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1. Genetic Variants Associated With Human Eye Size Are Distinct From Those Conferring Susceptibility to Myopia

Author

Plotnikov, D, Cui, J, Clark, R, Wedenoja, J, Parssinen, O, Tideman, JWL, Jonas, JB, Wang, Y, Rudan, I, Young, TL, Mackey, DA, Terry, L, Williams, C, Guggenheim, JA, Plotnikov, D, Cui, J, Clark, R, Wedenoja, J, Parssinen, O, Tideman, JWL, Jonas, JB, Wang, Y, Rudan, I, Young, TL, Mackey, DA, Terry, L, Williams, C, and Guggenheim, JA

Abstract

PURPOSE: Emmetropization requires coordinated scaling of the major ocular components, corneal curvature and axial length. This coordination is achieved in part through a shared set of genetic variants that regulate eye size. Poorly coordinated scaling of corneal curvature and axial length results in refractive error. We tested the hypothesis that genetic variants regulating eye size in emmetropic eyes are distinct from those conferring susceptibility to refractive error. METHODS: A genome-wide association study (GWAS) for corneal curvature in 22,180 adult emmetropic individuals was performed as a proxy for a GWAS for eye size. A polygenic score created using lead GWAS variants was tested for association with corneal curvature and axial length in an independent sample: 437 classified as emmetropic and 637 as ametropic. The genetic correlation between eye size and refractive error was calculated using linkage disequilibrium score regression for approximately 1 million genetic variants. RESULTS: The GWAS for corneal curvature in emmetropes identified 32 independent genetic variants (P < 5.0e-08). A polygenic score created using these 32 genetic markers explained 3.5% (P < 0.001) and 2.0% (P = 0.001) of the variance in corneal curvature and axial length, respectively, in the independent sample of emmetropic individuals but was not predictive of these traits in ametropic individuals. The genetic correlation between eye size and refractive error was close to zero (rg = 0.00; SE = 0.06; P = 0.95). CONCLUSIONS: These results support the hypothesis that genetic variants regulating eye size in emmetropic eyes do not overlap with those conferring susceptibility to myopia. This suggests that distinct biological pathways regulate normal eye growth and myopia development.

Published
2021

2. IMI Prevention of Myopia and Its Progression

Author

Jonas, JB, Ang, M, Cho, P, Guggenheim, JA, He, MG, Jong, M, Logan, NS, Liu, M, Morgan, I, Ohno-Matsui, K, Parssinen, O, Resnikoff, S, Sankaridurg, P, Saw, S-M, Smith, EL, Tan, DTH, Walline, JJ, Wildsoet, CF, Wu, P-C, Zhu, X, Wolffsohn, JS, Jonas, JB, Ang, M, Cho, P, Guggenheim, JA, He, MG, Jong, M, Logan, NS, Liu, M, Morgan, I, Ohno-Matsui, K, Parssinen, O, Resnikoff, S, Sankaridurg, P, Saw, S-M, Smith, EL, Tan, DTH, Walline, JJ, Wildsoet, CF, Wu, P-C, Zhu, X, and Wolffsohn, JS

Abstract

The prevalence of myopia has markedly increased in East and Southeast Asia, and pathologic consequences of myopia, including myopic maculopathy and high myopia-associated optic neuropathy, are now some of the most common causes of irreversible blindness. Hence, strategies are warranted to reduce the prevalence of myopia and the progression to high myopia because this is the main modifiable risk factor for pathologic myopia. On the basis of published population-based and interventional studies, an important strategy to reduce the development of myopia is encouraging schoolchildren to spend more time outdoors. As compared with other measures, spending more time outdoors is the safest strategy and aligns with other existing health initiatives, such as obesity prevention, by promoting a healthier lifestyle for children and adolescents. Useful clinical measures to reduce or slow the progression of myopia include the daily application of low-dose atropine eye drops, in concentrations ranging between 0.01% and 0.05%, despite the side effects of a slightly reduced amplitude of accommodation, slight mydriasis, and risk of an allergic reaction; multifocal spectacle design; contact lenses that have power profiles that produce peripheral myopic defocus; and orthokeratology using corneal gas-permeable contact lenses that are designed to flatten the central cornea, leading to midperipheral steeping and peripheral myopic defocus, during overnight wear to eliminate daytime myopia. The risk-to-benefit ratio needs to be weighed up for the individual on the basis of their age, health, and lifestyle. The measures listed above are not mutually exclusive and are beginning to be examined in combination.

Published
2021

3. Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

Author

Fan, Q., Pozarickij, A., Tan, N.Y.Q., Guo, X., Verhoeven, V.J.M., Vitart, V., Guggenheim, J.A., Miyake, M., Tideman, J.W.L., Khawaja, A.P., Zhang, L., MacGregor, S., Hohn, R., Chen, P., Biino, G., Wedenoja, J., Saffari, S.E., Tedja, M.S., Xie, J, Lanca, C., Wang, Y.X., Sahebjada, S., Mazur, J., Mirshahi, A., Martin, N.G., Yazar, S., Pennell, C.E., Yap, M., Haarman, A.E.G., Enthoven, C.A., Polling, J., Hewitt, A.W., Jaddoe, V.W.V., Duijn, C.M. van, Hayward, C., Polasek, O., Tai, E.S., Yoshikatsu, H., Hysi, P.G., Young, T.L., Tsujikawa, A., Wang, J.J., Mitchell, P., Pfeiffer, N., Parssinen, O., Foster, P.J., Fossarello, M., Yip, S.P., Williams, C., Hammond, C.J., Jonas, J.B., He, M., Mackey, D.A., Wong, T.Y., Klaver, C.C.W., Saw, S.M., Baird, P.N., Cheng, C.Y., Fan, Q., Pozarickij, A., Tan, N.Y.Q., Guo, X., Verhoeven, V.J.M., Vitart, V., Guggenheim, J.A., Miyake, M., Tideman, J.W.L., Khawaja, A.P., Zhang, L., MacGregor, S., Hohn, R., Chen, P., Biino, G., Wedenoja, J., Saffari, S.E., Tedja, M.S., Xie, J, Lanca, C., Wang, Y.X., Sahebjada, S., Mazur, J., Mirshahi, A., Martin, N.G., Yazar, S., Pennell, C.E., Yap, M., Haarman, A.E.G., Enthoven, C.A., Polling, J., Hewitt, A.W., Jaddoe, V.W.V., Duijn, C.M. van, Hayward, C., Polasek, O., Tai, E.S., Yoshikatsu, H., Hysi, P.G., Young, T.L., Tsujikawa, A., Wang, J.J., Mitchell, P., Pfeiffer, N., Parssinen, O., Foster, P.J., Fossarello, M., Yip, S.P., Williams, C., Hammond, C.J., Jonas, J.B., He, M., Mackey, D.A., Wong, T.Y., Klaver, C.C.W., Saw, S.M., Baird, P.N., and Cheng, C.Y.

Abstract

Contains fulltext : 218869.pdf (publisher's version ) (Open Access), Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.

Published
2020

4. Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

Author

Fan, Q, Pozarickij, A, Tan, NYQ, Guo, X, Verhoeven, VJM, Vitart, V, Guggenheim, JA, Miyake, M, Tideman, JWL, Khawaja, AP, Zhang, L, MacGregor, S, Hoehn, R, Chen, P, Biino, G, Wedenoja, J, Saffari, SE, Tedja, MS, Xie, J, Lanca, C, Wang, YX, Sahebjada, S, Mazur, J, Mirshahi, A, Martin, NG, Yazar, S, Pennell, CE, Yap, M, Haarman, AEG, Enthoven, CA, Polling, J, Hewitt, AW, Jaddoe, VWV, van Duijn, CM, Hayward, C, Polasek, O, Tai, E-S, Yoshikatsu, H, Hysi, PG, Young, TL, Tsujikawa, A, Wang, JJ, Mitchell, P, Pfeiffer, N, Parssinen, O, Foster, PJ, Fossarello, M, Yip, SP, Williams, C, Hammond, CJ, Jonas, JB, He, M, Mackey, DA, Wong, T-Y, Klaver, CCW, Saw, S-M, Baird, PN, Cheng, C-Y, Fan, Q, Pozarickij, A, Tan, NYQ, Guo, X, Verhoeven, VJM, Vitart, V, Guggenheim, JA, Miyake, M, Tideman, JWL, Khawaja, AP, Zhang, L, MacGregor, S, Hoehn, R, Chen, P, Biino, G, Wedenoja, J, Saffari, SE, Tedja, MS, Xie, J, Lanca, C, Wang, YX, Sahebjada, S, Mazur, J, Mirshahi, A, Martin, NG, Yazar, S, Pennell, CE, Yap, M, Haarman, AEG, Enthoven, CA, Polling, J, Hewitt, AW, Jaddoe, VWV, van Duijn, CM, Hayward, C, Polasek, O, Tai, E-S, Yoshikatsu, H, Hysi, PG, Young, TL, Tsujikawa, A, Wang, JJ, Mitchell, P, Pfeiffer, N, Parssinen, O, Foster, PJ, Fossarello, M, Yip, SP, Williams, C, Hammond, CJ, Jonas, JB, He, M, Mackey, DA, Wong, T-Y, Klaver, CCW, Saw, S-M, Baird, PN, and Cheng, C-Y

Abstract

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.

Published
2020

5. IMI - Myopia Genetics Report

Author

Tedja, MS, Haarman, AEG, Meester-Smoor, MA, Kaprio, J, Mackey, DA, Guggenheim, JA, Hammond, CJ, Verhoeven, VJM, Klaver, CCW, Bailey-Wilson, JE, Baird, PN, Veluchamy, AB, Biino, G, Burdon, KP, Campbell, H, Chen, LJ, Cheng, C-Y, Chew, EY, Craig, JE, Cumberland, PM, Deangelis, MM, Delcourt, C, Ding, X, van Duijn, CM, Evans, DM, Fan, Q, Fossarello, M, Foster, PJ, Gharahkhani, P, Iglesias, AI, Guol, X, Haller, T, Han, X, Hayward, C, He, M, Hewitt, AW, Hoang, Q, Hysi, PG, Igo, RP, Iyengar, SK, Jonas, JB, Kahonen, M, Khawaja, AP, Klein, BE, Klein, R, Lass, JH, Lee, K, Lehtimaki, T, Lewis, D, Li, Q, Li, S-M, Lyytikainen, L-P, MacGregor, S, Martin, NG, Meguro, A, Metspalu, A, Middlebrooks, C, Miyake, M, Mizuki, N, Musolf, A, Nickels, S, Oexle, K, Pang, CP, Parssinen, O, Paterson, AD, Pfeiffer, N, Polasek, O, Rahi, JS, Raitakari, O, Rudan, I, Sahebjada, S, Saw, S-M, Stambolian, D, Simpson, CL, Tai, E-S, Tideman, JWL, Tsujikawa, A, Vitart, V, Wang, N, Wedenoja, J, Wei, WB, Williams, C, Williams, KM, Wilson, JF, Wojciechowski, R, Wang, YX, Yamashiro, K, Yam, JCS, Yap, MKH, Yazar, S, Yip, SP, Young, TL, Zhou, X, Tedja, MS, Haarman, AEG, Meester-Smoor, MA, Kaprio, J, Mackey, DA, Guggenheim, JA, Hammond, CJ, Verhoeven, VJM, Klaver, CCW, Bailey-Wilson, JE, Baird, PN, Veluchamy, AB, Biino, G, Burdon, KP, Campbell, H, Chen, LJ, Cheng, C-Y, Chew, EY, Craig, JE, Cumberland, PM, Deangelis, MM, Delcourt, C, Ding, X, van Duijn, CM, Evans, DM, Fan, Q, Fossarello, M, Foster, PJ, Gharahkhani, P, Iglesias, AI, Guol, X, Haller, T, Han, X, Hayward, C, He, M, Hewitt, AW, Hoang, Q, Hysi, PG, Igo, RP, Iyengar, SK, Jonas, JB, Kahonen, M, Khawaja, AP, Klein, BE, Klein, R, Lass, JH, Lee, K, Lehtimaki, T, Lewis, D, Li, Q, Li, S-M, Lyytikainen, L-P, MacGregor, S, Martin, NG, Meguro, A, Metspalu, A, Middlebrooks, C, Miyake, M, Mizuki, N, Musolf, A, Nickels, S, Oexle, K, Pang, CP, Parssinen, O, Paterson, AD, Pfeiffer, N, Polasek, O, Rahi, JS, Raitakari, O, Rudan, I, Sahebjada, S, Saw, S-M, Stambolian, D, Simpson, CL, Tai, E-S, Tideman, JWL, Tsujikawa, A, Vitart, V, Wang, N, Wedenoja, J, Wei, WB, Williams, C, Williams, KM, Wilson, JF, Wojciechowski, R, Wang, YX, Yamashiro, K, Yam, JCS, Yap, MKH, Yazar, S, Yip, SP, Young, TL, and Zhou, X

Abstract

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 environmental 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.

Published
2019

6. Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error

Author

TEDJA, M. S., WOJCIECHOWSKI, R., HYSI, P. G., ERIKSSON, N., FURLOTTE, N. A., VERHOEVEN, V. J. M., IGLESIAS, A. I., MEESTER-SMOOR, M. A., TOMPSON, S. W., Fan, Q., KHAWAJA, A. P., CHENG, C. Y., HOHN, R., YAMASHIRO, K., WENOCUR, A., GRAZAL, C., Haller, T., Metspalu, A., WEDENOJA, J., JONAS, J. B., WANG, Y. X., Xie, J., Mitchell, P., FOSTER, P. J., KLEIN, B. E. K., Klein, R., PATERSON, A. D., HOSSEINI, S. M., SHAH, R. L., Williams, C., TEO, Y. Y., THAM, Y. C., Gupta, P., Zhao, W., Shi, Y., SAW, W. Y., TAI, E. S., SIM, X. L., HUFFMAN, J. E., POLASEK, O., Hayward, C., BENCIC, G., RUDAN, I., WILSON, J. F., Joshi, P. K., TSUJIKAWA, A., Matsuda, F., WHISENHUNT, K. N., Zeller, T., VAN DER SPEK, P. J., HAAK, R., Meijers-Heijboer, H., VAN LEEUWEN, E. M., IYENGAR, S. K., LASS, J. H., Hofman, A., Rivadeneira, F., UITTERLINDEN, A. G., VINGERLING, J. R., LEHTIMAKI, T., RAITAKARI, O. T., BIINO, G., CONCAS, M. P., SCHWANTES-AN, T. H., IGO, R. P., Jr., CUELLAR-PARTIDA, G., Martin, N. G., CRAIG, J. E., GHARAHKHANI, P., Williams, K. M., NAG, A., RAHI, J. S., CUMBERLAND, P. M., Delcourt, Cécile, Bellenguez, C., RIED, J. S., BERGEN, A. A., Meitinger, T., Gieger, C., WONG, T. Y., HEWITT, A. W., MACKEY, D. A., SIMPSON, C. L., Pfeiffer, N., PARSSINEN, O., BAIRD, P. N., Vitart, V., Amin, N., VAN DUIJN, C. M., BAILEY-WILSON, J. E., YOUNG, T. L., SAW, S. M., STAMBOLIAN, D., MACGREGOR, S., GUGGENHEIM, J. A., TUNG, J. Y., HAMMOND, C. J., KLAVER, C. C. W., Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, sense organs, LEHA
Abstract

Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.

Published
2018

7. Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error

Author

Tedja, M.S., Wojciechowski, R., Hysi, P.G., Eriksson, N., Furlotte, N.A., Verhoeven, V.J., Iglesias, A.I., Meester-Smoor, M.A., Tompson, S.W., Fan, Q., Khawaja, A.P., Cheng, C.Y., Hohn, R., Yamashiro, K., Wenocur, A., Grazal, C., Haller, T., Metspalu, A., Wedenoja, J., Jonas, J.B., Wang, Y.X., Xie, J, Mitchell, P., Foster, P.J., Klein, B.E., Klein, R., Paterson, A.D., Hosseini, S.M., Shah, R.L., Williams, C., Teo, Y.Y., Tham, Y.C., Gupta, P., Zhao, W., Shi, Yuan, Saw, W.Y., Tai, E.S., Sim, X.L., Huffman, J.E., Polasek, O., Hayward, C., Bencic, G., Rudan, I., Wilson, J.F., Joshi, P.K., Tsujikawa, A., Matsuda, F., Whisenhunt, K.N., Zeller, T., Spek, P.J. van der, Haak, R., Meijers-Heijboer, H., Leeuwen, E.M. van, Iyengar, S.K., Lass, J.H., Hofman, A., Rivadeneira, F., Uitterlinden, A.G., Vingerling, J.R., Lehtimaki, T., Raitakari, O.T., Biino, G., Concas, M.P., Schwantes-An, T.H., Igo, R.P., Jr., Cuellar-Partida, G., Martin, N.G., Craig, J.E., Gharahkhani, P., Williams, K.M., Nag, A., Rahi, J.S., Cumberland, P.M., Delcourt, C, Bellenguez, C., Ried, J.S., Bergen, A.A., Meitinger, T., Gieger, C., Wong, T.Y., Hewitt, A.W., Mackey, D.A., Simpson, C.L., Pfeiffer, N., Parssinen, O., Baird, P.N., Vitart, V., Amin, N., Duijn, C.M. van, Bailey-Wilson, J.E., Young, T.L., Saw, S.M., Stambolian, D., MacGregor, S., Guggenheim, J.A., Tung, J.Y., Hammond, C.J., Klaver, C.C.W., Tedja, M.S., Wojciechowski, R., Hysi, P.G., Eriksson, N., Furlotte, N.A., Verhoeven, V.J., Iglesias, A.I., Meester-Smoor, M.A., Tompson, S.W., Fan, Q., Khawaja, A.P., Cheng, C.Y., Hohn, R., Yamashiro, K., Wenocur, A., Grazal, C., Haller, T., Metspalu, A., Wedenoja, J., Jonas, J.B., Wang, Y.X., Xie, J, Mitchell, P., Foster, P.J., Klein, B.E., Klein, R., Paterson, A.D., Hosseini, S.M., Shah, R.L., Williams, C., Teo, Y.Y., Tham, Y.C., Gupta, P., Zhao, W., Shi, Yuan, Saw, W.Y., Tai, E.S., Sim, X.L., Huffman, J.E., Polasek, O., Hayward, C., Bencic, G., Rudan, I., Wilson, J.F., Joshi, P.K., Tsujikawa, A., Matsuda, F., Whisenhunt, K.N., Zeller, T., Spek, P.J. van der, Haak, R., Meijers-Heijboer, H., Leeuwen, E.M. van, Iyengar, S.K., Lass, J.H., Hofman, A., Rivadeneira, F., Uitterlinden, A.G., Vingerling, J.R., Lehtimaki, T., Raitakari, O.T., Biino, G., Concas, M.P., Schwantes-An, T.H., Igo, R.P., Jr., Cuellar-Partida, G., Martin, N.G., Craig, J.E., Gharahkhani, P., Williams, K.M., Nag, A., Rahi, J.S., Cumberland, P.M., Delcourt, C, Bellenguez, C., Ried, J.S., Bergen, A.A., Meitinger, T., Gieger, C., Wong, T.Y., Hewitt, A.W., Mackey, D.A., Simpson, C.L., Pfeiffer, N., Parssinen, O., Baird, P.N., Vitart, V., Amin, N., Duijn, C.M. van, Bailey-Wilson, J.E., Young, T.L., Saw, S.M., Stambolian, D., MacGregor, S., Guggenheim, J.A., Tung, J.Y., Hammond, C.J., and Klaver, C.C.W.

Abstract

Item does not contain fulltext, Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.

Published
2018

8. A genome-wide association study of corneal astigmatism: The CREAM Consortium

Author

Shah, R.L., Li, Q., Zhao, W., Tedja, M.S., Tideman, J.W., Khawaja, A.P., Fan, Q., Yazar, S., Williams, K.M., Verhoeven, V.J., Xie, J., Wang, Y.X., Hess, M., Nickels, S., Lackner, K.J., Parssinen, O., Wedenoja, J., Biino, G., Concas, M.P., Uitterlinden, A., Rivadeneira, F., Jaddoe, V.W., Hysi, P.G., Sim, X., Tan, N., Tham, Y.C., Sensaki, S., Hofman, A., Vingerling, J.R., Jonas, J.B., Mitchell, P., Hammond, C.J., Hohn, R., Baird, P.N., Wong, T.Y., Cheng, C.Y., Teo, Y.Y., Mackey, D.A., Williams, C., Saw, S.M., Klaver, C.C.W., Guggenheim, J.A., Bailey-Wilson, J.E., Shah, R.L., Li, Q., Zhao, W., Tedja, M.S., Tideman, J.W., Khawaja, A.P., Fan, Q., Yazar, S., Williams, K.M., Verhoeven, V.J., Xie, J., Wang, Y.X., Hess, M., Nickels, S., Lackner, K.J., Parssinen, O., Wedenoja, J., Biino, G., Concas, M.P., Uitterlinden, A., Rivadeneira, F., Jaddoe, V.W., Hysi, P.G., Sim, X., Tan, N., Tham, Y.C., Sensaki, S., Hofman, A., Vingerling, J.R., Jonas, J.B., Mitchell, P., Hammond, C.J., Hohn, R., Baird, P.N., Wong, T.Y., Cheng, C.Y., Teo, Y.Y., Mackey, D.A., Williams, C., Saw, S.M., Klaver, C.C.W., Guggenheim, J.A., and Bailey-Wilson, J.E.

Abstract

Contains fulltext : 191261.pdf (publisher's version ) (Open Access), Purpose: To identify genes and genetic markers associated with corneal astigmatism. Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. Results: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55x10(-9). No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.

Published
2018

9. Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error

Author

Tedja, Milly S, Wojciechowski, Robert, Hysi, Pirro G, Eriksson, Nicholas, Furlotte, Nicholas A, Verhoeven, Virginie J M, Iglesias, Adriana I, Meester-Smoor, Magda A, Tompson, Stuart W, Fan, Qiao, Khawaja, Anthony P, Cheng, Ching-Yu, Höhn, René, Yamashiro, Kenji, Wenocur, Adam, Grazal, Clare, Haller, Toomas, Metspalu, Andres, Wedenoja, Juho, Jonas, Jost B, Wang, Ya Xing, Xie, Jing, Mitchell, Paul, Foster, Paul J, Klein, Barbara E K, Klein, Ronald, Paterson, Andrew D, Hosseini, S Mohsen, Shah, Rupal L, Williams, Cathy, Teo, Yik-Ying, Tham, Yih Chung, Gupta, Preeti, Zhao, Wanting, Shi, Yuan, Saw, Woei-Yuh, Tai, E-Shyong, Sim, Xue Ling, Huffman, Jennifer E, Polašek, Ozren, Hayward, Caroline, Bencic, Goran, Rudan, Igor, Wilson, James F, CREAM Consortium, Joshi, Peter K, Tsujikawa, Akitaka, Matsuda, Fumihiko, Whisenhunt, Kristina N, Zeller, Tanja, Van der Spek, P.J., Haak, R., Meijers-Heijboer, Hanne, van Leeuwen, Elisabeth M, Iyengar, Sudha K, Lass, J.H., Hofman, A., Rivadeneira, F., Uitterlinden, A.G., Vingerling, J.R., Lehtimaki, T., Raitakari, O.T., Biino, G., Concas, M.P., Schwantes-An, T.H., Igo, R.P., Cuellar-Partida, G., Martin, N.G., Craig, J.E., Gharahkhani, P., Williams, K.M., Naq, A., Rahi, J.S., Cumberland, P.M., Delcourt, C., Bellenquez, C., Ried, J.S., Bergen, Arthur A, Meitinger, T., Gieger, C., Wong, T.Y., Hewitt, A.W., Mackey, D.A., Simpson, C.L., Pfeiffer, N., Parssinen, O., Baird, P.N., Vitart, V., Amin, N., Van Duijn, C.M., Bailey-Wilson, J.E., Young, T.L., Saw, S.M., Stambolian, D., MacGregor, S., Guggenheim, J.A., Tung, J.Y., Hammond, C.J., Klaver, C.C.W., Tedja, Milly S, Wojciechowski, Robert, Hysi, Pirro G, Eriksson, Nicholas, Furlotte, Nicholas A, Verhoeven, Virginie J M, Iglesias, Adriana I, Meester-Smoor, Magda A, Tompson, Stuart W, Fan, Qiao, Khawaja, Anthony P, Cheng, Ching-Yu, Höhn, René, Yamashiro, Kenji, Wenocur, Adam, Grazal, Clare, Haller, Toomas, Metspalu, Andres, Wedenoja, Juho, Jonas, Jost B, Wang, Ya Xing, Xie, Jing, Mitchell, Paul, Foster, Paul J, Klein, Barbara E K, Klein, Ronald, Paterson, Andrew D, Hosseini, S Mohsen, Shah, Rupal L, Williams, Cathy, Teo, Yik-Ying, Tham, Yih Chung, Gupta, Preeti, Zhao, Wanting, Shi, Yuan, Saw, Woei-Yuh, Tai, E-Shyong, Sim, Xue Ling, Huffman, Jennifer E, Polašek, Ozren, Hayward, Caroline, Bencic, Goran, Rudan, Igor, Wilson, James F, CREAM Consortium, Joshi, Peter K, Tsujikawa, Akitaka, Matsuda, Fumihiko, Whisenhunt, Kristina N, Zeller, Tanja, Van der Spek, P.J., Haak, R., Meijers-Heijboer, Hanne, van Leeuwen, Elisabeth M, Iyengar, Sudha K, Lass, J.H., Hofman, A., Rivadeneira, F., Uitterlinden, A.G., Vingerling, J.R., Lehtimaki, T., Raitakari, O.T., Biino, G., Concas, M.P., Schwantes-An, T.H., Igo, R.P., Cuellar-Partida, G., Martin, N.G., Craig, J.E., Gharahkhani, P., Williams, K.M., Naq, A., Rahi, J.S., Cumberland, P.M., Delcourt, C., Bellenquez, C., Ried, J.S., Bergen, Arthur A, Meitinger, T., Gieger, C., Wong, T.Y., Hewitt, A.W., Mackey, D.A., Simpson, C.L., Pfeiffer, N., Parssinen, O., Baird, P.N., Vitart, V., Amin, N., Van Duijn, C.M., Bailey-Wilson, J.E., Young, T.L., Saw, S.M., Stambolian, D., MacGregor, S., Guggenheim, J.A., Tung, J.Y., Hammond, C.J., and Klaver, C.C.W.

Abstract

Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.

Published
2018

10. A genome-wide association study of corneal astigmatism: The CREAM Consortium

Author

Shah, RL, Li, Q, Zhao, W, Tedja, MS, Tideman, JWL, Khawaja, AP, Fan, Q, Yazar, S, Williams, KM, Verhoeven, VJM, Xie, J, Wang, YX, Hess, M, Nickels, S, Lackner, KJ, Parssinen, O, Wedenoja, J, Biino, G, Concas, MP, Uitterlinden, A, Rivadeneira, F, Jaddoe, VWV, Hysi, PG, Sim, X, Tan, N, Tham, Y-C, Sensaki, S, Hofman, A, Vingerling, JR, Jonas, JB, Mitchell, P, Hammond, CJ, Hoehn, R, Baird, PN, Wong, T-Y, Cheng, C-Y, Teo, YY, Mackey, DA, Williams, C, Saw, S-M, Klaver, CCW, Guggenheim, JA, Bailey-Wilson, JE, Shah, RL, Li, Q, Zhao, W, Tedja, MS, Tideman, JWL, Khawaja, AP, Fan, Q, Yazar, S, Williams, KM, Verhoeven, VJM, Xie, J, Wang, YX, Hess, M, Nickels, S, Lackner, KJ, Parssinen, O, Wedenoja, J, Biino, G, Concas, MP, Uitterlinden, A, Rivadeneira, F, Jaddoe, VWV, Hysi, PG, Sim, X, Tan, N, Tham, Y-C, Sensaki, S, Hofman, A, Vingerling, JR, Jonas, JB, Mitchell, P, Hammond, CJ, Hoehn, R, Baird, PN, Wong, T-Y, Cheng, C-Y, Teo, YY, Mackey, DA, Williams, C, Saw, S-M, Klaver, CCW, Guggenheim, JA, and Bailey-Wilson, JE

Abstract

PURPOSE: To identify genes and genetic markers associated with corneal astigmatism. METHODS: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression. RESULTS: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha (PDGFRA) gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55×10-9. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (CLDN7), acid phosphatase 2, lysosomal (ACP2), and TNF alpha-induced protein 8 like 3 (TNFAIP8L3). CONCLUSIONS: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the PDGFRA gene, gene-based analysis identified three novel candidate genes, CLDN7, ACP2, and TNFAIP8L3, that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.

Published
2018

11. Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium

Author

Fan, Q, Guo, X, Tideman, Willem, Williams, KM, Yazar, S, Hosseini, SM, Howe, LD, St Pourcain, B, Evans, DM, Timpson, NJ, McMahon, G, Hysi, PG, Krapohl, E, Wang, YX, Jonas, JB, Baird, PN, Wang, JJ, Cheng, CY (Ching-Yu), Teo, YY, Wong, TY, Ding, X, Wojciechowski, R, Young, TL, Parssinen, O, Oexle, K, Pfeiffer, N, Bailey-Wilson, JE, Paterson, AD, Klaver, Caroline, Plomin, R, Hammond, CJ, Mackey, DA, He, MG, Saw, SM, Williams, C, Guggenheim, JA, Epidemiology, and Ophthalmology

Subjects
Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12]
Abstract

Contains fulltext : 167190.pdf (Publisher’s version ) (Open Access) Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).

Published
2016

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

Author

Fan, Q., Verhoeven, V.J., Wojciechowski, R., Barathi, V.A., Hysi, P.G., Guggenheim, J.A., Hohn, R., Vitart, V., Khawaja, A.P., Yamashiro, K., Hosseini, S.M., Lehtimaki, T., Lu, Y., Haller, T., Xie, J., Delcourt, C, Pirastu, M., Wedenoja, J., Gharahkhani, P., Venturini, C., Miyake, M., Hewitt, A.W., Guo, X., Mazur, J., Huffman, J.E., Williams, K.M., Polasek, O., Campbell, H., Rudan, I., Vatavuk, Z., Wilson, J.F., Joshi, P.K., McMahon, G., St Pourcain, B., Evans, D.M., Simpson, C.L., Schwantes-An, T.H., Igo, R.P., Jr., Mirshahi, A., Cougnard-Gregoire, A., Bellenguez, C., Blettner, M., Raitakari, O., Kahonen, M., Seppala, I., Zeller, T., Meitinger, T., Ried, J.S., Gieger, C., Portas, L., Leeuwen, E.M. van, Amin, N., Uitterlinden, A.G., Rivadeneira, F., Hofman, A., Vingerling, J.R., Wang, Y.X., Wang, X., Boh, E.T.H., Ikram, M.K., Sabanayagam, C., Gupta, P., Tan, V., Zhou, L, Ho, C.E., Lim, W., Beuerman, R.W., Siantar, R., Tai, E.S., Vithana, E., Mihailov, E., Khor, C.C., Hayward, C., Luben, R.N., Foster, P.J., Klein, B.E., Klein, R., Wong, H.S., Mitchell, P., Metspalu, A., Aung, T., Young, T.L., He, M., Parssinen, O., Duijn, C.M. van, Wang, J.J., Williams, C., Jonas, J.B., Teo, Y.Y., Mackey, D.A., Oexle, K., Yoshimura, N., Paterson, A.D., Pfeiffer, N., Wong, T.Y., Baird, P.N., Stambolian, D., Wilson, J.E., Cheng, C.Y., Hammond, C.J., Klaver, C.C.W., et al., Fan, Q., Verhoeven, V.J., Wojciechowski, R., Barathi, V.A., Hysi, P.G., Guggenheim, J.A., Hohn, R., Vitart, V., Khawaja, A.P., Yamashiro, K., Hosseini, S.M., Lehtimaki, T., Lu, Y., Haller, T., Xie, J., Delcourt, C, Pirastu, M., Wedenoja, J., Gharahkhani, P., Venturini, C., Miyake, M., Hewitt, A.W., Guo, X., Mazur, J., Huffman, J.E., Williams, K.M., Polasek, O., Campbell, H., Rudan, I., Vatavuk, Z., Wilson, J.F., Joshi, P.K., McMahon, G., St Pourcain, B., Evans, D.M., Simpson, C.L., Schwantes-An, T.H., Igo, R.P., Jr., Mirshahi, A., Cougnard-Gregoire, A., Bellenguez, C., Blettner, M., Raitakari, O., Kahonen, M., Seppala, I., Zeller, T., Meitinger, T., Ried, J.S., Gieger, C., Portas, L., Leeuwen, E.M. van, Amin, N., Uitterlinden, A.G., Rivadeneira, F., Hofman, A., Vingerling, J.R., Wang, Y.X., Wang, X., Boh, E.T.H., Ikram, M.K., Sabanayagam, C., Gupta, P., Tan, V., Zhou, L, Ho, C.E., Lim, W., Beuerman, R.W., Siantar, R., Tai, E.S., Vithana, E., Mihailov, E., Khor, C.C., Hayward, C., Luben, R.N., Foster, P.J., Klein, B.E., Klein, R., Wong, H.S., Mitchell, P., Metspalu, A., Aung, T., Young, T.L., He, M., Parssinen, O., Duijn, C.M. van, Wang, J.J., Williams, C., Jonas, J.B., Teo, Y.Y., Mackey, D.A., Oexle, K., Yoshimura, N., Paterson, A.D., Pfeiffer, N., Wong, T.Y., Baird, P.N., Stambolian, D., Wilson, J.E., Cheng, C.Y., Hammond, C.J., Klaver, C.C.W., and et al.

Abstract

Contains fulltext : 167942.pdf (publisher's version ) (Open Access), Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP x education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 x 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.

Published
2016

13. Childhood gene-environment interactions and age-dependent effects of genetic variants associated with refractive error and myopia: The CREAM Consortium

Author

Fan, Q., Guo, X., Tideman, J.W., Williams, K.M., Yazar, S., Hosseini, S.M., Howe, L.D., Pourcain, B.S., Evans, D.M., Timpson, N.J., McMahon, G., Hysi, P.G., Krapohl, E., Wang, Y.X., Jonas, J.B., Baird, P.N., Wang, J.J., Cheng, C.Y., Teo, Y.Y., Wong, T.Y., Ding, X., Wojciechowski, R., Young, T.L., Parssinen, O., Oexle, K., Pfeiffer, N., Bailey-Wilson, J.E., Paterson, A.D., Klaver, C.C.W., Plomin, R., Hammond, C.J., Mackey, D.A., He, M., Saw, S.M., Williams, C., Guggenheim, J.A., Fan, Q., Guo, X., Tideman, J.W., Williams, K.M., Yazar, S., Hosseini, S.M., Howe, L.D., Pourcain, B.S., Evans, D.M., Timpson, N.J., McMahon, G., Hysi, P.G., Krapohl, E., Wang, Y.X., Jonas, J.B., Baird, P.N., Wang, J.J., Cheng, C.Y., Teo, Y.Y., Wong, T.Y., Ding, X., Wojciechowski, R., Young, T.L., Parssinen, O., Oexle, K., Pfeiffer, N., Bailey-Wilson, J.E., Paterson, A.D., Klaver, C.C.W., Plomin, R., Hammond, C.J., Mackey, D.A., He, M., Saw, S.M., Williams, C., and Guggenheim, J.A.

Abstract

Contains fulltext : 167190.pdf (publisher's version ) (Open Access), Myopia, currently at epidemic levels in East Asia, is a leading cause of untreatable visual impairment. Genome-wide association studies (GWAS) in adults have identified 39 loci associated with refractive error and myopia. Here, the age-of-onset of association between genetic variants at these 39 loci and refractive error was investigated in 5200 children assessed longitudinally across ages 7-15 years, along with gene-environment interactions involving the major environmental risk-factors, nearwork and time outdoors. Specific variants could be categorized as showing evidence of: (a) early-onset effects remaining stable through childhood, (b) early-onset effects that progressed further with increasing age, or (c) onset later in childhood (N = 10, 5 and 11 variants, respectively). A genetic risk score (GRS) for all 39 variants explained 0.6% (P = 6.6E-08) and 2.3% (P = 6.9E-21) of the variance in refractive error at ages 7 and 15, respectively, supporting increased effects from these genetic variants at older ages. Replication in multi-ancestry samples (combined N = 5599) yielded evidence of childhood onset for 6 of 12 variants present in both Asians and Europeans. There was no indication that variant or GRS effects altered depending on time outdoors, however 5 variants showed nominal evidence of interactions with nearwork (top variant, rs7829127 in ZMAT4; P = 6.3E-04).

Published
2016

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

Author

Li, Q, Wojciechowski, R, Simpson, CL, Hysi, PG, Verhoeven, VJM, Ikram, MK, Hoehn, R, Vitart, V, Hewitt, AW, Oexle, K, Makela, K-M, MacGregor, S, Pirastu, M, Fan, Q, Cheng, C-Y, St Pourcain, B, McMahon, G, Kemp, JP, Northstone, K, Rahi, JS, Cumberland, PM, Martin, NG, Sanfilippo, PG, Lu, Y, Wang, YX, Hayward, C, Polasek, O, Campbell, H, Bencic, G, Wright, AF, Wedenoja, J, Zeller, T, Schillert, A, Mirshahi, A, Lackner, K, Yip, SP, Yap, MKH, Ried, JS, Gieger, C, Murgia, F, Wilson, JF, Fleck, B, Yazar, S, Vingerling, JR, Hofman, A, Uitterlinden, A, Rivadeneira, F, Amin, N, Karssen, L, Oostra, BA, Zhou, X, Teo, Y-Y, Tai, ES, Vithana, E, Barathi, V, Zheng, Y, Siantar, RG, Neelam, K, Shin, Y, Lam, J, Yonova-Doing, E, Venturini, C, Hosseini, SM, Wong, H-S, Lehtimaki, T, Kahonen, M, Raitakari, O, Timpson, NJ, Evans, DM, Khor, C-C, Aung, T, Young, TL, Mitchell, P, Klein, B, van Duijn, CM, Meitinger, T, Jonas, JB, Baird, PN, Mackey, DA, Wong, TY, Saw, S-M, Parssinen, O, Stambolian, D, Hammond, CJ, Klaver, CCW, Williams, C, Paterson, AD, Bailey-Wilson, JE, Guggenheim, JA, Li, Q, Wojciechowski, R, Simpson, CL, Hysi, PG, Verhoeven, VJM, Ikram, MK, Hoehn, R, Vitart, V, Hewitt, AW, Oexle, K, Makela, K-M, MacGregor, S, Pirastu, M, Fan, Q, Cheng, C-Y, St Pourcain, B, McMahon, G, Kemp, JP, Northstone, K, Rahi, JS, Cumberland, PM, Martin, NG, Sanfilippo, PG, Lu, Y, Wang, YX, Hayward, C, Polasek, O, Campbell, H, Bencic, G, Wright, AF, Wedenoja, J, Zeller, T, Schillert, A, Mirshahi, A, Lackner, K, Yip, SP, Yap, MKH, Ried, JS, Gieger, C, Murgia, F, Wilson, JF, Fleck, B, Yazar, S, Vingerling, JR, Hofman, A, Uitterlinden, A, Rivadeneira, F, Amin, N, Karssen, L, Oostra, BA, Zhou, X, Teo, Y-Y, Tai, ES, Vithana, E, Barathi, V, Zheng, Y, Siantar, RG, Neelam, K, Shin, Y, Lam, J, Yonova-Doing, E, Venturini, C, Hosseini, SM, Wong, H-S, Lehtimaki, T, Kahonen, M, Raitakari, O, Timpson, NJ, Evans, DM, Khor, C-C, Aung, T, Young, TL, Mitchell, P, Klein, B, van Duijn, CM, Meitinger, T, Jonas, JB, Baird, PN, Mackey, DA, Wong, TY, Saw, S-M, Parssinen, O, Stambolian, D, Hammond, CJ, Klaver, CCW, Williams, C, Paterson, AD, Bailey-Wilson, JE, and Guggenheim, JA

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 <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.

Published
2015

15. Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia (vol 45, pg 314, 2013)

Author

Verhoeven, Virginie, Hysi, PG, Wojciechowski, R, Fan, Q, Guggenheim, JA, Hohn, R, Macgregor, S, Hewitt, AW, Nag, A, Cheng, CY (Ching-Yu), Yonova-Doing, E, Zhou, X, Ikram, Kamran, Buitendijk, Gabriëlle, McMahon, G, Kemp, JP, St Pourcain, B, Simpson, CL, Makela, KM, Lehtimaki, T, Kahonen, M, Paterson, AD, Hosseini, SM, Wong, HS, Xu, L, Jonas, JB, Parssinen, O, Wedenoja, J, Yip, SP, Ho, DWH, Pang, CP, Chen, LJ, Burdon, KP, Craig, JE, Klein, BEK, Klein, R, Haller, T, Metspalu, A, Khor, CC, Tai, ES, Aung, T, Vithana, E, Tay, WT, Barathi, VA, Chen, Peng, Li, RY, Liao, JM, Zheng, YF, Ong, RT, Doring, A, Evans, DM, Timpson, NJ, Verkerk, AJMH, Meitinger, T, Raitakari, O, Hawthorne, F, Spector, TD, Karssen, Lennart, Pirastu, M, Murgia, F, Ang, W, Mishra, A, Montgomery, GW, Pennell, CE, Cumberland, PM, Cotlarciuc, I, Mitchell, P, Wang, JJ, Schache, M, Janmahasathian, S, Igo, RP, Lass, JH, Chew, E, KIyengar, S, Gorgels, TGMF (Theo), Rudan, I, Hayward, C, Wright, AF, Polasek, O, Vatavuk, Z, Wilson, JF, Fleck, B, Zeller, T, Mirshahi, A, Müller, Caspar, Uitterlinden, André, Rivadeneira, Fernando, Vingerling, Hans, Hofman, Bert, Oostra, Ben, Amin, Najaf, Bergen, Arthur, Teo, YY, Rahi, JS, Vitart, V, Williams, C, Baird, PN, Wong, TY (Tien Yin), Oexle, K, Pfeiffer, N, Mackey, DA, Young, TL, Duijn, Cornelia, Saw, SM, Bailey-Wilson, JE, Stambolian, D, Klaver, Caroline, Hammond, CJ, Ophthalmology, Pathology, Epidemiology, Cell biology, Anesthesiology, Internal Medicine, Clinical Genetics, and Obstetrics & Gynecology

Published
2013

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

Author

Verhoeven, VJM, Hysi, PG, Saw, S-M, Vitart, V, Mirshahi, A, Guggenheim, JA, Cotch, MF, Yamashiro, K, Baird, PN, Mackey, DA, Wojciechowski, R, Ikram, MK, Hewitt, AW, Duggal, P, Janmahasatian, S, Khor, C-C, Fan, Q, Zhou, X, Young, TL, Tai, E-S, Goh, L-K, Li, Y-J, Aung, T, Vithana, E, Teo, Y-Y, Tay, W, Sim, X, Rudan, I, Hayward, C, Wright, AF, Polasek, O, Campbell, H, Wilson, JF, Fleck, BW, Nakata, I, Yoshimura, N, Yamada, R, Matsuda, F, Ohno-Matsui, K, Nag, A, McMahon, G, St Pourcain, B, Lu, Y, Rahi, JS, Cumberland, PM, Bhattacharya, S, Simpson, CL, Atwood, LD, Li, X, Raffel, LJ, Murgia, F, Portas, L, Despriet, DDG, van Koolwijk, LME, Wolfram, C, Lackner, KJ, Toenjes, A, Maegi, R, Lehtimaki, T, Kahonen, M, Esko, T, Metspalu, A, Rantanen, T, Parssinen, O, Klein, BE, Meitinger, T, Spector, TD, Oostra, BA, Smith, AV, de Jong, PTVM, Hofman, A, Amin, N, Karssen, LC, Rivadeneira, F, Vingerling, JR, Eiriksdottir, G, Gudnason, V, Doering, A, Bettecken, T, Uitterlinden, AG, Williams, C, Zeller, T, Castagne, R, Oexle, K, van Duijn, CM, Iyengar, SK, Mitchell, P, Wang, JJ, Hoehn, R, Pfeiffer, N, Bailey-Wilson, JE, Stambolian, D, Wong, T-Y, Hammond, CJ, Klaver, CCW, Verhoeven, VJM, Hysi, PG, Saw, S-M, Vitart, V, Mirshahi, A, Guggenheim, JA, Cotch, MF, Yamashiro, K, Baird, PN, Mackey, DA, Wojciechowski, R, Ikram, MK, Hewitt, AW, Duggal, P, Janmahasatian, S, Khor, C-C, Fan, Q, Zhou, X, Young, TL, Tai, E-S, Goh, L-K, Li, Y-J, Aung, T, Vithana, E, Teo, Y-Y, Tay, W, Sim, X, Rudan, I, Hayward, C, Wright, AF, Polasek, O, Campbell, H, Wilson, JF, Fleck, BW, Nakata, I, Yoshimura, N, Yamada, R, Matsuda, F, Ohno-Matsui, K, Nag, A, McMahon, G, St Pourcain, B, Lu, Y, Rahi, JS, Cumberland, PM, Bhattacharya, S, Simpson, CL, Atwood, LD, Li, X, Raffel, LJ, Murgia, F, Portas, L, Despriet, DDG, van Koolwijk, LME, Wolfram, C, Lackner, KJ, Toenjes, A, Maegi, R, Lehtimaki, T, Kahonen, M, Esko, T, Metspalu, A, Rantanen, T, Parssinen, O, Klein, BE, Meitinger, T, Spector, TD, Oostra, BA, Smith, AV, de Jong, PTVM, Hofman, A, Amin, N, Karssen, LC, Rivadeneira, F, Vingerling, JR, Eiriksdottir, G, Gudnason, V, Doering, A, Bettecken, T, Uitterlinden, AG, Williams, C, Zeller, T, Castagne, R, Oexle, K, van Duijn, CM, Iyengar, SK, Mitchell, P, Wang, JJ, Hoehn, R, Pfeiffer, N, Bailey-Wilson, JE, Stambolian, D, Wong, T-Y, Hammond, CJ, and Klaver, CCW

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 < 0.001) for homozygous carriers of the risk allele at the top SNP rs634990, and OR 1.33 (95 % CI 1.19, 1.49, P < 0.001) for heterozygous carriers. SNPs at locus 15q25 did not replicate significantly (P value 5.81 × 10(-2) for top SNP rs939661). We conclude that common variants at chromosome 15q14 influence susceptibility for myopia in Caucasian and Asian populations world-wide.

Published
2012

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

Author

Verhoeven, Virginie, Hysi, PG, Saw, SM, Vitart, V, Mirshahi, A, Guggenheim, JA, Cotch, MF, Yamashiro, K, Baird, PN, Mackey, DA, Wojciechowski, R, Ikram, Kamran, Hewitt, AW, Duggal, P, Janmahasatian, S, Khor, CC, Fan, Q, Zhou, X, Young, TL, Tai, ES, Goh, LK, Li, YJ, Aung, T, Vithana, E, Teo, YY, Tay, W, Sim, X, Rudan, I, Hayward, C, Wright, AF, Polasek, O, Campbell, H, Wilson, JF, Fleck, BW, Nakata, I, Yoshimura, N, Yamada, R, Matsuda, F, Ohno-Matsui, K, Nag, A, McMahon, G, St Pourcain, B, Lu, Y (Yi), Rahi, JS, Cumberland, PM, Bhattacharya, S, Simpson, CL, Atwood, LD, Li, XH, Raffel, LJ, Murgia, F, Portas, L, Despriet, Dominiek, Koolwijk, Leonieke, Wolfram, C, Lackner, KJ, Tonjes, A, Magi, R, Lehtimaki, T, Kahonen, M, Esko, T, Metspalu, A, Rantanen, T, Parssinen, O, Klein, BE, Meitinger, T, Spector, TD, Oostra, Ben, Smith, AV, de Jong, PTVM (Paulus), Hofman, Bert, Amin, Najaf, Karssen, Lennart, Rivadeneira, Fernando, Vingerling, Hans, Eiriksdottir, G, Gudnason, V, Doring, A, Bettecken, T, Uitterlinden, André, Williams, C, Zeller, T, Castagne, R, Oexle, K, Duijn, Cornelia, Iyengar, SK, Mitchell, P, Wang, JJ, Hohn, R, Pfeiffer, N, Bailey-Wilson, JE, Stambolian, D, Wong, TY, Hammond, CJ, Klaver, Caroline, Verhoeven, Virginie, Hysi, PG, Saw, SM, Vitart, V, Mirshahi, A, Guggenheim, JA, Cotch, MF, Yamashiro, K, Baird, PN, Mackey, DA, Wojciechowski, R, Ikram, Kamran, Hewitt, AW, Duggal, P, Janmahasatian, S, Khor, CC, Fan, Q, Zhou, X, Young, TL, Tai, ES, Goh, LK, Li, YJ, Aung, T, Vithana, E, Teo, YY, Tay, W, Sim, X, Rudan, I, Hayward, C, Wright, AF, Polasek, O, Campbell, H, Wilson, JF, Fleck, BW, Nakata, I, Yoshimura, N, Yamada, R, Matsuda, F, Ohno-Matsui, K, Nag, A, McMahon, G, St Pourcain, B, Lu, Y (Yi), Rahi, JS, Cumberland, PM, Bhattacharya, S, Simpson, CL, Atwood, LD, Li, XH, Raffel, LJ, Murgia, F, Portas, L, Despriet, Dominiek, Koolwijk, Leonieke, Wolfram, C, Lackner, KJ, Tonjes, A, Magi, R, Lehtimaki, T, Kahonen, M, Esko, T, Metspalu, A, Rantanen, T, Parssinen, O, Klein, BE, Meitinger, T, Spector, TD, Oostra, Ben, Smith, AV, de Jong, PTVM (Paulus), Hofman, Bert, Amin, Najaf, Karssen, Lennart, Rivadeneira, Fernando, Vingerling, Hans, Eiriksdottir, G, Gudnason, V, Doring, A, Bettecken, T, Uitterlinden, André, Williams, C, Zeller, T, Castagne, R, Oexle, K, Duijn, Cornelia, Iyengar, SK, Mitchell, P, Wang, JJ, Hohn, R, Pfeiffer, N, Bailey-Wilson, JE, Stambolian, D, Wong, TY, Hammond, CJ, and Klaver, Caroline

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 x 10(-12) for SNP rs634990 in Caucasians, and 9.65 x 10(-4) for rs8032019 in Asians. The overall meta-analysis provided P value 9.20 x 10(-23) for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95 % CI 1.64, 2.16, P < 0.001) for homozygous carriers of the risk allele at the top SNP rs634990, and OR 1.33 (95 % CI 1.19, 1.49, P < 0.001) for heterozygous carriers. SNPs at locus 15q25 did not replicate significantly (P value 5.81 x 10(-2) for top SNP rs939661). We conclude that common variants at chromosome 15q14 influence susceptibility for myopia in Caucasian and Asian populations world-wide.

Published
2012

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