding Proteins, Heritability, medicine.disease, NONCODING RNAS, 030221 ophthalmology & optometry, Genome-Wide Association Study
Abstract

To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged

Published
2015

10. Genome-Wide Meta-Analysis of Myopia and Hyperopia Provides Evidence for Replication of 11 Loci

Author

Mario Pirastu, G. E. Munn, L. H. Ketai, K. Taylor, Angela Döring, R. Chan, Jeffrey L. Mahon, Bradley D. Jones, M. Hebdon, Williams L. Dews, Douglas A. Greene, Michael D. Weiss, Sapna Gangaputra, E. A. Tanaka, J. Ginsberg, Ben A. Oostra, Alka Jain, D. Singer, M. Burger, Szilard Kiss, David A. Bluemke, Barbara H. Braffett, Jugnoo S Rahi, L. Sun, C. Clark, Richard M. Bergenstal, Patricia Gatcomb, Paul Mitchell, R. Trail, D. Ryan, Robert Bergren, D. D. Joseph, G. Grand, Blanche M. Chavers, J. M.Verhoeven Virginie, David S. Schade, C. Cowie, Sharon B. Schwartz, G. Ziegler, Lloyd Paul Aiello, Michael H. Brent, John I. Malone, C. Pittman, M. Reid, Stephen S. Feman, Maurizio Fossarello, Kathie L. Hermayer, J. Parker, M. N. Iyer, Hamid Mojibian, Rose Gubitosi-Klug, P. W. Conrad, Daniel T. Lackland, Michael Brändle, C. Canny, Alan F. Wright, M. E. Lackaye, David A. Lee, Rickey E. Carter, J. Brown-Friday, J. K. Jones, J. Distad, A. Thomas, Gordon C. Weir, S. Caulder, M. Szpiech, R. Gstalder, D. Rubinstein, Fred W. Whitehouse, T. Adkins, Gayle M. Lorenzi, L. Survant, Naji Younes, Robert Detrano, Lucy A. Levandoski, Charles Campbell, Lawrence J. Singerman, Johannes R. Vingerling, Joao A.C. Lima, D. Counts, V. Gama, D. M. Nathan, John Dupre, Cornelia M. van Duijn, N. Wong, Anita Harrington, Caroline Hayward, Shelley B. Bull, R. Hackel, William I. Sivitz, Enrico Cagliero, M. Spencer, Albert Hofman, Samuel S. Engel, John E. Hokanson, Julio V. Santiago, David M. Kendall, O. Crofford, T. Thompson, Lee M. Jampol, Kevin Morgan, R. Sussman, James W. Albers, Anita Agarwal, Kevin J. Blinder, Anthony D. Morrison, Nikhil D. Patel, R. Prusak, S. Hitt, Alexander R. Lyon, Saul Genuth, J. Sheindlin, J. Vaccaro-Kish, Goran Benčić, P. Titus, Lisa Diminick, N. Wimmergren, Shelly Olson, Z. Strugula, L. Goings, Lennart C. Karssen, A. Blevins, Harjit Chahal, Ronald K. Mayfield, S. Pendegast, T. J. Lyons, Ozren Polasek, Matthew A. Thomas, Annette Barnie, P. Lindsey, L. Funk, James L. Kinyoun, Neil H. White, L. Mayer, Rodney A. Lorenz, Susan G. Elner, R. L. Pate, E. Simjanoski, R. Beaser, J. Gothrup, Tien Yin Wong, Thomas Bettecken, Jae-Ho Lee, Elsayed Z. Soliman, Ronald P. Danis, Phillippa M. Cumberland, J. Selby, Pamela Rath, H. Martinez, S. Neill, D. Rosenberg, D. Zheng, R. Devenyi, Murk-Hein Heinemann, Albert V. Smith, Alicia J. Jenkins, Rukhsana G. Mirza, Konrad Oexle, Osama Hamdy, John D. Brunzell, Trevor J. Orchard, Daniel Cornfeld, K. Nickander, Igor Rudan, L. Kim, T. Williams, Christopher M. Ryan, William Dahms, P. Paczan Rath, S. Elsing, Matthew J. Budoff, Orville G. Kolterman, Seang-Mei Saw, Lisa A. Prosser, A. Determan, M. Espeland, L. Van Ottingham, B. Petty, A. Farr, Brandy N. Rutledge, Patricia A. Cleary, Margaret L. Bayless, E. Cupelli, Ronald J. Prineas, Jonathan Goldstein, Stefan Fritz, J. Harth, K. Stoessel, Jerry P. Palmer, J. Soule, John A. Colwell, Stephen W. Scherer, Cyndi F. Liu, M. Phillips, Alexander J. Brucker, B. Rogness, Caroline C W Klaver, Joan E. Bailey-Wilson, Claire L. Simpson, Gaurav K. Shah, Louis A. Lobes, S. Mohsen Hosseini, Veronique Vitart, Dwight Stambolian, Mark S. Mandelcorn, John E. Godine, Gabriel Virella, A. Cochrane, David A. Nicolle, Timothy J. Lyons, S. Schussler, Abbas E. Kitabchi, N. Grove, Matthew D. Davis, Andrew K. Vine, Joseph F. Polak, Helen Lambeth, Ayad A. Jaffa, S. Rogers, Samuel Dagogo-Jack, C. Siebert, K. Hansen, H. Shamoon, David J. Brillon, D. Schlossman, H. Ricks, Toby A. Gardner, Mary Frances Cotch, J. Quin, Om P. Ganda, Fernando Rivadeneira, F. Thoma, Brian Fleck, K. Klumpp, Manjot K. Gill, R. J. van der Geest, Hunter Wessells, P. Salemi, P. Gaston, Tae Sup Lee, T. Woodfill, Scott M. Steidl, Thomas Meitinger, Laura Portas, John E. Chapin, Robert Wojciechowski, Martin J. Stevens, Z. M. Zhang, John D. Maynard, Paul G. Arrigg, S. Yacoub-Wasef, Andrew D. Paterson, Barbara J. Maschak-Carey, Ramzi K. Hemady, J. Dingledine, Sheila Smith-Brewer, D. Ostrowski, D. Kenny, Leslie J. Raffel, R. Jarboe, E. Angus, G. Sharuk, Jie Jin Wang, Jye-Yu C. Backlund, K. Chan, R. K. Mayfield, M. Nutaitis, William V. Tamborlane, Emily Y. Chew, Michael H. Goldbaum, S. Kwon, Davida F. Kruger, Mary E. Larkin, Catherine L. Martin, M. Novak, David E. Goldstein, J. Rosenzwieg, D. J. Becker, A. E. Boulton, Jean M. Bucksa, Richard S. Crow, Thomas Donner, Philip A. Low, J. Fradkin, K. Folino, M. L. Bernal, Daniel L. McGee, R. D′Agostino, David G. Miller, Evrim B. Turkbey, Eva L. Feldman, Larry Rand, Harry Campbell, Mark R. Palmert, N. Silvers, M. Driscoll, M. Bracey, Mark E. Molitch, Boniuk Burgess, John P. Bantle, J. D. Carey, Edward Chaum, Philip Raskin, I. H. de Boer, Peter R. Pavan, C. Wigley, Maria F. Lopes-Virella, Pirro G. Hysi, C. Sommer, R. Eastman, B. Schaefer, Maren Nowicki, K. Lee, S. Braunstein, Hugh D. Wabers, A. F. Burrows, M. Johnson, B. Zinman, M. Ong, Samir S. Deeb, C. Gauthier-Kelly, S. Novella, C. Miao, S. Strowig, S. Crowell, Teri A. Manolio, S. Yalamanchi, Christian Gieger, D. Meyer, Louis M. Luttrell, Janie Lipps, William H. Herman, Michael W. Steffes, A. Galprin, A. Iannacone, Federico Murgia, E. Steuer, KyungMann Kim, James F. Wilson, S. Genuth, André G. Uitterlinden, Dean P. Hainsworth, J. Giangiacomo, Wanjie Sun, Aruna V. Sarma, R. Liss, S. Catton, Rodica Pop-Busui, S. Moser, Bernard H. Doft, A. Malayeri, B. Gloeb, W. T. Garvey, Andrew P. Boright, Alan M. Jacobson, Larry D. Hubbard, Barbara E.K. Klein, Shyam M. Thomas, Allan Gordon, Allan L. Drash, S. Yoser, S. Johnsonbaugh, L. Kaminski, G. Meekins, Jonathan Q. Purnell, B. Burzuk, John M. Lachin, M. Geckle, Ronald J. Oudiz, Isaac Boniuk, Xiaohui Li, V. Reppucci, H. Wolpert, D. Etzwiler, M. Brabham, Maria Schache, E. Golden, M. Fox, Jyotika K. Fernandes, Jerome I. Rotter, Paul N. Baird, Michael Bryer-Ash, M. Stern, H. Engel, M. Hawkins, Najaf Amin, C. O′Donnell, M. McLellan, G. Comer, Ronald Klein, D. Sandstrom, H. Zegarra, J. Gordon, M. B. Murphy, P. A. Bourne, L. Baker, Cristina Venturini, D. Wood, H.-Erich Wichmann, M. May, A. Kowarski, Timothy W. Olsen, Thomas J. Songer, Christopher J Hammond, P. Lou, Jill P. Crandall, Miao, Xiaoping, Ophthalmology, Obstetrics & Gynecology, Epidemiology, Clinical Genetics, and Internal Medicine

Subjects
Male, Linkage disequilibrium, Refractive error, genetic structures, Epidemiology, Genome-wide association study, Plant Science, Eye, Linkage Disequilibrium, ASSOCIATION SCANS, MULTIPLE, Medicine and Health Sciences, Myopia, 80 and over, 2.1 Biological and endogenous factors, Aetiology, Age of Onset, FAMILIAL AGGREGATION, Genetics, Aged, 80 and over, Multidisciplinary, AUSTRALIAN SCHOOL-CHILDREN, COMMON VARIANTS, Single Nucleotide, Middle Aged, RETINAL-PIGMENT EPITHELIUM, OUTDOOR ACTIVITY, Hyperopia, Phenotype, Genetic Epidemiology, Medicine, Female, Research Article, Genetic Markers, Adult, General Science & Technology, Science, DCCT/EDIC Research Group, European Continental Ancestry Group, Locus (genetics), Single-nucleotide polymorphism, and over, Biology, Disease Surveillance, Polymorphism, Single Nucleotide, White People, medicine, Genome-Wide Association Studies, Humans, Inherited Eye Disorders, Genetic Predisposition to Disease, Allele, Polymorphism, Eye Disease and Disorders of Vision, Alleles, Genetic Association Studies, Aged, Whites, Human Genome, Biology and Life Sciences, Computational Biology, Human Genetics, Heritability, Plant Pathology, medicine.disease, Genome Analysis, GENE, eye diseases, Ophthalmology, REFRACTIVE ERROR, Genetics of Disease, LINKAGE-DISEQUILIBRIUM, Age of onset
Abstract

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10-8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10-11) and 8q12 (minimum p value 1.82×10-11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

Published
2014

11. Nine Loci for Ocular Axial Length Identified through Genome-wide Association Studies, Including Shared Loci with Refractive Error

Author

Ching-Yu Cheng, Maria Schache, M. Kamran Ikram, Terri L. Young, Jeremy A. Guggenheim, Veronique Vitart, Stuart MacGregor, Virginie J.M. Verhoeven, Veluchamy A. Barathi, Jiemin Liao, Pirro G. Hysi, Joan E. Bailey-Wilson, Beate St. Pourcain, John P. Kemp, George McMahon, Nicholas J. Timpson, David M. Evans, Grant W. Montgomery, Aniket Mishra, Ya Xing Wang, Jie Jin Wang, Elena Rochtchina, Ozren Polasek, Alan F. Wright, Najaf Amin, Elisabeth M. van Leeuwen, James F. Wilson, Craig E. Pennell, Cornelia M. van Duijn, Paulus T.V.M. de Jong, Johannes R. Vingerling, Xin Zhou, Peng Chen, Ruoying Li, Wan-Ting Tay, Yingfeng Zheng, Merwyn Chew, Kathryn P. Burdon, Jamie E. Craig, Sudha K. Iyengar, Robert P. Igo, Jonathan H. Lass, Emily Y. Chew, Toomas Haller, Evelin Mihailov, Andres Metspalu, Juho Wedenoja, Claire L. Simpson, Robert Wojciechowski, René Höhn, Alireza Mirshahi, Tanja Zeller, Norbert Pfeiffer, Karl J. Lackner, Thomas Bettecken, Thomas Meitinger, Konrad Oexle, Mario Pirastu, Laura Portas, Abhishek Nag, Katie M. Williams, Ekaterina Yonova-Doing, Ronald Klein, Barbara E. Klein, S. Mohsen Hosseini, Andrew D. Paterson, Kari-Matti Makela, Terho Lehtimaki, Mika Kahonen, Olli Raitakari, Nagahisa Yoshimura, Fumihiko Matsuda, Li Jia Chen, Chi Pui Pang, Shea Ping Yip, Maurice K.H. Yap, Akira Meguro, Nobuhisa Mizuki, Hidetoshi Inoko, Paul J. Foster, Jing Hua Zhao, Eranga Vithana, E-Shyong Tai, Qiao Fan, Liang Xu, Harry Campbell, Brian Fleck, Igor Rudan, Tin Aung, Albert Hofman, André G. Uitterlinden, Goran Bencic, Chiea-Chuen Khor, Hannah Forward, Olavi Pärssinen, Paul Mitchell, Fernando Rivadeneira, Alex W. Hewitt, Cathy Williams, Ben A. Oostra, Yik-Ying Teo, Christopher J. Hammond, Dwight Stambolian, David A. Mackey, Caroline C.W. Klaver, Tien-Yin Wong, Seang-Mei Saw, Paul N. Baird, William Reinhart, Michael W. Belin, Robert L. Schultze, Todd Morason, Alan Sugar, Shahzad Mian, Hunson Kaz Soong, Kathryn Colby, Ula Jurkunas, Richard Yee, Mark Vital, Eduardo Alfonso, Carol Karp, Yunhee Lee, Sonia Yoo, Kristin Hammersmith, Elisabeth Cohen, Peter Laibson, Christopher Rapuano, Brandon Ayres, Christopher Croasdale, James Caudill, Sanjay Patel, Keith Baratz, William Bourne, Leo Maguire, Joel Sugar, Elmer Tu, Ali Djalilian, Vinod Mootha, James McCulley, Wayne Bowman, H. Dwight Cavanaugh, Steven Verity, David Verdier, Ann Renucci, Matt Oliva, Walter Rotkis, David R. Hardten, Ahmad Fahmy, Marlene Brown, Sherman Reeves, Elizabeth A. Davis, Richard Lindstrom, Scott Hauswirth, Stephen Hamilton, W. Barry Lee, Francis Price, Marianne Price, Kathleen Kelly, Faye Peters, Michael Shaughnessy, Thomas Steinemann, B.J. Dupps, David M. Meisler, Mark Mifflin, Randal Olson, Anthony Aldave, Gary Holland, Bartly J. Mondino, George Rosenwasser, Mark Gorovoy, Steven P. Dunn, David G. Heidemann, Mark Terry, Neda Shamie, Steven I. Rosenfeld, Brandon Suedekum, David Hwang, Donald Stone, James Chodosh, Paul G. Galentine, David Bardenstein, Katrina Goddard, Hemin Chin, Mark Mannis, Rohit Varma, Ingrid Borecki, Ophthalmology, Epidemiology, Internal Medicine, Clinical Genetics, Obstetrics & Gynecology, and Netherlands Institute for Neuroscience (NIN)

Subjects
Adult, Male, Refractive error, Adolescent, Gene Expression, Locus (genetics), Genome-wide association study, Biology, Ocular Axial Length, Polymorphism, Single Nucleotide, White People, Article, 03 medical and health sciences, 0302 clinical medicine, Asian People, SDG 3 - Good Health and Well-being, medicine, Genetics, Humans, GWAS, Genetic Predisposition to Disease, Genetics(clinical), RSPO1, Eye Proteins, Gene, Genetics (clinical), 030304 developmental biology, Genetic association, Aged, 0303 health sciences, ta1184, Heritability, Middle Aged, ta3121, medicine.disease, Refractive Errors, Axial Length, Eye, Genetic Loci, 030221 ophthalmology & optometry, Eye disorder, Female, Genome-Wide Association Study, Signal Transduction
Abstract

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.

Published
2013

12. Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium

Author

Beate St Pourcain, Vilmundur Gudnason, Taina Rantanen, Joan E. Bailey-Wilson, Anke Tönjes, Sudha K. Iyengar, Caroline Hayward, Ben A. Oostra, Lennart C. Karssen, Yi Lu, Barbara E.K. Klein, Igor Rudan, Federico Murgia, Wan Ting Tay, Veronique Vitart, M. Kamran Ikram, Tien Yin Wong, James F. Wilson, Seang-Mei Saw, Kyoko Ohno-Matsui, Tin Aung, Christian Wolfram, Liang Kee Goh, Ozren Polasek, Olavi Pärssinen, Cathy Williams, Paul Mitchell, Thomas Meitinger, Thomas Bettecken, Mika Kähönen, Dominiek D. G. Despriet, Guðný Eiríksdóttir, Angela Döring, Alireza Mirshahi, Eranga N. Vithana, Yi-Ju Li, Jie Jin Wang, David A. Mackey, Brian W Fleck, Laura Portas, Isao Nakata, Tõnu Esko, George McMahon, Tanja Zeller, Terri L. Young, Albert V. Smith, Phillippa M. Cumberland, Shomi S. Bhattacharya, Norbert Pfeiffer, Karl J. Lackner, Johannes R. Vingerling, Fernando Rivadeneira, Andres Metspalu, Caroline C W Klaver, Xin Zhou, Alan F. Wright, Priya Duggal, Leslie J. Raffel, Albert Hofman, Jugnoo S Rahi, Kenji Yamashiro, Ryo Yamada, Reedik Mägi, Cornelia M. van Duijn, Jeremy A. Guggenheim, Virginie J. M. Verhoeven, René Höhn, Nagahisa Yoshimura, Xueling Sim, Terho Lehtimäki, Harry Campbell, Pirro G. Hysi, Konrad Oexle, Raphaële Castagné, Mary Frances Cotch, Robert Wojciechowski, E-Shyong Tai, Tim D. Spector, Claire L. Simpson, Dwight Stambolian, Yik Ying Teo, André G. Uitterlinden, Larry D. Atwood, Abhishek Nag, Paul N. Baird, Qiao Fan, Najaf Amin, Chiea Chuen Khor, Paulus T. V. M. de Jong, Xiaohui Li, Christopher J Hammond, Sarayut Janmahasatian, Fumihiko Matsuda, Alex W. Hewitt, Leonieke M E van Koolwijk, Ophthalmology, Erasmus MC other, Epidemiology, Clinical Genetics, and Internal Medicine

Subjects
Population, Locus (genetics), Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Myopia, Genetics, Humans, SNP, Genetics(clinical), Allele, education, Alleles, Genetics (clinical), Original Investigation, 030304 developmental biology, Genetic association, Chromosomes, Human, Pair 15, 0303 health sciences, education.field_of_study, 3. Good health, Phenotype, 030221 ophthalmology & optometry, Population study, RE
Abstract

Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on 15q25 using linear regression analysis with spherical equivalent as a quantitative outcome, adjusted for age and sex. We calculated the odds ratio (OR) of myopia versus hyperopia for carriers of the top-SNP alleles using a fixed effects meta-analysis. At locus 15q14, all SNPs were significantly replicated, with the lowest P value 3.87 × 10−12 for SNP rs634990 in Caucasians, and 9.65 × 10−4 for rs8032019 in Asians. The overall meta-analysis provided P value 9.20 × 10−23 for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95 % CI 1.64, 2.16, P

Published
2012

13. Heritability of Refractive Error and Familial Aggregation of Myopia in an Elderly American Population

Author

Donna Gilbert, Robert Wojciechowski, Beatriz Munoz, Sheila K. West, Nathan Congdon, and Heidi Bowie

Subjects
Male, Refractive error, genetic structures, Dizygotic twin, medicine.medical_treatment, Population, Visual Acuity, Black People, Biology, Refraction, Ocular, Article, White People, Refractive surgery, Surveys and Questionnaires, medicine, Myopia, Prevalence, Humans, education, Aged, Aged, 80 and over, education.field_of_study, Maryland, Siblings, Family aggregation, Heritability, medicine.disease, Refractive Errors, Twin study, eye diseases, Optometry, Female, sense organs, Demography, Population variance
Abstract

Myopia is the leading cause of visual impairment in nearly all population-based studies of ocular disease, and correction of refractive error consumed over $12 billion per year in the United States 10 years ago, even before the recent surge in refractive surgery.1 In some populations of east Asia, studies suggest that the prevalence of myopia may exceed 80% among young persons,2 and there is some evidence that rates may be increasing rapidly.3 There is also evidence for a recent increase in the prevalence of myopia in populations such as Eskimos, in whom myopia was rare only a few generations ago.4 Such apparent rapid changes in the prevalence of myopia within defined populations argue for strong environmental influences in the development of myopia. For example, much evidence exists that implicates near work as an important determinant of myopia.5–10 Nevertheless, there is also considerable evidence that myopia is under genetic control. Studies have consistently shown strong correlations between the refractive errors of first-degree relatives.11–13 Twin studies by Hammond et al.,14 Teikari et al.,15,16 and Lyhne et al.17 have suggested that the heritability—that is, the proportion of the population variance under genetic control—for refraction may exceed 80%. It is therefore likely that the development of myopia is mediated by both environmental and genetic risk factors. At least four chromosomal locations18–22 have been linked to high (that is, in excess of 5 D) myopia. No such loci had been identified for moderate myopia (1–5 D), which comprises some 80% of myopia among American adults,23 until a recent report by Stambolian et al.24 who found significant genetic linkage of myopia to a region on chromosome 22 in an Ashkenazi Jewish population. Moreover, in a genome-wide scan of 221 dizygotic twin pairs, Hammond et al.25 reported significant linkage signals to multiple genetic loci when analyzing refractive error as a quantitative trait. Their highest linkage peak was observed at chromosomal location 11p13 while evidence for linkage was also noted at regions 3q26, 8p23, and 4q12. The relative paucity of evidence for linkage in lower levels of refractive error, compared with high myopia, is partly because high myopia may be more likely to present in an autosomal dominant fashion,22 whereas the genetics of lower refractive errors may be more complex and multifactorial. Nevertheless, Farbrother et al.26 argue that even high myopia phenotypes are unlikely to be inherited in an autosomal dominant fashion and that a multifactorial etiology is more likely. In view of the high prevalence (some 20 million American adults23) and the resultant significant impact on the health economy in the cost of spectacles, contact lenses, and refractive surgery, it certainly seems that moderate myopia is deserving of genetic study to elucidate its fundamental mechanisms, which may or may not be the same as those of high myopia. Using linear regression models and generalized estimating equations (GEEs), we estimated the heritability of refractive error in a population-based sample of elderly sibships in eastern Maryland. We also used logistic regression models to calculate the odds of myopia in siblings of myopic individuals compared with siblings of nonmyopes, using four thresholds to define myopia.

Published
2005

14. Evaluation of random forests performance for genome-wide association studies in the presence of interaction effects

Author

Li Wang, James D. Malley, Rasika A. Mathias, Heejong Sung, Joan E. Bailey-Wilson, Yoonhee Kim, Rhoshel K. Lenroot, Alison P. Klein, and Robert Wojciechowski

Subjects
0303 health sciences, Mean squared error, business.industry, Association (object-oriented programming), 0206 medical engineering, Genome-wide association study, 02 engineering and technology, General Medicine, Interaction, computer.software_genre, General Biochemistry, Genetics and Molecular Biology, Regression, Random forest, 03 medical and health sciences, Proceedings, Specification, Medicine, Data mining, business, computer, 020602 bioinformatics, 030304 developmental biology, Genetic association
Abstract

Random forests (RF) is one of a broad class of machine learning methods that are able to deal with large-scale data without model specification, which makes it an attractive method for genome-wide association studies (GWAS). The performance of RF and other association methods in the presence of interactions was evaluated using the simulated data from Genetic Analysis Workshop 16 Problem 3, with knowledge of the major causative markers, risk factors, and their interactions in the simulated traits. There was good power to detect the environmental risk factors using RF, trend tests, or regression analyses but the power to detect the effects of the causal markers was poor for all methods. The causal marker that had an interactive effect with smoking did show moderate evidence of association in the RF and regression analyses, suggesting that RF may perform well at detecting such interactions in larger, more highly powered datasets.

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