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2. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

Author

Gharahkhani, P., Jorgenson, E., Hysi, P., Khawaja, A.P., Pendergrass, S., Han, X., Ong, J.S., Hewitt, A.W., Segrè, A.V., Rouhana, J.M., Hamel, A.R., Igo, R.P., Jr., Choquet, H., Qassim, A., Josyula, N.S., Bailey, J.N., Bonnemaijer, P.W.M., Iglesias, A., Siggs, O.M., Young, T.L., Vitart, V., Thiadens, A., Karjalainen, J., Uebe, S., Melles, R.B., Nair, K.S., Luben, R., Simcoe, M., Amersinghe, N., Cree, A.J., Hohn, R., Poplawski, A., Chen, L.J., Rong, S.S., Aung, T., Vithana, E.N., Tamiya, G., Shiga, Y., Yamamoto, M., Nakazawa, T., Currant, H., Birney, E., Wang, X, Auton, A., Lupton, M.K., Martin, N.G., Ashaye, A., Olawoye, O., Williams, S.E., Akafo, S., Ramsay, M., Hashimoto, K., Kamatani, Y., Akiyama, M., Momozawa, Y., Foster, P.J., Khaw, P.T., Morgan, J.E., Strouthidis, N.G., Kraft, P., Kang, J.H., Pang, C.P., Pasutto, F., Mitchell, P., Lotery, A.J., Palotie, A., Duijn, C. van, Haines, J.L., Hammond, C., Pasquale, L.R., Klaver, C.C.W., Hauser, M., Khor, C.C., Mackey, D.A., Kubo, M., Cheng, C.Y., Craig, J.E., MacGregor, S., Wiggs, J.L., Gharahkhani, P., Jorgenson, E., Hysi, P., Khawaja, A.P., Pendergrass, S., Han, X., Ong, J.S., Hewitt, A.W., Segrè, A.V., Rouhana, J.M., Hamel, A.R., Igo, R.P., Jr., Choquet, H., Qassim, A., Josyula, N.S., Bailey, J.N., Bonnemaijer, P.W.M., Iglesias, A., Siggs, O.M., Young, T.L., Vitart, V., Thiadens, A., Karjalainen, J., Uebe, S., Melles, R.B., Nair, K.S., Luben, R., Simcoe, M., Amersinghe, N., Cree, A.J., Hohn, R., Poplawski, A., Chen, L.J., Rong, S.S., Aung, T., Vithana, E.N., Tamiya, G., Shiga, Y., Yamamoto, M., Nakazawa, T., Currant, H., Birney, E., Wang, X, Auton, A., Lupton, M.K., Martin, N.G., Ashaye, A., Olawoye, O., Williams, S.E., Akafo, S., Ramsay, M., Hashimoto, K., Kamatani, Y., Akiyama, M., Momozawa, Y., Foster, P.J., Khaw, P.T., Morgan, J.E., Strouthidis, N.G., Kraft, P., Kang, J.H., Pang, C.P., Pasutto, F., Mitchell, P., Lotery, A.J., Palotie, A., Duijn, C. van, Haines, J.L., Hammond, C., Pasquale, L.R., Klaver, C.C.W., Hauser, M., Khor, C.C., Mackey, D.A., Kubo, M., Cheng, C.Y., Craig, J.E., MacGregor, S., and Wiggs, J.L.

Abstract

Contains fulltext : 235429.pdf (Publisher’s version ) (Open Access), Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

Published
2021

3. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

Author

Gharahkhani, P, Jorgenson, E, Hysi, P, Khawaja, AP, Pendergrass, S, Han, X, Ong, JS, Hewitt, AW, Segre, A, Rouhana, JM, Hamel, AR, Igo, RP, Choquet, H, Qassim, A, Josyula, NS, Bailey, JNC, Bonnemaijer, PWM, Iglesias, A, Siggs, OM, Young, TL, Vitart, V, Thiadens, AAHJ, Karjalainen, J, Uebe, S, Melles, RB, Nair, KS, Luben, R, Simcoe, M, Amersinghe, N, Cree, AJ, Hohn, R, Poplawski, A, Chen, LJ, Rong, S-S, Aung, T, Vithana, EN, Tamiya, G, Shiga, Y, Yamamoto, M, Nakazawa, T, Currant, H, Birney, E, Wang, X, Auton, A, Lupton, MK, Martin, NG, Ashaye, A, Olawoye, O, Williams, SE, Akafo, S, Ramsay, M, Hashimoto, K, Kamatani, Y, Akiyama, M, Momozawa, Y, Foster, PJ, Khaw, PT, Morgan, JE, Strouthidis, NG, Kraft, P, Kang, JH, Pang, CP, Pasutto, F, Mitchell, P, Lotery, AJ, Palotie, A, van Duijn, C, Haines, JL, Hammond, C, Pasquale, LR, Klaver, CCW, Hauser, M, Khor, CC, Mackey, DA, Kubo, M, Cheng, C-Y, Craig, JE, MacGregor, S, Wiggs, JL, Gharahkhani, P, Jorgenson, E, Hysi, P, Khawaja, AP, Pendergrass, S, Han, X, Ong, JS, Hewitt, AW, Segre, A, Rouhana, JM, Hamel, AR, Igo, RP, Choquet, H, Qassim, A, Josyula, NS, Bailey, JNC, Bonnemaijer, PWM, Iglesias, A, Siggs, OM, Young, TL, Vitart, V, Thiadens, AAHJ, Karjalainen, J, Uebe, S, Melles, RB, Nair, KS, Luben, R, Simcoe, M, Amersinghe, N, Cree, AJ, Hohn, R, Poplawski, A, Chen, LJ, Rong, S-S, Aung, T, Vithana, EN, Tamiya, G, Shiga, Y, Yamamoto, M, Nakazawa, T, Currant, H, Birney, E, Wang, X, Auton, A, Lupton, MK, Martin, NG, Ashaye, A, Olawoye, O, Williams, SE, Akafo, S, Ramsay, M, Hashimoto, K, Kamatani, Y, Akiyama, M, Momozawa, Y, Foster, PJ, Khaw, PT, Morgan, JE, Strouthidis, NG, Kraft, P, Kang, JH, Pang, CP, Pasutto, F, Mitchell, P, Lotery, AJ, Palotie, A, van Duijn, C, Haines, JL, Hammond, C, Pasquale, LR, Klaver, CCW, Hauser, M, Khor, CC, Mackey, DA, Kubo, M, Cheng, C-Y, Craig, JE, MacGregor, S, and Wiggs, JL

Abstract

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

Published
2021

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, 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

5. The Decreasing Prevalence of Nonrefractive Visual Impairment in Older Europeans: A Meta-analysis of Published and Unpublished Data

Author

Delcourt, C., Le Goff, M., von Hanno, T., Mirshahi, A., Khawaja, A. P., Verhoeven, V. J. M., Hogg, R. E., Anastosopoulos, E., Cachulo, M. L., Hohn, R., Wolfram, C., Bron, A., Miotto, S., Carriere, I., Colijn, J. M., Buitendijk, G. H. S., Evans, J., Nitsch, D., Founti, P., Yip, J. L. Y., Pfeiffer, N., Creuzot-Garcher, C., Silva, R., Piermarocchi, S., Topouzis, F., Bertelsen, G., Foster, P. J., Fletcher, A., Klaver, C. C. W., Korobelnik, J. -F., Acar, N., Azuara-Blanco, A., Berendschot, T., Bergen, A., Binquet, C., Bird, A., Bobak, M., Boon, C., Bretillon, L., Broe, R., Buitendijk, G., Capuano, V., Chakravarthy, U., Chan, M., Chang, P., Colijn, J., Cougnard-Gregoire, A., Cree, A., Cumberland, P., Cunha-Vaz, J., Daien, V., De Jong, E., Deak, G., Delyfer, M. -N., den Hollander, A., Dietzel, M., Erke, M. G., Faria, P., Farinha, C., Fauser, S., Finger, R., Foster, P., Gorgels, T., Grauslund, J., Grus, F., Hammond, C., Hansen, M., Helmer, C., Hense, H. -W., Hermann, M., Hoehn, R., Hogg, R., Holz, F., Hoyng, C., Jansonius, N., Janssen, S., Kersten, E., Khawaja, A., Klaver, C., Lamparter, J., Lechanteur, Y., Lehtimaki, T., Leung, I., Lotery, A., Mauschitz, M., Meester, M., Merle, B., Meyer zu Westrup, V., Midena, E., Mohan-Said, S., Mueller, M., Muldrew, A., Murta, J., Nickels, S., Nunes, S., Owen, C., Peto, T., Prokofyeva, E., Rahi, J., Raitakari, O., Rauscher, F., Ribeiro, L., Rougier, M. -B., Rudnicka, A., Randjvar, Sahel, Salonikiou, A., Sanchez, C., Schmitz-Valckenberg, S., Schouten, J., Schuster, A., Schweitzer, C., Segato, T., Shehata, J., Silvestri, G., Simader, C., Souied, E., Speckauskas, M., Springelkamp, H., Tapp, R., van Leeuwen, E., Verhoeven, V., Verzijden, T., Von Hanno, T., Vujosevic, S., Wiedemann, P., Williams, K., Yip, J., and Zerbib, J.

Subjects
Europe, Aged, Humans, Prevalence, Vision, Low, Visually Impaired Persons, Visual Acuity, Vision, Low
Abstract

TOPIC: To estimate the prevalence of nonrefractive visual impairment and blindness in European persons 55 years of age and older. CLINICAL RELEVANCE: Few visual impairment and blindness prevalence estimates are available for the European population. In addition, many of the data collected in European population-based studies currently are unpublished and have not been included in previous estimates. METHODS: Fourteen European population-based studies participating in the European Eye Epidemiology Consortium (n = 70 723) were included. Each study provided nonrefractive visual impairment and blindness prevalence estimates stratified by age (10-year strata) and gender. Nonrefractive visual impairment and blindness were defined as best-corrected visual acuity worse than 20/60 and 20/400 in the better eye, respectively. Using random effects meta-analysis, prevalence rates were estimated according to age, gender, geographical area, and period (1991-2006 and 2007-2012). Because no data were available for Central and Eastern Europe, population projections for numbers of affected people were estimated using Eurostat population estimates for European high-income countries in 2000 and 2010. RESULTS: The age-standardized prevalence of nonrefractive visual impairment in people 55 years of age or older decreased from 2.22% (95% confidence interval [CI], 1.34-3.10) from 1991 through 2006 to 0.92% (95% CI, 0.42-1.42) from 2007 through 2012. It strongly increased with age in both periods (up to 15.69% and 4.39% in participants 85 years of age or older from 1991 through 2006 and from 2007 through 2012, respectively). Age-standardized prevalence of visual impairment tended to be higher in women than men from 1991 through 2006 (2.67% vs. 1.88%), but not from 2007 through 2012 (0.87% vs. 0.88%). No differences were observed between northern, western, and southern regions of Europe. The projected numbers of affected older inhabitants in European high-income countries decreased from 2.5 million affected individuals in 2000 to 1.2 million in 2010. Of those, 584 000 were blind in 2000, in comparison with 170 000 who were blind in 2010. CONCLUSIONS: Despite the increase in the European older population, our study indicated that the number of visually impaired people has decreased in European high-income countries in the last 20 years. This may be the result of major improvements in eye care and prevention, the decreasing prevalence of eye diseases, or both.

Published
2018

6. Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

Author

Bonnemaijer, P.W.M., Leeuwen, E.M. van, Iglesias, A.I., Gharahkhani, P., Vitart, V., Khawaja, A.P., Simcoe, M., Hohn, R., Cree, A.J., Igo, R.P., Jr., Gerhold-Ay, A., Nickels, S., Wilson, J.F., Hayward, C., Boutin, T.S., Polasek, O., Aung, T., Khor, C.C., Amin, N., Lotery, A.J., Wiggs, J.L., Cheng, C.Y., Hysi, P.G., Hammond, C.J., Thiadens, A., MacGregor, S., Klaver, C.C.W., Duijn, C.M. van, Bonnemaijer, P.W.M., Leeuwen, E.M. van, Iglesias, A.I., Gharahkhani, P., Vitart, V., Khawaja, A.P., Simcoe, M., Hohn, R., Cree, A.J., Igo, R.P., Jr., Gerhold-Ay, A., Nickels, S., Wilson, J.F., Hayward, C., Boutin, T.S., Polasek, O., Aung, T., Khor, C.C., Amin, N., Lotery, A.J., Wiggs, J.L., Cheng, C.Y., Hysi, P.G., Hammond, C.J., Thiadens, A., MacGregor, S., Klaver, C.C.W., and Duijn, C.M. van

Abstract

Contains fulltext : 215476.pdf (publisher's version ) (Open Access), A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH.

Published
2019

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. 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

8. The Decreasing Prevalence of Nonrefractive Visual Impairment in Older Europeans: A Meta-analysis of Published and Unpublished Data

Author

Delcourt, C, Goff, M. Le, Hanno, T. von, Mirshahi, A., Khawaja, A.P., Verhoeven, V.J., Hogg, R.E., Anastosopoulos, E., Cachulo, M.L., Hohn, R., Wolfram, C., Bron, A.M., Miotto, S., Carriere, I., Colijn, J.M., Buitendijk, G.H., Evans, J., Nitsch, D., Founti, P., Yip, J.L.Y., Pfeiffer, N., Creuzot-Garcher, C., Silva, R. de, Piermarocchi, S., Topouzis, F., Bertelsen, G., Foster, P.J., Fletcher, A., Klaver, C.C.W., Korobelnik, J.F., Delcourt, C, Goff, M. Le, Hanno, T. von, Mirshahi, A., Khawaja, A.P., Verhoeven, V.J., Hogg, R.E., Anastosopoulos, E., Cachulo, M.L., Hohn, R., Wolfram, C., Bron, A.M., Miotto, S., Carriere, I., Colijn, J.M., Buitendijk, G.H., Evans, J., Nitsch, D., Founti, P., Yip, J.L.Y., Pfeiffer, N., Creuzot-Garcher, C., Silva, R. de, Piermarocchi, S., Topouzis, F., Bertelsen, G., Foster, P.J., Fletcher, A., Klaver, C.C.W., and Korobelnik, J.F.

Abstract

Item does not contain fulltext, TOPIC: To estimate the prevalence of nonrefractive visual impairment and blindness in European persons 55 years of age and older. CLINICAL RELEVANCE: Few visual impairment and blindness prevalence estimates are available for the European population. In addition, many of the data collected in European population-based studies currently are unpublished and have not been included in previous estimates. METHODS: Fourteen European population-based studies participating in the European Eye Epidemiology Consortium (n = 70 723) were included. Each study provided nonrefractive visual impairment and blindness prevalence estimates stratified by age (10-year strata) and gender. Nonrefractive visual impairment and blindness were defined as best-corrected visual acuity worse than 20/60 and 20/400 in the better eye, respectively. Using random effects meta-analysis, prevalence rates were estimated according to age, gender, geographical area, and period (1991-2006 and 2007-2012). Because no data were available for Central and Eastern Europe, population projections for numbers of affected people were estimated using Eurostat population estimates for European high-income countries in 2000 and 2010. RESULTS: The age-standardized prevalence of nonrefractive visual impairment in people 55 years of age or older decreased from 2.22% (95% confidence interval [CI], 1.34-3.10) from 1991 through 2006 to 0.92% (95% CI, 0.42-1.42) from 2007 through 2012. It strongly increased with age in both periods (up to 15.69% and 4.39% in participants 85 years of age or older from 1991 through 2006 and from 2007 through 2012, respectively). Age-standardized prevalence of visual impairment tended to be higher in women than men from 1991 through 2006 (2.67% vs. 1.88%), but not from 2007 through 2012 (0.87% vs. 0.88%). No differences were observed between northern, western, and southern regions of Europe. The projected numbers of affected older inhabitants in European high-income countries decreased from 2.5 m

Published
2018

9. 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

10. 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

11. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author

Iglesias Gonzalez, Adriana, Mishra, A, Vitart, V, Bykhovskaya, Y, Hohn, R, Springelkamp, Henriët, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, XH, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, Leeuwen, Elisa, Taylor, KD, Bonnemaijer, Pieter, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, André, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, Caroline, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, CY (Ching-Yu), Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, Duijn, Cornelia, Macgregor, S, Iglesias Gonzalez, Adriana, Mishra, A, Vitart, V, Bykhovskaya, Y, Hohn, R, Springelkamp, Henriët, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, XH, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, Leeuwen, Elisa, Taylor, KD, Bonnemaijer, Pieter, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, André, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, Caroline, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, CY (Ching-Yu), Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, Duijn, Cornelia, and Macgregor, S

Published
2018

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

Author

Shah, RL, Li, Q, Zhao, WT, Tedja, Milly, Tideman, Willem, Khawaja, AP, Fan, Q, Yazar, S, Williams, KM, Verhoeven, Virginie, Xie, J, Wang, YX, Hess, M, Nickels, S, Lackner, KJ, Parssinen, O, Wedenoja, J, Biino, G, Concas, MP, Uitterlinden, André, Rivadeneira, Fernando, Jaddoe, Vincent, Hysi, PG, Sim, XL, Tan, N, Tham, YC, Sensaki, S, Hofman, Bert, Vingerling, Hans, Jonas, JB, Mitchell, P, Hammond, CJ, Hohn, R, Baird, PN, Wong, TY, Cheng, CY (Ching-Yu), Teo, YY, Mackey, DA, Williams, C, Saw, SM, Klaver, Caroline, Guggenheim, JA, Bailey-Wilson, JE, Shah, RL, Li, Q, Zhao, WT, Tedja, Milly, Tideman, Willem, Khawaja, AP, Fan, Q, Yazar, S, Williams, KM, Verhoeven, Virginie, Xie, J, Wang, YX, Hess, M, Nickels, S, Lackner, KJ, Parssinen, O, Wedenoja, J, Biino, G, Concas, MP, Uitterlinden, André, Rivadeneira, Fernando, Jaddoe, Vincent, Hysi, PG, Sim, XL, Tan, N, Tham, YC, Sensaki, S, Hofman, Bert, Vingerling, Hans, Jonas, JB, Mitchell, P, Hammond, CJ, Hohn, R, Baird, PN, Wong, TY, Cheng, CY (Ching-Yu), Teo, YY, Mackey, DA, Williams, C, Saw, SM, Klaver, Caroline, Guggenheim, JA, and Bailey-Wilson, JE

Published
2018

14. Haplotype reference consortium panel: Practical implications of imputations with large reference panels

Author

Iglesias, A.I., Lee, S.J. van der, Bonnemaijer, P.W.M., Hohn, R., Nag, A., Gharahkhani, P., Khawaja, A.P., Broer, L., Foster, P.J., Hammond, C.J., Hysi, P.G., Leeuwen, E.M. van, MacGregor, S., Mackey, D.A., Mazur, J., Nickels, S., Uitterlinden, A.G., Klaver, C.C.W., Amin, N., Duijn, C.M. van, Iglesias, A.I., Lee, S.J. van der, Bonnemaijer, P.W.M., Hohn, R., Nag, A., Gharahkhani, P., Khawaja, A.P., Broer, L., Foster, P.J., Hammond, C.J., Hysi, P.G., Leeuwen, E.M. van, MacGregor, S., Mackey, D.A., Mazur, J., Nickels, S., Uitterlinden, A.G., Klaver, C.C.W., Amin, N., and Duijn, C.M. van

Abstract

Contains fulltext : 177754.pdf (Publisher’s version ) (Open Access), Recently, the Haplotype Reference Consortium (HRC) released a large imputation panel that allows more accurate imputation of genetic variants. In this study, we compared a set of directly assayed common and rare variants from an exome array to imputed genotypes, that is, 1000 genomes project (1000GP) and HRC. We showed that imputation using the HRC panel improved the concordance between assayed and imputed genotypes at common, and especially, low-frequency variants. Furthermore, we performed a genome-wide association meta-analysis of vertical cup-disc ratio, a highly heritable endophenotype of glaucoma, in four cohorts using 1000GP and HRC imputations. We compared the results of the meta-analysis using 1000GP to the meta-analysis results using HRC. Overall, we found that using HRC imputation significantly improved P values (P = 3.07 x 10-61 ), particularly for suggestive variants. Both meta-analyses were performed in the same sample size, yet we found eight genome-wide significant loci in the HRC-based meta-analysis versus seven genome-wide significant loci in the 1000GP-based meta-analysis. This study provides supporting evidence of the new avenues for gene discovery and fine mapping that the HRC imputation panel offers.

Published
2017

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

Author

Springelkamp, H., Iglesias, A.I., Mishra, A, Hohn, R., Wojciechowski, R., Khawaja, A.P., Nag, A., Wang, Y.X., Wang, J.J., Cuellar-Partida, G., Gibson, J., Bailey, J.N., Vithana, E.N., Gharahkhani, P., Boutin, T., Ramdas, W.D., Zeller, T., Luben, R.N., Yonova-Doing, E., Viswanathan, A.C., Yazar, S., Cree, A.J., Haines, J.L., Koh, J.Y., Souzeau, E., Wilson, J.F., Amin, N., Muller, C., Venturini, C., Kearns, L.S., Kang, J.H., Tham, Y.C., Zhou, T., Leeuwen, E.M. van, Nickels, S., Sanfilippo, P., Liao, J., Linde, H. van der, Zhao, W., Koolwijk, L.M. van, Zheng, L., Rivadeneira, F., Baskaran, M., Lee, S.J. van der, Perera, S., Jong, P.T., Oostra, B.A., Uitterlinden, A.G., Fan, Q., Hofman, A., Tai, E.S., Vingerling, J.R., Sim, X., Wolfs, R.C., Teo, Y.Y., Lemij, H.G., Khor, C.C., Willemsen, R., Lackner, K.J., Aung, T., Jansonius, N.M., Montgomery, G., Wild, P.S., Young, T.L., Burdon, K.P., Hysi, P.G., Pasquale, L.R., Wong, T.Y., Klaver, C.C.W., Hewitt, A.W., Jonas, J.B., Mitchell, P., Lotery, A.J., Foster, P.J., Vitart, V., Pfeiffer, N., Craig, J.E., Mackey, D.A., Hammond, C.J., Wiggs, J.L., Cheng, C.Y., Duijn, C.M. van, MacGregor, S., Springelkamp, H., Iglesias, A.I., Mishra, A, Hohn, R., Wojciechowski, R., Khawaja, A.P., Nag, A., Wang, Y.X., Wang, J.J., Cuellar-Partida, G., Gibson, J., Bailey, J.N., Vithana, E.N., Gharahkhani, P., Boutin, T., Ramdas, W.D., Zeller, T., Luben, R.N., Yonova-Doing, E., Viswanathan, A.C., Yazar, S., Cree, A.J., Haines, J.L., Koh, J.Y., Souzeau, E., Wilson, J.F., Amin, N., Muller, C., Venturini, C., Kearns, L.S., Kang, J.H., Tham, Y.C., Zhou, T., Leeuwen, E.M. van, Nickels, S., Sanfilippo, P., Liao, J., Linde, H. van der, Zhao, W., Koolwijk, L.M. van, Zheng, L., Rivadeneira, F., Baskaran, M., Lee, S.J. van der, Perera, S., Jong, P.T., Oostra, B.A., Uitterlinden, A.G., Fan, Q., Hofman, A., Tai, E.S., Vingerling, J.R., Sim, X., Wolfs, R.C., Teo, Y.Y., Lemij, H.G., Khor, C.C., Willemsen, R., Lackner, K.J., Aung, T., Jansonius, N.M., Montgomery, G., Wild, P.S., Young, T.L., Burdon, K.P., Hysi, P.G., Pasquale, L.R., Wong, T.Y., Klaver, C.C.W., Hewitt, A.W., Jonas, J.B., Mitchell, P., Lotery, A.J., Foster, P.J., Vitart, V., Pfeiffer, N., Craig, J.E., Mackey, D.A., Hammond, C.J., Wiggs, J.L., Cheng, C.Y., Duijn, C.M. van, and MacGregor, S.

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

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

Author

Springelkamp, Henriët, Iglesias Gonzalez, Adriana, Mishra, A, Hohn, R, Wojciechowski, R, Khawaja, AP, Nag, A, Wang, YX, Wang, JJ, Cuellar-Partida, G, Gibson, J, Bailey, JNC, Vithana, EN, Gharahkhani, P, Boutin, T, Ramdas, Wishal, Zeller, T, Luben, RN, Yonova-Doing, E, Viswanathan, AC, Yazar, S, Cree, AJ, Haines, JL, Koh, JY, Souzeau, E, Wilson, JF, Amin, Najaf, Muller, C, Venturini, C, Kearns, LS, Kang, JH, Tham, YC, Zhou, T, van Leeuwen, EM, Nickels, S, Sanfilippo, P, Liao, JM, van der Linde, HC, Zhao, WT, Koolwijk, Leonieke, Zheng, L, Rivadeneira, Fernando, Baskaran, M, van der Lee, Sven, Perera, S, Jong, P, Oostra, Ben, Uitterlinden, André, Fan, Q, Hofman, Bert, Tai, ES, Vingerling, Hans, Sim, XL, Wolfs, R.C.W., Teo, YY, Lemij, HG, Khor, CC, Willemsen, Rob, Lackner, KJ, Aung, T, Jansonius, NM, Montgomery, G, Wild, PS, Young, TL, Burdon, KP, Hysi, PG, Pasquale, LR, Wong, TY, Klaver, Caroline, Hewitt, AW, Jonas, JB, Mitchell, P, Lotery, AJ, Foster, PJ, Vitart, V, Pfeiffer, N, Craig, JE, Mackey, DA, Hammond, CJ, Wiggs, JL, Cheng, CY (Ching-Yu), Duijn, Cornelia, Macgregor, S, Springelkamp, Henriët, Iglesias Gonzalez, Adriana, Mishra, A, Hohn, R, Wojciechowski, R, Khawaja, AP, Nag, A, Wang, YX, Wang, JJ, Cuellar-Partida, G, Gibson, J, Bailey, JNC, Vithana, EN, Gharahkhani, P, Boutin, T, Ramdas, Wishal, Zeller, T, Luben, RN, Yonova-Doing, E, Viswanathan, AC, Yazar, S, Cree, AJ, Haines, JL, Koh, JY, Souzeau, E, Wilson, JF, Amin, Najaf, Muller, C, Venturini, C, Kearns, LS, Kang, JH, Tham, YC, Zhou, T, van Leeuwen, EM, Nickels, S, Sanfilippo, P, Liao, JM, van der Linde, HC, Zhao, WT, Koolwijk, Leonieke, Zheng, L, Rivadeneira, Fernando, Baskaran, M, van der Lee, Sven, Perera, S, Jong, P, Oostra, Ben, Uitterlinden, André, Fan, Q, Hofman, Bert, Tai, ES, Vingerling, Hans, Sim, XL, Wolfs, R.C.W., Teo, YY, Lemij, HG, Khor, CC, Willemsen, Rob, Lackner, KJ, Aung, T, Jansonius, NM, Montgomery, G, Wild, PS, Young, TL, Burdon, KP, Hysi, PG, Pasquale, LR, Wong, TY, Klaver, Caroline, Hewitt, AW, Jonas, JB, Mitchell, P, Lotery, AJ, Foster, PJ, Vitart, V, Pfeiffer, N, Craig, JE, Mackey, DA, Hammond, CJ, Wiggs, JL, Cheng, CY (Ching-Yu), Duijn, Cornelia, and Macgregor, S

Published
2017

17. Haplotype reference consortium panel: Practical implications of imputations with large reference panels

Author

Iglesias Gonzalez, Adriana, van der Lee, Sven, Bonnemaijer, Pieter, Hohn, R, Nag, A, Gharahkhani, P, Khawaja, AP, Broer, Linda, Foster, PJ, Hammond, CJ, Hysi, PG, Leeuwen, Elisa, Macgregor, S, Mackey, DA, Mazur, J, Nickels, S, Uitterlinden, André, Klaver, Caroline, Amin, Najaf, Duijn, Cornelia, Iggc, Iglesias Gonzalez, Adriana, van der Lee, Sven, Bonnemaijer, Pieter, Hohn, R, Nag, A, Gharahkhani, P, Khawaja, AP, Broer, Linda, Foster, PJ, Hammond, CJ, Hysi, PG, Leeuwen, Elisa, Macgregor, S, Mackey, DA, Mazur, J, Nickels, S, Uitterlinden, André, Klaver, Caroline, Amin, Najaf, Duijn, Cornelia, and Iggc

Published
2017

20. 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

21. When do myopia genes have their effect? Comparison of genetic risks between children and adults

Author

Tideman, J.W., Fan, Q., Polling, J.R., Guo, X., Yazar, S., Khawaja, A., Hohn, R., Lu, Y., Jaddoe, V.W., Yamashiro, K., Yoshikawa, M., Gerhold-Ay, A., Nickels, S., Zeller, T., He, M., Boutin, T., Bencic, G., Vitart, V., Mackey, D.A., Foster, P.J., MacGregor, S., Williams, C., Saw, S.M., Guggenheim, J.A., Klaver, C.C.W., Tideman, J.W., Fan, Q., Polling, J.R., Guo, X., Yazar, S., Khawaja, A., Hohn, R., Lu, Y., Jaddoe, V.W., Yamashiro, K., Yoshikawa, M., Gerhold-Ay, A., Nickels, S., Zeller, T., He, M., Boutin, T., Bencic, G., Vitart, V., Mackey, D.A., Foster, P.J., MacGregor, S., Williams, C., Saw, S.M., Guggenheim, J.A., and Klaver, C.C.W.

Abstract

Item does not contain fulltext, Previous studies have identified many genetic loci for refractive error and myopia. We aimed to investigate the effect of these loci on ocular biometry as a function of age in children, adolescents, and adults. The study population consisted of three age groups identified from the international CREAM consortium: 5,490 individuals aged <10 years; 5,000 aged 10-25 years; and 16,274 aged >25 years. All participants had undergone standard ophthalmic examination including measurements of axial length (AL) and corneal radius (CR). We examined the lead SNP at all 39 currently known genetic loci for refractive error identified from genome-wide association studies (GWAS), as well as a combined genetic risk score (GRS). The beta coefficient for association between SNP genotype or GRS versus AL/CR was compared across the three age groups, adjusting for age, sex, and principal components. Analyses were Bonferroni-corrected. In the age group <10 years, three loci (GJD2, CHRNG, ZIC2) were associated with AL/CR. In the age group 10-25 years, four loci (BMP2, KCNQ5, A2BP1, CACNA1D) were associated; and in adults 20 loci were associated. Association with GRS increased with age; beta = 0.0016 per risk allele (P = 2 x 10-8 ) in <10 years, 0.0033 (P = 5 x 10-15 ) in 10- to 25-year-olds, and 0.0048 (P = 1 x 10-72 ) in adults. Genes with strongest effects (LAMA2, GJD2) had an early effect that increased with age. Our results provide insights on the age span during which myopia genes exert their effect. These insights form the basis for understanding the mechanisms underlying high and pathological myopia.

Published
2016

22. Associations with intraocular pressure across Europe: The European Eye Epidemiology (E-3) Consortium

Author

Khawaja, AP, Springelkamp, Henriët, Creuzot-Garcher, C, Delcourt, C, Hofman, Bert, Hohn, R, Iglesias Gonzalez, Adriana, Wolfs, R.C.W., Korobelnik, JF, de Silva, R, Topouzis, F, Williams, KM, Bron, AM, Buitendijk, Gabriëlle, Cachulo, MD, Cougnard-Gregoire, A, Dartigues, JF, Hammond, CJ, Pfeiffer, N, Salonikiou, A, Duijn, Cornelia, Vingerling, Hans, Luben, RN, Mirshahi, A, Lamparter, J, Klaver, Caroline, Jansonius, NM (Nomdo), Foster, PJ, Khawaja, AP, Springelkamp, Henriët, Creuzot-Garcher, C, Delcourt, C, Hofman, Bert, Hohn, R, Iglesias Gonzalez, Adriana, Wolfs, R.C.W., Korobelnik, JF, de Silva, R, Topouzis, F, Williams, KM, Bron, AM, Buitendijk, Gabriëlle, Cachulo, MD, Cougnard-Gregoire, A, Dartigues, JF, Hammond, CJ, Pfeiffer, N, Salonikiou, A, Duijn, Cornelia, Vingerling, Hans, Luben, RN, Mirshahi, A, Lamparter, J, Klaver, Caroline, Jansonius, NM (Nomdo), and Foster, PJ

Abstract

Raised intraocular pressure (IOP) is the most important risk factor for developing glaucoma, the second commonest cause of blindness globally. Understanding associations with IOP and variations in IOP between countries may teach us about mechanisms underlying glaucoma. We examined cross-sectional associations with IOP in 43,500 European adults from 12 cohort studies belonging to the European Eye Epidemiology (E-3) consortium. Each study conducted multivariable linear regression with IOP as the outcome variable and results were pooled using random effects meta-analysis. The association of standardized study IOP with latitude was tested using meta-regression. Higher IOP was observed in men (0.18 mmHg; 95 % CI 0.06, 0.31; P = 0.004) and with higher body mass index (0.21 mmHg per 5 kg/m(2); 95 % CI 0.14, 0.28; P < 0.001), shorter height (-0.17 mmHg per 10 cm; 95 % CI -0.25, -0.08; P < 0.001), higher systolic blood pressure (0.17 mmHg per 10 mmHg; 95 % CI 0.12, 0.22; P < 0.001) and more myopic refraction (0.06 mmHg per Dioptre; 95 % CI 0.03, 0.09; P < 0.001). An inverted U-shaped trend was observed between age and IOP, with IOP increasing up to the age of 60 and decreasing in participants older than 70 years. We found no significant association between standardized IOP and study location latitude (P = 0.76). Novel findings of our study include the association of lower IOP in taller people and an inverted-U shaped association of IOP with age. We found no evidence of significant variation in IOP across Europe. Despite the limited range of latitude amongst included studies, this finding is in favour of collaborative pooling of data from studies examining environmental and genetic determinants of IOP in Europeans.

Published
2016

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

Author

Fan, Q, Verhoeven, Virginie, Wojciechowski, R, Barathi, VA, Hysi, PG, Guggenheim, JA, Hohn, R, Vitart, V, Khawaja, AP, Yamashiro, K, Hosseini, SM, Lehtimaki, T, Lu, Y (Yi), Haller, T, Xie, J, Delcourt, C, Pirastu, M, Wedenoja, J, Gharahkhani, P, Venturini, C, Miyake, M, Hewitt, AW, Guo, XB, Mazur, J, Huffman, JE, Williams, KM, Polasek, O, Campbell, H, Rudan, I, Vatavuk, Z, Wilson, JF, Joshi, PK, McMahon, G, St Pourcain, B, Evans, DM, Simpson, CL, Schwantes-An, TH, Igo, RP, Mirshahi, A, Cougnard-Gregoire, A, Bellenguez, C, Blettner, M, Raitakari, O, Kaehoenen, M, Seppala, I, Zeller, T, Meitinger, T, Ried, JS, Gieger, C, Portas, L, Leeuwen, Elisa, Amin, Najaf, Uitterlinden, André, Rivadeneira, Fernando, Hofman, Bert, Vingerling, Hans, Wang, YX, Wang, X, Boh, ETH, Ikram, Kamran, Sabanayagam, C, Gupta, P, Tan, V, Zhou, L, Ho, CEH, Lim, W, Beuerman, RW, Siantar, R, Tai, ES, Vithana, E, Mihailov, E, Khor, CC, Hayward, C, Luben, RN, Foster, PJ, Klein, BEK, Klein, R, Wong, HS, Mitchell, P, Metspalu, A, Aung, T, Young, TL, He, MG, Paerssinen, O, Duijn, Cornelia, Wang, JJ, Williams, C, Jonas, JB, Teo, YY, David, AMM, Oexle, K, Yoshimura, N, Paterson, AD, Pfeiffer, N, Wong, TY (Tien Yin), Baird, PN, Stambolian, D, Bailey-Wilson, JE, Cheng, CY (Ching-Yu), Hammond, CJ, Klaver, Caroline, Saw, SM, Rahi, JS, Korobelnik, JF, Kemp, JP, Timpson, NJ, Smith, GD, Craig, JE, Burdon, KP, Fogarty, RD, Iyengar, SK, Chew, E, Janmahasatian, S, Martin, NG, Macgregor, S, Xu, L, Schache, M, Nangia, V, Panda-Jonas, S, Wright, AF, Fondran, JR, Lass, JH, Feng, S, Zhao, JH, Khaw, KT, Wareham, NJ, Rantanen, T, Kaprio, J, Pang, CP, Chen, LJ, Tam, PO, Jhanji, V, Young, AL, Doering, A, Raffel, LJ, Cotch, MF, Li, XH, Yip, SP, Yap, MKH, Biino, G, Vaccargiu, S, Fossarello, M, Fleck, B, Yazar, S, Tideman, Willem, Tedja, M, DeAngelis, MM, Morrison, M, Farrer, L, Zhou, XT, Chen, W, Mizuki, N, Meguro, A, Makela, KM, Fan, Q, Verhoeven, Virginie, Wojciechowski, R, Barathi, VA, Hysi, PG, Guggenheim, JA, Hohn, R, Vitart, V, Khawaja, AP, Yamashiro, K, Hosseini, SM, Lehtimaki, T, Lu, Y (Yi), Haller, T, Xie, J, Delcourt, C, Pirastu, M, Wedenoja, J, Gharahkhani, P, Venturini, C, Miyake, M, Hewitt, AW, Guo, XB, Mazur, J, Huffman, JE, Williams, KM, Polasek, O, Campbell, H, Rudan, I, Vatavuk, Z, Wilson, JF, Joshi, PK, McMahon, G, St Pourcain, B, Evans, DM, Simpson, CL, Schwantes-An, TH, Igo, RP, Mirshahi, A, Cougnard-Gregoire, A, Bellenguez, C, Blettner, M, Raitakari, O, Kaehoenen, M, Seppala, I, Zeller, T, Meitinger, T, Ried, JS, Gieger, C, Portas, L, Leeuwen, Elisa, Amin, Najaf, Uitterlinden, André, Rivadeneira, Fernando, Hofman, Bert, Vingerling, Hans, Wang, YX, Wang, X, Boh, ETH, Ikram, Kamran, Sabanayagam, C, Gupta, P, Tan, V, Zhou, L, Ho, CEH, Lim, W, Beuerman, RW, Siantar, R, Tai, ES, Vithana, E, Mihailov, E, Khor, CC, Hayward, C, Luben, RN, Foster, PJ, Klein, BEK, Klein, R, Wong, HS, Mitchell, P, Metspalu, A, Aung, T, Young, TL, He, MG, Paerssinen, O, Duijn, Cornelia, Wang, JJ, Williams, C, Jonas, JB, Teo, YY, David, AMM, Oexle, K, Yoshimura, N, Paterson, AD, Pfeiffer, N, Wong, TY (Tien Yin), Baird, PN, Stambolian, D, Bailey-Wilson, JE, Cheng, CY (Ching-Yu), Hammond, CJ, Klaver, Caroline, Saw, SM, Rahi, JS, Korobelnik, JF, Kemp, JP, Timpson, NJ, Smith, GD, Craig, JE, Burdon, KP, Fogarty, RD, Iyengar, SK, Chew, E, Janmahasatian, S, Martin, NG, Macgregor, S, Xu, L, Schache, M, Nangia, V, Panda-Jonas, S, Wright, AF, Fondran, JR, Lass, JH, Feng, S, Zhao, JH, Khaw, KT, Wareham, NJ, Rantanen, T, Kaprio, J, Pang, CP, Chen, LJ, Tam, PO, Jhanji, V, Young, AL, Doering, A, Raffel, LJ, Cotch, MF, Li, XH, Yip, SP, Yap, MKH, Biino, G, Vaccargiu, S, Fossarello, M, Fleck, B, Yazar, S, Tideman, Willem, Tedja, M, DeAngelis, MM, Morrison, M, Farrer, L, Zhou, XT, Chen, W, Mizuki, N, Meguro, A, and Makela, KM

Abstract

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

24. A genome-wide association study of intra-ocular pressure suggests a novel association in the gene FAM125B in the TwinsUK cohort

Author

Nag, A., Venturini, C., Small, K.S., Young, T. L., Viswanathan, A.C., Mackey, D.A., Hysi, P.G., Hammond, C., Aung, T., Cheng, C.-Y., Fleck, B.W., Gibson, J., Hewitt, A.W., Hofman, A., Hohn, R., Jonas, J.B., Khor, C.-C., Klaver, C.C., Lemij, H.G., Liao, J., Lotery, A.J., Lu, Y., Macgregor, S., Mitchell, P., Ramdas, W.D., Springelkamp, H., Tai, E.-S., Teo, Y.-Y., Uitterlinden, A.G., van Duijn, C.M., van Koolwijk, L.M., Vingerling, J.R., Vitart, V., Vithana, E., Wang, J.J., Williams, K.M., Wojciechowski, R., Wong, T.-Y., WTCCC, None, Xu, L., Yonova-Doing, E., and Tanja, Z.

Subjects
genetic structures, eye diseases
Abstract

Glaucoma is a major cause of blindness in the world. To date, common genetic variants associated with glaucoma only explain a small proportion of its heritability. We performed a genome-wide association study of intra-ocular pressure (IOP), an underlying endophenotype for glaucoma. The discovery phase of the study was carried out in the TwinsUK cohort (N = 2774) analyzing association between IOP and single nucleotide polymorphisms (SNPs) imputed to HapMap2. The results were validated in 12 independent replication cohorts of European ancestry (combined N = 22 789) that were a part of the International Glaucoma Genetics Consortium. Expression quantitative trait locus (eQTL) analyses of the significantly associated SNPs were performed using data from the Multiple Tissue Human Expression Resource (MuTHER) Study. In the TwinsUK cohort, IOP was significantly associated with a number of SNPs at 9q33.3 (P = 3.48 × 10(-8) for rs2286885, the most significantly associated SNP at this locus), within the genomic sequence of the FAM125B gene. Independent replication in a composite panel of 12 cohorts revealed consistent direction of effect and significant association (P = 0.003, for fixed-effect meta-analysis). Suggestive evidence for an eQTL effect of rs2286885 was observed for one of the probes targeting the coding region of the FAM125B gene. This gene codes for a component of a membrane complex involved in vesicular trafficking process, a function similar to that of the Caveolin genes (CAV1 and CAV2) which have previously been associated with primary open-angle glaucoma. This study suggests a novel association between SNPs in FAM125B and IOP in the TwinsUK cohort, though further studies to elucidate the functional role of this gene in glaucoma are necessary.

Published
2014

25. Increasing Prevalence of Myopia in Europe and the Impact of Education

Author

Williams, KM, Bertelsen, G, Cumberland, P, Wolfram, C, Verhoeven, Virginie, Anastasopoulos, E, Buitendijk, Gabriëlle, Cougnard-Gregoire, A, Creuzot-Garcher, C, Erke, MG, Hogg, R, Hohn, R, Hysi, P, Khawaja, AP, Korobelnik, JF, Ried, J, Vingerling, Hans, Bron, A, Dartigues, JF, Fletcher, A, Hofman, Bert, Kuijpers, Robert, Luben, RN, Oxele, K, Topouzis, F, von Hanno, T, Mirshahi, A, Foster, PJ, Duijn, Cornelia, Pfeiffer, N, Delcourt, C, Klaver, Caroline, Rahi, J, Hammond, CJ, Williams, KM, Bertelsen, G, Cumberland, P, Wolfram, C, Verhoeven, Virginie, Anastasopoulos, E, Buitendijk, Gabriëlle, Cougnard-Gregoire, A, Creuzot-Garcher, C, Erke, MG, Hogg, R, Hohn, R, Hysi, P, Khawaja, AP, Korobelnik, JF, Ried, J, Vingerling, Hans, Bron, A, Dartigues, JF, Fletcher, A, Hofman, Bert, Kuijpers, Robert, Luben, RN, Oxele, K, Topouzis, F, von Hanno, T, Mirshahi, A, Foster, PJ, Duijn, Cornelia, Pfeiffer, N, Delcourt, C, Klaver, Caroline, Rahi, J, and Hammond, CJ

Abstract

Purpose: To investigate whether myopia is becoming more common across Europe and explore whether increasing education levels, an important environmental risk factor for myopia, might explain any temporal trend. Design: Meta-analysis of population-based, cross-sectional studies from the European Eye Epidemiology (E-3) Consortium. Participants: The E-3 Consortium is a collaborative network of epidemiological studies of common eye diseases in adults across Europe. Refractive data were available for 61 946 participants from 15 population-based studies performed between 1990 and 2013; participants had a range of median ages from 44 to 78 years. Methods: Noncycloplegic refraction, year of birth, and highest educational level achieved were obtained for all participants. Myopia was defined as a mean spherical equivalent <=-0.75 diopters. A random-effects meta-analysis of age-specific myopia prevalence was performed, with sequential analyses stratified by year of birth and highest level of educational attainment. Main Outcome Measures: Variation in age-specific myopia prevalence for differing years of birth and educational level. Results: There was a significant cohort effect for increasing myopia prevalence across more recent birth decades; age-standardized myopia prevalence increased from 17.8% (95% confidence interval [CI], 17.6-18.1) to 23.5% (95% CI, 23.2-23.7) in those born between 1910 and 1939 compared with 1940 and 1979 (P = 0.03). Education was significantly associated with myopia; for those completing primary, secondary, and higher education, the age-standardized prevalences were 25.4% (CI, 25.0-25.8), 29.1% (CI, 28.8-29.5), and 36.6% (CI, 36.1-37.2), respectively. Although more recent birth cohorts were more educated, this did not fully explain the cohort effect. Compared with the reference risk of participants born in the 1920s with only primary education, higher education or being born in the 1960s doubled the myopia prevalence ratio-2.43 (CI, 1.26-4.17) and

Published
2015

26. Prevalence of refractive error in Europe: the European Eye Epidemiology (E-3) Consortium

Author

Williams, KM, Verhoeven, Virginie, Cumberland, P, Bertelsen, G, Wolfram, C, Buitendijk, Gabriëlle, Hofman, Bert, Duijn, Cornelia, Vingerling, Hans, Kuijpers, Robert, Hohn, R, Mirshahi, A, Khawaja, AP, Luben, RN, Erke, MG, von Hanno, T, Mahroo, O, Hogg, R, Gieger, C, Cougnard-Gregoire, A, Anastasopoulos, E, Bron, A, Dartigues, JF, Korobelnik, JF, Creuzot-Garcher, C, Topouzis, F, Delcourt, C, Rahi, J, Meitinger, T, Fletcher, A, Foster, PJ, Pfeiffer, N, Klaver, Caroline, Hammond, CJ, Williams, KM, Verhoeven, Virginie, Cumberland, P, Bertelsen, G, Wolfram, C, Buitendijk, Gabriëlle, Hofman, Bert, Duijn, Cornelia, Vingerling, Hans, Kuijpers, Robert, Hohn, R, Mirshahi, A, Khawaja, AP, Luben, RN, Erke, MG, von Hanno, T, Mahroo, O, Hogg, R, Gieger, C, Cougnard-Gregoire, A, Anastasopoulos, E, Bron, A, Dartigues, JF, Korobelnik, JF, Creuzot-Garcher, C, Topouzis, F, Delcourt, C, Rahi, J, Meitinger, T, Fletcher, A, Foster, PJ, Pfeiffer, N, Klaver, Caroline, and Hammond, CJ

Abstract

To estimate the prevalence of refractive error in adults across Europe. Refractive data (mean spherical equivalent) collected between 1990 and 2013 from fifteen population-based cohort and cross-sectional studies of the European Eye Epidemiology (E-3) Consortium were combined in a random effects meta-analysis stratified by 5-year age intervals and gender. Participants were excluded if they were identified as having had cataract surgery, retinal detachment, refractive surgery or other factors that might influence refraction. Estimates of refractive error prevalence were obtained including the following classifications: myopia a parts per thousand currency signa'0.75 diopters (D), high myopia a parts per thousand currency signa'6D, hyperopia a parts per thousand yen1D and astigmatism a parts per thousand yen1D. Meta-analysis of refractive error was performed for 61,946 individuals from fifteen studies with median age ranging from 44 to 81 and minimal ethnic variation (98 % European ancestry). The age-standardised prevalences (using the 2010 European Standard Population, limited to those a parts per thousand yen25 and < 90 years old) were: myopia 30.6 % [95 % confidence interval (CI) 30.4-30.9], high myopia 2.7 % (95 % CI 2.69-2.73), hyperopia 25.2 % (95 % CI 25.0-25.4) and astigmatism 23.9 % (95 % CI 23.7-24.1). Age-specific estimates revealed a high prevalence of myopia in younger participants [47.2 % (CI 41.8-52.5) in 25-29 years-olds]. Refractive error affects just over a half of European adults. The greatest burden of refractive error is due to myopia, with high prevalence rates in young adults. Using the 2010 European population estimates, we estimate there are 227.2 million people with myopia across Europe.

Published
2015

27. 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, Virginie, Ikram, MK, Hohn, R, Vitart, V, Hewitt, AW, Oexle, K, Makela, KM, Macgregor, S, Pirastu, M, Fan, Q, Cheng, CY (Ching-Yu), St Pourcain, B, McMahon, G, Kemp, JP, Northstone, K, Rahi, JS, Cumberland, PM, Martin, NG, Sanfilippo, PG, Lu, Y (Yi), 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, Hans, Hofman, Bert, Uitterlinden, André, Rivadeneira, Fernando, Amin, Najaf, Karssen, L, Oostra, Ben, Zhou, X, Teo, YY, Tai, ES, Vithana, E, Barathi, V, Zheng, YF, Siantar, RG, Neelam, K, Shin, YC, Lam, J (Jan), Yonova-Doing, E, Venturini, C, Hosseini, SM, Wong, HS, Lehtimaki, T, Kahonen, M, Raitakari, O, Timpson, NJ, Evans, DM, Khor, CC, Aung, T, Young, TL, Mitchell, P, Klein, B, Duijn, Cornelia, Meitinger, T, Jonas, JB, Baird, PN, Mackey, DA, Wong, TY, Saw, SM, Parssinen, O, Stambolian, D, Hammond, CJ, Klaver, Caroline, Williams, C, Paterson, AD, Bailey-Wilson, JE, Guggenheim, JA, Li, Q, Wojciechowski, R, Simpson, CL, Hysi, PG, Verhoeven, Virginie, Ikram, MK, Hohn, R, Vitart, V, Hewitt, AW, Oexle, K, Makela, KM, Macgregor, S, Pirastu, M, Fan, Q, Cheng, CY (Ching-Yu), St Pourcain, B, McMahon, G, Kemp, JP, Northstone, K, Rahi, JS, Cumberland, PM, Martin, NG, Sanfilippo, PG, Lu, Y (Yi), 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, Hans, Hofman, Bert, Uitterlinden, André, Rivadeneira, Fernando, Amin, Najaf, Karssen, L, Oostra, Ben, Zhou, X, Teo, YY, Tai, ES, Vithana, E, Barathi, V, Zheng, YF, Siantar, RG, Neelam, K, Shin, YC, Lam, J (Jan), Yonova-Doing, E, Venturini, C, Hosseini, SM, Wong, HS, Lehtimaki, T, Kahonen, M, Raitakari, O, Timpson, NJ, Evans, DM, Khor, CC, Aung, T, Young, TL, Mitchell, P, Klein, B, Duijn, Cornelia, Meitinger, T, Jonas, JB, Baird, PN, Mackey, DA, Wong, TY, Saw, SM, Parssinen, O, Stambolian, D, Hammond, CJ, Klaver, Caroline, 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

28. 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

29. Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

Author

Hysi, PG, Cheng, C-Y, Springelkamp, H, Macgregor, S, Bailey, JNC, Wojciechowski, R, Vitart, V, Nag, A, Hewitt, AW, Hohn, R, Venturini, C, Mirshahi, A, Ramdas, WD, Thorleifsson, G, Vithana, E, Khor, C-C, Stefansson, AB, Liao, J, Haines, JL, Amin, N, Wang, YX, Wild, PS, Ozel, AB, Li, JZ, Fleck, BW, Zeller, T, Staffieri, SE, Teo, Y-Y, Cuellar-Partida, G, Luo, X, Allingham, RR, Richards, JE, Senft, A, Karssen, LC, Zheng, Y, Bellenguez, C, Xu, L, Iglesias, AI, Wilson, JF, Kang, JH, van Leeuwen, EM, Jonsson, V, Thorsteinsdottir, U, Despriet, DDG, Ennis, S, Moroi, SE, Martin, NG, Jansonius, NM, Yazar, S, Tai, E-S, Amouyel, P, Kirwan, J, van Koolwijk, LME, Hauser, MA, Jonasson, F, Leo, P, Loomis, SJ, Fogarty, R, Rivadeneira, F, Kearns, L, Lackner, KJ, de Jong, PTVM, Simpson, CL, Pennell, CE, Oostra, BA, Uitterlinden, AG, Saw, S-M, Lotery, AJ, Bailey-Wilson, JE, Hofman, A, Vingerling, JR, Maubaret, C, Pfeiffer, N, Wolfs, RCW, Lemij, HG, Young, TL, Pasquale, LR, Delcourt, C, Spector, TD, Klaver, CCW, Small, KS, Burdon, KP, Stefansson, K, Wong, T-Y, Viswanathan, A, Mackey, DA, Craig, JE, Wiggs, JL, van Duijn, CM, Hammond, CJ, Aung, T, Hysi, PG, Cheng, C-Y, Springelkamp, H, Macgregor, S, Bailey, JNC, Wojciechowski, R, Vitart, V, Nag, A, Hewitt, AW, Hohn, R, Venturini, C, Mirshahi, A, Ramdas, WD, Thorleifsson, G, Vithana, E, Khor, C-C, Stefansson, AB, Liao, J, Haines, JL, Amin, N, Wang, YX, Wild, PS, Ozel, AB, Li, JZ, Fleck, BW, Zeller, T, Staffieri, SE, Teo, Y-Y, Cuellar-Partida, G, Luo, X, Allingham, RR, Richards, JE, Senft, A, Karssen, LC, Zheng, Y, Bellenguez, C, Xu, L, Iglesias, AI, Wilson, JF, Kang, JH, van Leeuwen, EM, Jonsson, V, Thorsteinsdottir, U, Despriet, DDG, Ennis, S, Moroi, SE, Martin, NG, Jansonius, NM, Yazar, S, Tai, E-S, Amouyel, P, Kirwan, J, van Koolwijk, LME, Hauser, MA, Jonasson, F, Leo, P, Loomis, SJ, Fogarty, R, Rivadeneira, F, Kearns, L, Lackner, KJ, de Jong, PTVM, Simpson, CL, Pennell, CE, Oostra, BA, Uitterlinden, AG, Saw, S-M, Lotery, AJ, Bailey-Wilson, JE, Hofman, A, Vingerling, JR, Maubaret, C, Pfeiffer, N, Wolfs, RCW, Lemij, HG, Young, TL, Pasquale, LR, Delcourt, C, Spector, TD, Klaver, CCW, Small, KS, Burdon, KP, Stefansson, K, Wong, T-Y, Viswanathan, A, Mackey, DA, Craig, JE, Wiggs, JL, van Duijn, CM, Hammond, CJ, and Aung, T

Abstract

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 × 10(-11) for rs2472493 near ABCA1 and P = 6.39 × 10(-11) for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10(-11) for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.

Published
2014

30. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process

Author

Springelkamp, Henriët, Hohn, R, Mishra, A, Hysi, PG, Khor, CC, Loomis, SJ, Bailey, JNC, Gibson, J, Thorleifsson, G, Janssen, SF, Luo, XY, Ramdas, Wishal, Vithana, E, Nongpiur, ME, Montgomery, G, Xu, L, Mountain, JE, Gharahkhani, P, Lu, Y (Yi), Amin, Najaf, Karssen, Lennart, Sim, KS, Leeuwen, Elisa, Iglesias, AI, Verhoeven, Virginie, Hauser, MA, Loon, SC, Despriet, Dominiek, Nag, A, Venturini, C, Sanfilippo, PG, Schillert, A, Kang, JH, Landers, J, Jonasson, F, Cree, AJ, Koolwijk, Leonieke, Rivadeneira, Fernando, Souzeau, E, Jonsson, V, Menon, G, Weinreb, RN, Oostra, Ben, Uitterlinden, André, Hofman, Bert, Ennis, S, Thorsteinsdottir, U, Burdon, KP, Spector, TD, Mirshahi, A, Saw, SM, Vingerling, Hans, Teo, YY, Haines, JL, Wolfs, R.C.W., Lemij, HG, Tai, ES, Jansonius, NM (Nomdo), Jonas, JB, Cheng, CY (Ching-Yu), Aung, T, Viswanathan, AC, Klaver, Caroline, Craig, JE, Macgregor, S, Mackey, DA, Lotery, AJ, Stefansson, K, Young, TL, Wiggs, JL, Pfeiffer, N, Wong, TY (Tien Yin), Pasquale, LR, Hewitt, AW, Duijn, Cornelia, Hammond, CJ, Bergen, AAB, Springelkamp, Henriët, Hohn, R, Mishra, A, Hysi, PG, Khor, CC, Loomis, SJ, Bailey, JNC, Gibson, J, Thorleifsson, G, Janssen, SF, Luo, XY, Ramdas, Wishal, Vithana, E, Nongpiur, ME, Montgomery, G, Xu, L, Mountain, JE, Gharahkhani, P, Lu, Y (Yi), Amin, Najaf, Karssen, Lennart, Sim, KS, Leeuwen, Elisa, Iglesias, AI, Verhoeven, Virginie, Hauser, MA, Loon, SC, Despriet, Dominiek, Nag, A, Venturini, C, Sanfilippo, PG, Schillert, A, Kang, JH, Landers, J, Jonasson, F, Cree, AJ, Koolwijk, Leonieke, Rivadeneira, Fernando, Souzeau, E, Jonsson, V, Menon, G, Weinreb, RN, Oostra, Ben, Uitterlinden, André, Hofman, Bert, Ennis, S, Thorsteinsdottir, U, Burdon, KP, Spector, TD, Mirshahi, A, Saw, SM, Vingerling, Hans, Teo, YY, Haines, JL, Wolfs, R.C.W., Lemij, HG, Tai, ES, Jansonius, NM (Nomdo), Jonas, JB, Cheng, CY (Ching-Yu), Aung, T, Viswanathan, AC, Klaver, Caroline, Craig, JE, Macgregor, S, Mackey, DA, Lotery, AJ, Stefansson, K, Young, TL, Wiggs, JL, Pfeiffer, N, Wong, TY (Tien Yin), Pasquale, LR, Hewitt, AW, Duijn, Cornelia, Hammond, CJ, and Bergen, AAB

Abstract

Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.

Published
2014

31. 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

32. Optimisation of the water resources of a primary lead smelter: an example for sustainable good management.

Author

Hohn R., European metallurgical conference: EMC 2007, Dusseldorf, Germany, 11-14 June 2007, Meurer U., Wegewitz M., Hohn R., European metallurgical conference: EMC 2007, Dusseldorf, Germany, 11-14 June 2007, Meurer U., and Wegewitz M.

Abstract

The development is described of the water management strategy at the Binsfeldhammer Pb smelter in Stolberg, Germany, with reference to changes in legislation relating to discharge limits to the public water system. A new waste water treatment plant is currently being installed which involves solid/liquid separation at pH 2, separation of As at pH4 by Skorodit precipitation, separation of Cd, Pb, Zn and other heavy metals at pH 9, Tl removal as sulphide and removal of sulphide ions with Fe. A reverse osmosis process is being used to process different waste water streams in order to reduce the quantity of waste water produced., The development is described of the water management strategy at the Binsfeldhammer Pb smelter in Stolberg, Germany, with reference to changes in legislation relating to discharge limits to the public water system. A new waste water treatment plant is currently being installed which involves solid/liquid separation at pH 2, separation of As at pH4 by Skorodit precipitation, separation of Cd, Pb, Zn and other heavy metals at pH 9, Tl removal as sulphide and removal of sulphide ions with Fe. A reverse osmosis process is being used to process different waste water streams in order to reduce the quantity of waste water produced.

Published
2007

34. HABILIDADES DE RACIOCÍNIO CRÍTICO DE ALUNOS DE CONTABILIDADE

Author

Edgard B. Cornachione, Scott D. Johnson, and Hohn R. Duncan

Subjects
Business education, media_common.quotation_subject, Organic Chemistry, Biochemistry, language.human_language, Test (assessment), Critical thinking skills, Critical thinking, Reading (process), Cultural diversity, Perception, Pedagogy, language, Portuguese, Psychology, media_common
Abstract

Educational systems around the world judge student academic performance based upon reading and writing abilities, with evidence of critical thinking playing an essential role. In order to improve business education, a better understanding of students’ critical thinking and communication skill is required. This study aimed at assessing reading, writing, and critical thinking skills of accounting students using validated instruments: (a) Motivated Strategies for Learning Questionnaire, (b) Ennis-Weir Critical Thinking Essay Test, and (c) Flesch Reading Ease (English and Portuguese). Students wrote a short essay that was evaluated for writing quality and critical thinking based on the EW-CTET. Scores provided indications of good writing quality and evidence of high levels of critical thinking. No significant differences (i.e., gender, parenthood, program level, and program stage) of measured reading levels of the written products were found. Elements for improving learners’ performance aligned with their critical thinking skills are discussed along with a deep reflection on how educators would behave as agents of change in the reported scenario. Observed cultural differences in critical thinking related to perception of authority should be examined in further investigations.

Published
2008

36. The Cryogenic System of the Herschel Extended Payload Module.

Author

Hohn, R., Ruehe, W., and Jewell, C.

Subjects
*ASTRONOMICAL spectroscopy, *HELIUM, *LIQUID helium, *SUPERFLUIDITY, *SPACE vehicles, *CRYOSTATS, *THERMAL properties
Abstract

As part of the European Space Agency’s Herschel-Planck Mission, which will be launched by an Ariane 5 launcher in 2007, the Herschel Extended Payload Module will provide the required cryogenic thermal environment for the three scientific instruments. The instruments will measure astronomical signals in the wavelength range between 60 μm and 670 μm from an L2 orbit. The Cryostat has to provide as lowest stable temperature level 1.7 K to the instruments Focal Plane Units in order to measure the very low astronomical signals. Beside this temperature level three additional temperature levels have to be provided by the cryostat. The Herschel cryostat is equipped with two helium tanks. The main tank has a volume of 2367 1 and is filled with super-fluid helium to provide the cryogenic lifetime of 3.5 years and the required thermal environment. The auxiliary tank is mainly used for the autonomy phase of the satellite prior to launch, when no access to the cryostat is possible. The overall cryogenic system and the thermal design of the Herschel Extended Payload Module will be presented. © 2004 American Institute of Physics [ABSTRACT FROM AUTHOR]

Published
2004
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37. The Safety System of the Herschel Cryostat.

Author

Langfermann, M., Jahn, G., Hohn, R., Ruehe, W., and Jewell, C.

Subjects
CRYOSTATS, LOW temperature engineering equipment, SUPERFLUIDITY, LIQUID helium, PHOTOMETRY
Abstract

The cryostat for the ‘Herschel Space Observatory’ for the European Space Agency (ESA) science program, planned for a launch with Ariane 5 in 2007, is designed for 6 days ground hold time and 3.5 years lifetime in orbit. The system comprises two tanks containing about 346 kg of liquid and superfluid Helium, with two cryogenic cold safety valves and burst disks, surrounded by three vapor cooled shields and a vacuum vessel. The safety system is two faults tolerant with three independent paths for pressure relief. The analyses of failure modes and resulting mass flows and the safety elements of the cryogenic system will be discussed. © 2004 American Institute of Physics [ABSTRACT FROM AUTHOR]

Published
2004
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49. Electron microscopy of mammalian type-C RNA viruses: Use of conditional lethal mutants in studies of virion maturation and assembly

Author

V.I. Kalnins, H. Yeger, and Hohn R. Stephenson

Subjects
Budding, biology, Virology, Mutant, RNA, RNA virus, Embryo, Thermolabile, biology.organism_classification, Molecular biology, Reverse transcriptase, Virus
Abstract

Mouse embryo cultures infected with each of a number of physiologically-distinct temperature-sensitive mutants of R-MuLV were examined by electron microscopy in an attempt to further define the replication defects of these mutants at the nonpermissive temperature (39°). Three mutants, ts 24, ts 25, and ts 26, previously shown to be defective in postintegration steps, have been divided into two distinct subclasses. Mutants ts 25 and ts 26 synthesize viral antigens, but do not assemble viral particles at the nonpermissive temperature, whereas in mutant ts 24 infected cells, particles at a late stage of budding were observed at very high frequency. An additional R-MuLV mutant, ts 29, previously found to posses an early replication block associated with a thermolabile reverse transcriptase was shown to possess a second replication defect involving a very early stage of virus assembly. By examination of ts mutant infected cultures at various times following shift to their permissive temperatures partial synchronization was achieved with a high proportion of immature virions observed at similar stages of maturation. These findings more precisely define the stages of replication at which selected R-MuLV ts mutants are blocked at their nonpermissive temperatures, and illustrate the potential value of conditional lethal replication mutants for studies of type-C RNA virus maturation and assembly.

Published
1976

50. A Stability Algorithm for a Special Case of the Milling Process: Contribution to Machine Tool Chatter Research—6

Author

Hohn, R. E., Sridhar, R., and Long, G. W.

Abstract

In an effort to determine the stability of the milling process, and due to the complexity of its describing equation, a special case of this equation is considered. In this way, it is possible to isolate and study its salient characteristics. Moreover, the simplified equation is representative of a machining operation on which experimental data can be obtained. This special case is described by a linear differential equation with periodic coefficients. A computer algorithm is developed for determining the stability of this equation. To demonstrate the use of the algorithm on an example whose solution is known, the classical Mathieu equation is studied. Also, experimental results on an actual machining operation described by this type of equation are compared to the results found using the stability algorithm. As a result of this work, some knowledge about the stability solution of the general milling process is obtained.

Published
1968
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