Author: "Springelkamp, H" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Springelkamp, H"' showing total 49 results

Start Over Author "Springelkamp, H"

49 results on '"Springelkamp, H"'

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 The Decreasing Prevalence of Nonrefractive Visual Impairment in Older Europeans: A Meta-analysis of Published and Unpublished Data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

2. Increased High-Density Lipoprotein Levels Associated with Age-Related Macular Degeneration Evidence from the EYE-RISK and European Eye Epidemiology Consortia

Author: Colijn, J.M., Hollander, A.I. den, Demirkan, A., Cougnard-Gregoire, A., Verzijden, T., Kersten, E., Meester-Smoor, M.A., Merle, B.M.J., Papageorgiou, G., Ahmad, S., Mulder, M.T., Costa, M.A., Benlian, P., Bertelsen, G., Bron, A.M., Claes, B., Creuzot-Garcher, C., Erke, M.G., Fauser, S., Foster, P.J., Hammond, C.J., Hense, H.W., Hoyng, C.B., Khawaja, A.P., Korobelnik, J.F., Piermarocchi, S., Segato, T., Silva, R., Souied, E.H., Williams, K.M., Duijn, C.M. van, Delcourt, C., Klaver, C.C.W., Acar, N., Altay, L., Anastosopoulos, E., Azuara-Blanco, A., Berendschot, T., Bergen, A., Binquet, C., Bird, A., Bobak, M., Larsen, M.B., Boon, C., Bourne, R., Bretillon, L., Broe, R., Bron, A., Buitendijk, G., Cachulo, M.L., Capuano, V., Carriere, I., Chakravarthy, U., Chan, M., Chang, P., Colijn, J., Cree, A., Cumberland, P., Cunha-Vaz, J., Daien, V., Jong, E. de, Deak, G., Delyfer, M.N., Hollander, A. den, Dietzel, M., Faria, P., Farinha, C., Finger, R., Fletcher, A., Foster, P., Founti, P., Gorgels, T., Grauslund, J., Grus, F., Hammond, C., Heesterbeek, T., Hermann, M., Hoehn, R., Hogg, R., Holz, F., Hoyng, C., Jansonius, N., Janssen, S., Khawaja, A., Klaver, C., Lamparter, J., Goff, M. le, Lehtimaki, T., Leung, I., Lotery, A., Mauschitz, M., Meester, M., Merle, B., Westrup, V.M.Z., Midena, E., Miotto, S., Mirshahi, A., Mohan-Said, S., Mueller, M., Muldrew, A., Murta, J., Nickels, S., Nunes, S., Owen, C., Peto, T., Pfeiffer, N., Prokofyeva, E., Rahi, J., Raitakari, O., Rauscher, F., Ribeiro, L., Rougier, M.B., Rudnicka, A., Sahel, J., Salonikiou, A., Sanchez, C., Schick, T., Schmitz-Valckenberg, S., Schuster, A., Schweitzer, C., Shehata, J., Silvestri, G., Simader, C., Souied, E., Speckauskas, M., Springelkamp, H., Tapp, R., Topouzis, F., Leeuwen, E. van, Verhoeven, V., Vingerling, H., Hanno, T. von, Williams, K., Wolfram, C., Yip, J., Zerbib, J., Ajana, S., Arango-Gonzalez, B., Arndt, V., Bhatia, V., Bhattacharya, S.S., Biarnes, M., Borrell, A., Buhren, S., Calado, S.M., Dammeier, S., Jong, E.K. de, Cerda, B. de la, Diaz-Corrales, F.J., Diether, S., Emri, E., Endermann, T., Ferraro, L.L., Garcia, M., Heesterbeek, T.J., Honisch, S., Kilger, E., Langen, H., Lengyel, I., Luthert, P., Maugeais, C., Meester-Smoor, M., Inserm, B.M.J.M., Mones, J., Nogoceke, E., Pool, F.M., Rodriguez, E., Ueffing, M., Bartz-Schmidt, K.U.U., Leeuwen, E.M. van, Zumbansen, M., European Eye Epidemiology Consorti, and EYE-RISK Consortium
Published: 2019

3. Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author: Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Souzeau, E, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Pericak-Vance, MA, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Weinreb, RN, Wollstein, G, Zack, DJ, Zhang, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Grp, BMES-G, Consortium, N, and Control, WTC
Subjects: Lumican, genetic structures, Fibrillin-1, General Physics and Astronomy, Gene Expression, Q1, Corneal Diseases, Marfan Syndrome, Cornea, ADAMTS Proteins, Myopia, Link (knot theory), lcsh:Science, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Corneal Dystrophies, Hereditary, Multidisciplinary, Eye Diseases, Hereditary, symbols, NEIGHBORHOOD consortium, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Proteoglycans, Decorin, Glaucoma, Open-Angle, Science, Quantitative Trait Loci, Computational biology, Biology, Keratoconus, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, White People, Article, symbols.namesake, Transforming Growth Factor beta2, Quantitative Trait, Heritable, Asian People, Genome-Wide Association Analysis, Humans, Author Correction, Eye Disease and Disorders of Vision, Loeys-Dietz Syndrome, Genome, Human, Wellcome Trust Case Control Consortium 2, Blue Mountains Eye Study - GWAS group, General Chemistry, Mendelian Randomization Analysis, R1, eye diseases, Mendelian inheritance, Ehlers-Danlos Syndrome, lcsh:Q, sense organs, Genome-Wide Association Study
Abstract: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = −0.62, P = 5.30 × 10−5) but not between CCT and primary open-angle glaucoma (r = −0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation., Reduced central corneal thickness (CCT) is observed in common eye diseases as well as in rare Mendelian disorders. Here, in a cross-ancestry GWAS, the authors identify 19 novel genetic loci associated with CCT, a subset of which is involved in rare corneal or connective tissue disorders.
Published: 2019

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

Author: Bonnemaijer, P.W.M. (Pieter), Leeuwen, E.M. (Elisabeth M. van), Iglesias, A.I. (Adriana I.), Gharahkhani, P. (Puya), Vitart, V. (Veronique), Khawaja, A.P. (Anthony), Simcoe, M. (Mark), Höhn, R. (René), Cree, A.J. (Angela), Igo Jr., R.P. (Robert), Burdon, K.P. (Kathryn P.), Craig, J.E. (Jamie), Hewit, A.W. (Alex), Jonas, J.B., Khor, C.-C. (Chiea-Cheun), Pasutto, F. (Francesca), Mackey, D.A. (David), Mitchell, P. (Paul), Mishra, A. (Aniket), Pang, C.P. (Chi Pui), Pasquale, L.R. (Louis R), Springelkamp, H. (Henriët), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Viswanathan, A.C. (Ananth C.), Wojciechowski, R. (Robert), Wong, T.Y. (Tien Yin), Young, T.L. (Terrri L), Zeller, T. (Tanja), Allingham, R.R. (R Rand), Budenz, D.L. (Donald L.), Bailey, J.C. (Jessica Cooke), Fingert, J. (John), Gaasterland, D. (Douglas), Gaasterland, T. (Terry), Haines, J.L. (Jonathan), Hark, L. (Lisa), Hauser, M.A. (Michael), Kang, J.H. (Jae Hee), Kraft, P. (Peter), Lee, R.K. (Richard K.), Lichter, P.A. (Paul A.), Liu, Y. (Yutao), Moroi, S. (Syoko), Pasquale, L.R. (Louis), Pericak, M. (Margaret), Realini, A. (Anthony), Rhee, D. (Doug), Richards, J.R. (Julia R.), Ritch, R. (Robert), Scott, W.K. (William), Singh, K. (Kuldev), Sit, A.J. (Arthur J.), Vollrath, D. (Douglas), Weinreb, R.N. (Robert N.), Wollstein, G. (Gadi), Wilmer, D.Z. (Don Zack), Atan, D. (Denize), Aslam, T. (Tariq), Barman, S.A. (Sarah A.), Barrett, J.H. (Jennifer H.), Bishop, P.N. (Paul), Blows, P. (Peter), Bunce, C. (Catey), Carare, R.O. (Roxana O.), Chakravarthy, U. (Usha), Chan, M. (Michelle), Chua, S.Y.L. (Sharon Y. L.), Crabb, D.P. (David), Cumberland, P.M. (Philippa M.), Day, A. (Alexander), Desai, P. (Parul), Dhillon, B. (Bal), Dick, A.D. (Andrew D.), Egan, C. (Cathy), Ennis, S. (Sarah), Foster, P.J. (Paul), Fruttiger, M. (Marcus), Gallacher, J.E.J. (John E. J.), Garway, D.F. (David F.), Gibson, J. (Jane), Dan Gore, (), Guggenheim, J. (Jean), Hardcastle, A. (Alison), Harding, S.P. (Simon), Hogg, R. (Ruth), Keane, P.A. (Pearse A.), Khaw, P.T. (Peng T.), Lascaratos, G. (Gerassimos), Macgillivray, T. (Tom), Mackie, S. (Sarah), Martin, K. (Keith), McGaughey, M. (Michelle), McGuinness, B. (Bernadette), McKay, G.J. (Gareth), McKibbin, M. (Martin), Mitry, D. (Danny), Moore, T. (Tony), Morgan, J.E. (James E.), Muthy, Z.A. (Zaynah A.), O’Sullivan, E. (Eoin), Owen, C.G. (Chris G.), Patel, P. (Praveen), Paterson, E. (Euan), Peto, T. (Tünde), Petzold, A. (Axel), Rahi, J.S. (Jugnoo S.), Rudnikca, A.R. (Alicja R.), Self, J. (Jay), Sivaprasad, S., Steel, D. (David), Stratton, I. (Irene), Strouthidis, N. (Nicholas), Sudlow, C. (Cathie), Thomas, D. (Dhanes), Trucco, E. (Emanuele), Tufail, A. (Adnan), Vernon, S.A. (Stephen A.), Williams, C. (Cathy), Williams, K.M. (Katie M.), Woodside, J.V. (J.), Yates, M.M. (Max M.), Yip, J. (Jennifer), Zheng, Y. (Yalin), Gerhold-Ay, A. (Aslihan), Nickels, S. (Stefan), Wilson, J.F. (James), Hayward, C. (Caroline), Boutin, T.S. (Thibaud S.), Polasek, O. (Ozren), Aung, T. (Tin), Khor, C.C., Amin, N. (Najaf), Lotery, A.J. (Andrew), Wiggs, J.L. (Janey L.), Cheng, C.-Y. (Ching-Yu), Hysi, P.G. (Pirro G.), Hammond, C.J. (Christopher), Thiadens, A.A.H.J. (Alberta), MacGregor, S. (Stuart), Klaver, C.C.W. (Caroline), Duijn, C.M. (Cornelia) van, Bonnemaijer, P.W.M. (Pieter), Leeuwen, E.M. (Elisabeth M. van), Iglesias, A.I. (Adriana I.), Gharahkhani, P. (Puya), Vitart, V. (Veronique), Khawaja, A.P. (Anthony), Simcoe, M. (Mark), Höhn, R. (René), Cree, A.J. (Angela), Igo Jr., R.P. (Robert), Burdon, K.P. (Kathryn P.), Craig, J.E. (Jamie), Hewit, A.W. (Alex), Jonas, J.B., Khor, C.-C. (Chiea-Cheun), Pasutto, F. (Francesca), Mackey, D.A. (David), Mitchell, P. (Paul), Mishra, A. (Aniket), Pang, C.P. (Chi Pui), Pasquale, L.R. (Louis R), Springelkamp, H. (Henriët), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Viswanathan, A.C. (Ananth C.), Wojciechowski, R. (Robert), Wong, T.Y. (Tien Yin), Young, T.L. (Terrri L), Zeller, T. (Tanja), Allingham, R.R. (R Rand), Budenz, D.L. (Donald L.), Bailey, J.C. (Jessica Cooke), Fingert, J. (John), Gaasterland, D. (Douglas), Gaasterland, T. (Terry), Haines, J.L. (Jonathan), Hark, L. (Lisa), Hauser, M.A. (Michael), Kang, J.H. (Jae Hee), Kraft, P. (Peter), Lee, R.K. (Richard K.), Lichter, P.A. (Paul A.), Liu, Y. (Yutao), Moroi, S. (Syoko), Pasquale, L.R. (Louis), Pericak, M. (Margaret), Realini, A. (Anthony), Rhee, D. (Doug), Richards, J.R. (Julia R.), Ritch, R. (Robert), Scott, W.K. (William), Singh, K. (Kuldev), Sit, A.J. (Arthur J.), Vollrath, D. (Douglas), Weinreb, R.N. (Robert N.), Wollstein, G. (Gadi), Wilmer, D.Z. (Don Zack), Atan, D. (Denize), Aslam, T. (Tariq), Barman, S.A. (Sarah A.), Barrett, J.H. (Jennifer H.), Bishop, P.N. (Paul), Blows, P. (Peter), Bunce, C. (Catey), Carare, R.O. (Roxana O.), Chakravarthy, U. (Usha), Chan, M. (Michelle), Chua, S.Y.L. (Sharon Y. L.), Crabb, D.P. (David), Cumberland, P.M. (Philippa M.), Day, A. (Alexander), Desai, P. (Parul), Dhillon, B. (Bal), Dick, A.D. (Andrew D.), Egan, C. (Cathy), Ennis, S. (Sarah), Foster, P.J. (Paul), Fruttiger, M. (Marcus), Gallacher, J.E.J. (John E. J.), Garway, D.F. (David F.), Gibson, J. (Jane), Dan Gore, (), Guggenheim, J. (Jean), Hardcastle, A. (Alison), Harding, S.P. (Simon), Hogg, R. (Ruth), Keane, P.A. (Pearse A.), Khaw, P.T. (Peng T.), Lascaratos, G. (Gerassimos), Macgillivray, T. (Tom), Mackie, S. (Sarah), Martin, K. (Keith), McGaughey, M. (Michelle), McGuinness, B. (Bernadette), McKay, G.J. (Gareth), McKibbin, M. (Martin), Mitry, D. (Danny), Moore, T. (Tony), Morgan, J.E. (James E.), Muthy, Z.A. (Zaynah A.), O’Sullivan, E. (Eoin), Owen, C.G. (Chris G.), Patel, P. (Praveen), Paterson, E. (Euan), Peto, T. (Tünde), Petzold, A. (Axel), Rahi, J.S. (Jugnoo S.), Rudnikca, A.R. (Alicja R.), Self, J. (Jay), Sivaprasad, S., Steel, D. (David), Stratton, I. (Irene), Strouthidis, N. (Nicholas), Sudlow, C. (Cathie), Thomas, D. (Dhanes), Trucco, E. (Emanuele), Tufail, A. (Adnan), Vernon, S.A. (Stephen A.), Williams, C. (Cathy), Williams, K.M. (Katie M.), Woodside, J.V. (J.), Yates, M.M. (Max M.), Yip, J. (Jennifer), Zheng, Y. (Yalin), Gerhold-Ay, A. (Aslihan), Nickels, S. (Stefan), Wilson, J.F. (James), Hayward, C. (Caroline), Boutin, T.S. (Thibaud S.), Polasek, O. (Ozren), Aung, T. (Tin), Khor, C.C., Amin, N. (Najaf), Lotery, A.J. (Andrew), Wiggs, J.L. (Janey L.), Cheng, C.-Y. (Ching-Yu), Hysi, P.G. (Pirro G.), Hammond, C.J. (Christopher), Thiadens, A.A.H.J. (Alberta), MacGregor, S. (Stuart), Klaver, C.C.W. (Caroline), and Duijn, C.M. (Cornelia) van
Abstract: 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
Full Text: View/download PDF

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

Author: Bonnemaijer, PWM, van Leeuwen, EM, Iglesias, AI, Gharahkhani, P, Vitart, V, Khawaja, AP, Simcoe, M, Hoehn, R, Cree, AJ, Igo, RP, Burdon, KP, Craig, JE, Hewitt, AW, Jonas, J, Khor, C-C, Pasutto, F, Mackey, DA, Mitchell, P, Mishra, A, Pang, C, Pasquale, LR, Springelkamp, H, Thorleifsson, G, Thorsteinsdottir, U, Viswanathan, AC, Wojciechowski, R, Wong, T, Young, TL, Zeller, T, Atan, D, Aslam, T, Barman, SA, Barrett, JH, Bishop, P, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Chua, SYL, Crabb, DP, Cumberland, PM, Day, A, Desai, P, Dhillon, B, Dick, AD, Egan, C, Ennis, S, Foster, P, Fruttiger, M, Gallacher, JEJ, Garway, DF, Gibson, J, Gore, D, Guggenheim, JA, Hardcastle, A, Harding, SP, Hogg, RE, Keane, PA, Khaw, PT, Lascaratos, G, Macgillivray, T, Mackie, S, Martin, K, McGaughey, M, McGuinness, B, Mckay, GJ, McKibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Patel, P, Paterson, E, Peto, T, Petzold, A, Rahi, JS, Rudnikca, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Sudlow, C, Thomas, D, Trucco, E, Tufail, A, Vernon, SA, Williams, C, Williams, K, Woodside, JV, Yates, MM, Yip, J, Zheng, Y, Allingham, R, Budenz, D, Bailey, JC, Fingert, J, Gaasterland, D, Gaasterland, T, Haines, JL, Hark, L, Hauser, M, Kang, JH, Kraft, P, Lee, R, Lichter, P, Liu, Y, Moroi, S, Pericak, M, Realini, A, Rhee, D, Richards, JR, Ritch, R, Scott, WK, Singh, K, Sit, A, Vollrath, D, Weinreb, R, Wollstein, G, Wilmer, DZ, Gerhold-Ay, A, Nickels, S, Wilson, JF, Hayward, C, Boutin, TS, Polasek, O, Aung, T, Khor, CC, Amin, N, Lotery, AJ, Wiggs, JL, Cheng, C-Y, Hysi, PG, Hammond, CJ, Thiadens, AAHJ, MacGregor, S, Klaver, CCW, van Duijn, CM, Bonnemaijer, PWM, van Leeuwen, EM, Iglesias, AI, Gharahkhani, P, Vitart, V, Khawaja, AP, Simcoe, M, Hoehn, R, Cree, AJ, Igo, RP, Burdon, KP, Craig, JE, Hewitt, AW, Jonas, J, Khor, C-C, Pasutto, F, Mackey, DA, Mitchell, P, Mishra, A, Pang, C, Pasquale, LR, Springelkamp, H, Thorleifsson, G, Thorsteinsdottir, U, Viswanathan, AC, Wojciechowski, R, Wong, T, Young, TL, Zeller, T, Atan, D, Aslam, T, Barman, SA, Barrett, JH, Bishop, P, Blows, P, Bunce, C, Carare, RO, Chakravarthy, U, Chan, M, Chua, SYL, Crabb, DP, Cumberland, PM, Day, A, Desai, P, Dhillon, B, Dick, AD, Egan, C, Ennis, S, Foster, P, Fruttiger, M, Gallacher, JEJ, Garway, DF, Gibson, J, Gore, D, Guggenheim, JA, Hardcastle, A, Harding, SP, Hogg, RE, Keane, PA, Khaw, PT, Lascaratos, G, Macgillivray, T, Mackie, S, Martin, K, McGaughey, M, McGuinness, B, Mckay, GJ, McKibbin, M, Mitry, D, Moore, T, Morgan, JE, Muthy, ZA, O'Sullivan, E, Owen, CG, Patel, P, Paterson, E, Peto, T, Petzold, A, Rahi, JS, Rudnikca, AR, Self, J, Sivaprasad, S, Steel, D, Stratton, I, Strouthidis, N, Sudlow, C, Thomas, D, Trucco, E, Tufail, A, Vernon, SA, Williams, C, Williams, K, Woodside, JV, Yates, MM, Yip, J, Zheng, Y, Allingham, R, Budenz, D, Bailey, JC, Fingert, J, Gaasterland, D, Gaasterland, T, Haines, JL, Hark, L, Hauser, M, Kang, JH, Kraft, P, Lee, R, Lichter, P, Liu, Y, Moroi, S, Pericak, M, Realini, A, Rhee, D, Richards, JR, Ritch, R, Scott, WK, Singh, K, Sit, A, Vollrath, D, Weinreb, R, Wollstein, G, Wilmer, DZ, Gerhold-Ay, A, Nickels, S, Wilson, JF, Hayward, C, Boutin, TS, Polasek, O, Aung, T, Khor, CC, Amin, N, Lotery, AJ, Wiggs, JL, Cheng, C-Y, Hysi, PG, Hammond, CJ, Thiadens, AAHJ, MacGregor, S, Klaver, CCW, and van Duijn, CM
Abstract: 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

6. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases (vol 9, 1864, 2018)

Author: Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Souzeau, E, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Pericak-Vance, MA, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Weinreb, RN, Wollstein, G, Zack, DJ, Zhang, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Souzeau, E, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Pericak-Vance, MA, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Weinreb, RN, Wollstein, G, Zack, DJ, Zhang, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, and Whittaker, P
Abstract: Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article.
Published: 2019

7. Increased High-Density Lipoprotein Levels Associated with Age-Related Macular Degeneration: Evidence from the EYE-RISK and European Eye Epidemiology Consortia

Author: Colijn, J. M., Verzijden, T., Meester-Smoor, M. A., Klaver, C. C. W., Demirkan, A., Ahmad, S., van Duijn, C. M., den Hollander, A. I., Kersten, E., Hoyng, C. B., Cougnard-Gregoire, A., Merle, B. M. J., Korobelnik, J. -F., Delcourt, C., Papageorgiou, G., Mulder, M. T., Costa, M. A., Silva, R., Benlian, P., Bertelsen, G., Bron, A. M., Creuzot-Garcher, C., Claes, B., Hense, H. -W., Erke, M. G., Fauser, S., Foster, P. J., Khawaja, A. P., Hammond, C. J., Williams, K. M., Piermarocchi, S., Segato, T., Souied, E. H., Acar, N., Altay, L., Anastosopoulos, E., Azuara-Blanco, A., Berendschot, T., Bergen, A., Binquet, C., Bird, A., Bobak, M., Larsen, M. B., Boon, C., Bourne, R., Bretillon, L., Broe, R., Bron, A., Buitendijk, G., Cachulo, M. L., Capuano, V., Carriere, I., Chakravarthy, U., Chan, M., Chang, P., Colijn, J., Cree, A., Cumberland, P., Cunha-Vaz, J., Daien, V., De Jong, E., Deak, G., Delyfer, M. -N., Hollander, A. D., Dietzel, M., Faria, P., Farinha, C., Finger, R., Fletcher, A., Foster, P., Founti, P., Gorgels, T., Grauslund, J., Grus, F., Hammond, C., Heesterbeek, T., Hermann, M., Hoehn, R., Hogg, R., Holz, F., Hoyng, C., Jansonius, N., Janssen, S., de Jong, E., Khawaja, A., Klaver, C., Lamparter, J., Le Goff, M., Lehtimaki, T., Leung, I., Lotery, A., Mauschitz, M., Meester, M., Merle, B., Meyer zu Westrup, V., Midena, E., Miotto, S., Mirshahi, A., Mohan-Said, S., Mueller, M., Muldrew, A., Murta, J., Nickels, S., Nunes, S., Owen, C., Peto, T., Pfeiffer, N., Prokofyeva, E., Rahi, J., Raitakari, O., Rauscher, F., Ribeiro, L., Rougier, M. -B., Rudnicka, A., Randjvar, Sahel, Salonikiou, A., Sanchez, C., Schick, T., Schmitz-Valckenberg, S., Schuster, A., Schweitzer, C., Shehata, J., Silvestri, G., Simader, C., Souied, E., Speckauskas, M., Springelkamp, H., Tapp, R., Topouzis, F., van Leeuwen, E., Verhoeven, V., Vingerling, H., Von Hanno, T., Williams, K., Wolfram, C., Yip, J., Zerbib, J., Ajana, S., Arango-Gonzalez, B., Arndt, V., Bhatia, V., Bhattacharya, S. S., Biarnes, M., Borrell, A., Buhren, S., Calado, S. M., Dammeier, S., de Jong, E. K., De la Cerda, B., Diaz-Corrales, F. J., Diether, S., Emri, E., Endermann, T., Ferraro, L. L., Garcia, M., Heesterbeek, T. J., Honisch, S., Kilger, E., Langen, H., Lengyel, I., Luthert, P., Maugeais, C., Meester-Smoor, M., Merle Inserm, B. M. J., Mones, J., Nogoceke, E., Pool, F. M., Rodriguez, E., Ueffing, M., Ulrich Bartz-Schmidt, K. U., van Leeuwen, E. M., and Zumbansen, M.
Subjects: Male, Magnetic Resonance Spectroscopy, HDL, genetic structures, European Continental Ancestry Group, Polymorphism, Single Nucleotide, White People, LDL, Macular Degeneration, Risk Factors, 80 and over, Odds Ratio, Humans, Metabolomics, European Union, Polymorphism, Triglycerides, Aged, Aged, 80 and over, Cholesterol, HDL, Single Nucleotide, Cholesterol, LDL, Middle Aged, Lipid Metabolism, eye diseases, Cholesterol Ester Transfer Proteins, Cholesterol, Cross-Sectional Studies, lipids (amino acids, peptides, and proteins), Female, sense organs
Abstract: Purpose Genetic and epidemiologic studies have shown that lipid genes and high-density lipoproteins (HDLs) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relationship to AMD in a large European dataset. Design Pooled analysis of cross-sectional data. Participants Individuals (N = 30 953) aged 50 years or older participating in the European Eye Epidemiology (E3) consortium and 1530 individuals from the Rotterdam Study with lipid subfraction data. Methods AMD features were graded on fundus photographs using the Rotterdam classification. Routine blood lipid measurements, genetics, medication, and potential confounders were extracted from the E3 database. In a subgroup of the Rotterdam Study, lipid subfractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random effect were used to estimate associations. Main Outcome Measures AMD features and stage; lipid measurements. Results HDL was associated with an increased risk of AMD (odds ratio [OR], 1.21 per 1-mmol/l increase; 95% confidence interval [CI], 1.14–1.29), whereas triglycerides were associated with a decreased risk (OR, 0.94 per 1-mmol/l increase; 95% CI, 0.91–0.97). Both were associated with drusen size. Higher HDL raised the odds of larger drusen, whereas higher triglycerides decreases the odds. LDL cholesterol reached statistical significance only in the association with early AMD (P = 0.045). Regarding lipid subfractions, the concentration of extra-large HDL particles showed the most prominent association with AMD (OR, 1.24; 95% CI, 1.10–1.40). The cholesteryl ester transfer protein risk variant (rs17231506) for AMD was in line with increased HDL levels (P = 7.7 × 10–7), but lipase C risk variants (rs2043085, rs2070895) were associated in an opposite way (P = 1.0 × 10–6 and P = 1.6 × 10–4). Conclusions Our study suggested that HDL cholesterol is associated with increased risk of AMD and that triglycerides are negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL subfractions seem to be drivers in the relationship with AMD, and variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains to be answered.
Published: 2018

8. Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma

Author: King, R. (Richard), Struebing, F.L., Li, Y. (Yuwen), Wang, J., Koch, A.A., Bailey, JNC, Gharahkhani, P, Macgregor, S., Allingham, R.R. (R Rand), Hauser, M.A. (Michael), Wiggs, J.L. (Janey), Geisert, E.E., Allingham, R., Brilliant, M., Budenz, D., Bailey, J.C., Fingert, J., Gaasterland, D., Gaasterland, T., Haines, J.L. (Jonathan), Hark, L., Hauser, M., Igo, R., Kang, J.H. (Jae), Kraft, P. (Peter), Lee, R. (R.) van der, Lichter, P. (Peter), Liu, Y. (Yu), Moroi, S., Pasquale, L.R. (Louis), Pericak-Vance, M.A. (Margaret), Realini, A., Rhee, D., Richards, J. (John), Ritch, R., Schuman, J., Scott, W.K. (William), Singh, K, Sit, A., Vollrath, D., Weinreb, RN, Wollstein, G., Zack, D., Aung, T. (Tin), Burdon, K.P. (Kathryn), Cheng, C-Y. (Ching-Yu), Bailey, J.N.C., Craig, J.E. (Jamie), Cree, A.J. (Angela), Hammond, C.J. (Christopher), Hewit, A.W. (Alex), Höhn, R., Hysi, P.G. (Pirro), Gonzalez, A.I., Jonas, J., Khawaja, A, Khor, C.C., Klaver, C.C.W. (Caroline), Pasutto, F. (Francesca), Mackey, D., Mitchell, P. (Paul), Mishra, A. (Aniket), Pang, C., Springelkamp, H. (Henriët), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Duijn, C.M., Viswanathan, A. (Anand), Vitart, V. (Veronique), Wojciechowski, R. (Robert), Wong, T., Young, T.L. (Terri), Zeller, T. (Tanja), King, R. (Richard), Struebing, F.L., Li, Y. (Yuwen), Wang, J., Koch, A.A., Bailey, JNC, Gharahkhani, P, Macgregor, S., Allingham, R.R. (R Rand), Hauser, M.A. (Michael), Wiggs, J.L. (Janey), Geisert, E.E., Allingham, R., Brilliant, M., Budenz, D., Bailey, J.C., Fingert, J., Gaasterland, D., Gaasterland, T., Haines, J.L. (Jonathan), Hark, L., Hauser, M., Igo, R., Kang, J.H. (Jae), Kraft, P. (Peter), Lee, R. (R.) van der, Lichter, P. (Peter), Liu, Y. (Yu), Moroi, S., Pasquale, L.R. (Louis), Pericak-Vance, M.A. (Margaret), Realini, A., Rhee, D., Richards, J. (John), Ritch, R., Schuman, J., Scott, W.K. (William), Singh, K, Sit, A., Vollrath, D., Weinreb, RN, Wollstein, G., Zack, D., Aung, T. (Tin), Burdon, K.P. (Kathryn), Cheng, C-Y. (Ching-Yu), Bailey, J.N.C., Craig, J.E. (Jamie), Cree, A.J. (Angela), Hammond, C.J. (Christopher), Hewit, A.W. (Alex), Höhn, R., Hysi, P.G. (Pirro), Gonzalez, A.I., Jonas, J., Khawaja, A, Khor, C.C., Klaver, C.C.W. (Caroline), Pasutto, F. (Francesca), Mackey, D., Mitchell, P. (Paul), Mishra, A. (Aniket), Pang, C., Springelkamp, H. (Henriët), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Duijn, C.M., Viswanathan, A. (Anand), Vitart, V. (Veronique), Wojciechowski, R. (Robert), Wong, T., Young, T.L. (Terri), and Zeller, T. (Tanja)
Abstract: Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk of developing POAG. The BXD RI strain set was used to define mammalian genomic loci modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between 60–100 days of age). The mice were anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to QTLs modulating this phenotype using the bioinformatics tools on GeneNetwork (www.genenetwork.org). The candidate genes and genomic loci identified in the mouse were then directly compared with the summary data from a human POAG genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG.This analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region (Pou6f2) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2, two resulted in changes in the amino acid proline which could result in altered secondary structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were examined in the NEIGHBORHOOD database to determine if they are potential risk factors for human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided within one gene (POU6F2), with the highest significance level of p = 10−6 for SNP rs7631
Published: 2018
Full Text: View/download PDF

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

Author: Iglesias, A.I. (Adriana I.), Mishra, A. (Aniket), Vitart, V. (Veronique), Bykhovskaya, Y. (Yelena), Höhn, R. (René), Springelkamp, H. (Henriët), Cuellar-Partida, G. (Gabriel), Gharahkhani, P. (Puya), Bailey, J.N.C. (Jessica N. Cooke), Willoughby, C.E. (Colin E.), Li, X. (Xiaohui), Yazar, S. (Seyhan), Nag, A. (Abhishek), Khawaja, A.P. (Anthony), Polasek, O. (Ozren), Siscovick, D.S. (David), Mitchell, P. (Paul), Tham, Y.C. (Yih Chung), Haines, J.L. (Jonathan), Kearns, L.S. (Lisa S.), Hayward, C. (Caroline), Shi, Y. (Yuan), Van Leeuwen, E.M. (Elisabeth M.), Taylor, K.D. (Kent), Wang, J.J. (Jie Jin), Rochtchina, E. (Elena), Attia, J. (John), Scott, R. (Rodney), Holliday, E.G. (Elizabeth), Baird, P.N. (Paul), Xie, J. (Jing), Inouye, M. (Michael), Viswanathan, A. (Ananth), Sim, X. (Xueling), Bonnemaijer, P.W.M. (Pieter), Rotter, J.I. (Jerome I.), Martin, N.G. (Nicholas G.), Zeller, T. (Tanja), Mills, R.A. (Richard), Staffieri, S.E. (Sandra E.), Jonas, J.B. (Jost B.), Schmidtmann, I. (Irene), Boutin, T. (Thibaud), Kang, J.H. (Jae H.), Lucas, S.E.M. (Sionne E.M.), Wong, T.Y. (Tien Yin), Beutel, M.E. (Manfred E.), Wilson, J.F. (James F.), Allingham, R.R. (R Rand), Brilliant, M.H. (Murray H.), Budenz, D.L. (Donald L.), Christen, W.G. (William G.), Fingert, J. (John), Friedman, D.S. (David), Gaasterland, D. (Douglas), Gaasterland, T. (Terry), Hauser, M.A. (Michael), Kraft, P. (Peter), Lee, R.K. (Richard K.), Lichter, P.A. (Paul A.), Liu, Y. (Yutao), Loomis, S.J. (Stephanie J.), Moroi, S.E. (Sayoko), Pericak-Vance, M.A. (Margaret), Realini, A. (Anthony), Richards, J.E. (Julia E.), Schuman, J.S. (Joel S.), Scott, W.K. (William), Singh, K. (Kuldev), Sit, A.J. (Arthur J.), Vollrath, D. (Douglas), Weinreb, R.N. (Robert N.), Wollstein, G. (Gadi), Zack, D.J. (Donald), Zhang, K. (Kang), Donnelly, P. (Peter), Barroso, I.E. (Inês), Blackwell, J.M. (Jenefer M.), Bramon, E. (Elvira), Brown, M.A. (Matthew), Casas, J.P. (Juan), Corvin, A. (Aiden), Deloukas, P. (Panos), Duncanson, A. (Audrey), Jankowski, J. (Janusz), Markus, H.S. (Hugh), Mathew, J. (Joseph), Palmer, C.N.A. (Colin), Plomin, R. (Robert), Rautanen, A. (Anna), Sawcer, S.J. (Stephen), Trembath, R.C. (Richard), Wood, N.W. (Nicholas W.), Spencer, C.C.A. (Chris C.), Band, G. (Gavin), Bellenguez, C. (Céline), Freeman, C. (Colin), Hellenthal, F.A., Giannoulatou, E. (Eleni), Pirinen, M. (Matti), Pearson, R. (Ruth), Strange, A. (Amy), Su, Z. (Zhan), Vukcevic, D. (Damjan), Langford, C. (Cordelia), Hunt, S.E. (Sarah E.), Edkins, T. (Ted), Gwilliam, R. (Rhian), Blackburn, H. (Hannah), Bumpstead, S. (Suzannah), Dronov, S. (Serge), Gillman, M. (Matthew), Gray, E. (Emma), Hammond, N. (Naomi), Jayakumar, A. (Alagurevathi), McCann, O.T. (Owen), Liddle, J. (Jennifer), Potter, S.C. (Simon), Ravindrarajah, R. (Radhi), Ricketts, M. (Michelle), Waller, P. (Patrick), Weston, P. (Paul), Widaa, S. (Sara), Whittaker, P. (Pamela), Uitterlinden, A.G. (André), Vithana, E.N. (Eranga), Foster, P.J. (Paul), Hysi, P.G. (Pirro), Hewitt, A.W. (Alex W.), Khor, C.C., Pasquale, L.R. (Louis), Montgomery, G.W. (Grant W.), Klaver, C.C.W. (Caroline), Aung, T. (Tin), Pfeiffer, A.F.H. (Andreas), Mackey, D.A. (David), Hammond, C.J. (Christopher), Cheng, C.-Y. (Ching-Yu), Craig, J.E. (Jamie), Rabinowitz, Y.S. (Yaron), Wiggs, J.L. (Janey L.), Burdon, K.P. (Kathryn), Duijn, C.M. (Cornelia) van, MacGregor, S. (Stuart), Iglesias, A.I. (Adriana I.), Mishra, A. (Aniket), Vitart, V. (Veronique), Bykhovskaya, Y. (Yelena), Höhn, R. (René), Springelkamp, H. (Henriët), Cuellar-Partida, G. (Gabriel), Gharahkhani, P. (Puya), Bailey, J.N.C. (Jessica N. Cooke), Willoughby, C.E. (Colin E.), Li, X. (Xiaohui), Yazar, S. (Seyhan), Nag, A. (Abhishek), Khawaja, A.P. (Anthony), Polasek, O. (Ozren), Siscovick, D.S. (David), Mitchell, P. (Paul), Tham, Y.C. (Yih Chung), Haines, J.L. (Jonathan), Kearns, L.S. (Lisa S.), Hayward, C. (Caroline), Shi, Y. (Yuan), Van Leeuwen, E.M. (Elisabeth M.), Taylor, K.D. (Kent), Wang, J.J. (Jie Jin), Rochtchina, E. (Elena), Attia, J. (John), Scott, R. (Rodney), Holliday, E.G. (Elizabeth), Baird, P.N. (Paul), Xie, J. (Jing), Inouye, M. (Michael), Viswanathan, A. (Ananth), Sim, X. (Xueling), Bonnemaijer, P.W.M. (Pieter), Rotter, J.I. (Jerome I.), Martin, N.G. (Nicholas G.), Zeller, T. (Tanja), Mills, R.A. (Richard), Staffieri, S.E. (Sandra E.), Jonas, J.B. (Jost B.), Schmidtmann, I. (Irene), Boutin, T. (Thibaud), Kang, J.H. (Jae H.), Lucas, S.E.M. (Sionne E.M.), Wong, T.Y. (Tien Yin), Beutel, M.E. (Manfred E.), Wilson, J.F. (James F.), Allingham, R.R. (R Rand), Brilliant, M.H. (Murray H.), Budenz, D.L. (Donald L.), Christen, W.G. (William G.), Fingert, J. (John), Friedman, D.S. (David), Gaasterland, D. (Douglas), Gaasterland, T. (Terry), Hauser, M.A. (Michael), Kraft, P. (Peter), Lee, R.K. (Richard K.), Lichter, P.A. (Paul A.), Liu, Y. (Yutao), Loomis, S.J. (Stephanie J.), Moroi, S.E. (Sayoko), Pericak-Vance, M.A. (Margaret), Realini, A. (Anthony), Richards, J.E. (Julia E.), Schuman, J.S. (Joel S.), Scott, W.K. (William), Singh, K. (Kuldev), Sit, A.J. (Arthur J.), Vollrath, D. (Douglas), Weinreb, R.N. (Robert N.), Wollstein, G. (Gadi), Zack, D.J. (Donald), Zhang, K. (Kang), Donnelly, P. (Peter), Barroso, I.E. (Inês), Blackwell, J.M. (Jenefer M.), Bramon, E. (Elvira), Brown, M.A. (Matthew), Casas, J.P. (Juan), Corvin, A. (Aiden), Deloukas, P. (Panos), Duncanson, A. (Audrey), Jankowski, J. (Janusz), Markus, H.S. (Hugh), Mathew, J. (Joseph), Palmer, C.N.A. (Colin), Plomin, R. (Robert), Rautanen, A. (Anna), Sawcer, S.J. (Stephen), Trembath, R.C. (Richard), Wood, N.W. (Nicholas W.), Spencer, C.C.A. (Chris C.), Band, G. (Gavin), Bellenguez, C. (Céline), Freeman, C. (Colin), Hellenthal, F.A., Giannoulatou, E. (Eleni), Pirinen, M. (Matti), Pearson, R. (Ruth), Strange, A. (Amy), Su, Z. (Zhan), Vukcevic, D. (Damjan), Langford, C. (Cordelia), Hunt, S.E. (Sarah E.), Edkins, T. (Ted), Gwilliam, R. (Rhian), Blackburn, H. (Hannah), Bumpstead, S. (Suzannah), Dronov, S. (Serge), Gillman, M. (Matthew), Gray, E. (Emma), Hammond, N. (Naomi), Jayakumar, A. (Alagurevathi), McCann, O.T. (Owen), Liddle, J. (Jennifer), Potter, S.C. (Simon), Ravindrarajah, R. (Radhi), Ricketts, M. (Michelle), Waller, P. (Patrick), Weston, P. (Paul), Widaa, S. (Sara), Whittaker, P. (Pamela), Uitterlinden, A.G. (André), Vithana, E.N. (Eranga), Foster, P.J. (Paul), Hysi, P.G. (Pirro), Hewitt, A.W. (Alex W.), Khor, C.C., Pasquale, L.R. (Louis), Montgomery, G.W. (Grant W.), Klaver, C.C.W. (Caroline), Aung, T. (Tin), Pfeiffer, A.F.H. (Andreas), Mackey, D.A. (David), Hammond, C.J. (Christopher), Cheng, C.-Y. (Ching-Yu), Craig, J.E. (Jamie), Rabinowitz, Y.S. (Yaron), Wiggs, J.L. (Janey L.), Burdon, K.P. (Kathryn), Duijn, C.M. (Cornelia) van, and MacGregor, S. (Stuart)
Abstract: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
Published: 2018
Full Text: View/download PDF

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

Author: Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, 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, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, MacGregor, S, Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Hoehn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polasek, O, Siscovick, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, van Leeuwen, EM, Taylor, KD, Bonnemaijer, P, 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, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, C-Y, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, van Duijn, CM, and MacGregor, S
Abstract: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
Published: 2018

11. Incidence of glaucomatous visual field loss after two decades of follow-up: the Rotterdam Study

Author: Springelkamp, H., Wolfs, R.C., Ramdas, W.D., Hofman, A., Vingerling, J.R., Klaver, C.C.W., Jansonius, N.M., Springelkamp, H., Wolfs, R.C., Ramdas, W.D., Hofman, A., Vingerling, J.R., Klaver, C.C.W., and Jansonius, N.M.
Abstract: Contains fulltext : 182318.pdf (Publisher’s version ) (Open Access), To determine the incidence of glaucomatous visual field loss (GVFL) two decades after the start of the Rotterdam Study, and to compare known risk factors for open-angle glaucoma (OAG) between different clinical manifestations of OAG. Of 6806 participants aged 55 years and older from the population-based Rotterdam Study, 3939 underwent visual field testing at baseline and at least one follow-up round. The ophthalmic examinations included optic disc assessment and measurements of intraocular pressure (IOP), refractive error, diastolic blood pressure (DBP), and height and weight. The incidence rate of GVFL was calculated. Associations with the risk factors age, gender, baseline IOP, family history, myopia, DBP, and body-mass index [BMI] were assessed using Cox regression, with different clinical manifestations of OAG as outcome measure (glaucomatous optic neuropathy (GON), GVFL, GVFL and GON, GVFL without GON, and GON without GVFL). Median follow-up was 11.1 (IQR 6.8-17.2; range 5.0-20.3) years. The incidence rate of GVFL was 2.9 (95% confidence interval 2.4-3.4) per 1000 person years (140 cases with incident GVFL in one (n = 113) or both (n = 27) eyes). Baseline IOP and age were significantly associated with all OAG outcomes (all p < 0.001); BMI showed a non-significant protective effect in all outcomes (p = 0.01 to p = 0.09). Gender, myopia, and DBP were not associated with any outcome. Our study provides an estimate of the long-term incidence of GVFL in a predominantly white population. The development of GVFL was strongly associated with baseline IOP and age. Risk factor profiles were similar for the different outcomes.
Published: 2017

12. A Genome-Wide Scan for MicroRNA-Related Genetic Variants Associated With Primary Open-Angle Glaucoma

Author: Ghanbari, M., Iglesias, A.I., Springelkamp, H., Duijn, C.M. van, Ikram, M.A., Dehghan, A., Erkeland, S.J., Klaver, C.C.W., Meester-Smoor, M.A., Ghanbari, M., Iglesias, A.I., Springelkamp, H., Duijn, C.M. van, Ikram, M.A., Dehghan, A., Erkeland, S.J., Klaver, C.C.W., and Meester-Smoor, M.A.
Abstract: Contains fulltext : 181762.pdf (Publisher’s version ) (Open Access), Purpose: To identify microRNAs (miRNAs) involved in primary open-angle glaucoma (POAG), using genetic data. MiRNAs are small noncoding RNAs that posttranscriptionally regulate gene expression. Genetic variants in miRNAs or miRNA-binding sites within gene 3'-untranslated regions (3'UTRs) are expected to affect miRNA function and contribute to disease risk. Methods: Data from the recent genome-wide association studies on intraocular pressure, vertical cup-to-disc ratio (VCDR), cupa area and disc area were used to investigate the association of miRNAs with POAG endophenotypes. Putative targets of the associated miRNAs were studied according to their association with POAG and tested in cell line by transfection experiments for regulation by the miRNAs. Results: Of 411 miRNA variants, rs12803915:A/G in the terminal loop of pre-miR-612 and rs2273626:A/C in the seed sequence of miR-4707 were significantly associated with VCDR and cup area (P values < 1.2 x 10-4). The first variant is demonstrated to increase the miR-612 expression. We showed that the second variant does not affect the miR-4707 biogenesis, but reduces the binding of miR-4707-3p to CARD10, a gene known to be involved in glaucoma. Moreover, of 72,052 miRNA-binding-site variants, 47 were significantly associated with four POAG endophenotypes (P value < 6.9 x 10-6). Of these, we highlighted 10 variants that are more likely to affect miRNA-mediated gene regulation in POAG. These include rs3217992 and rs1063192, which have been shown experimentally to affect miR-138-3p- and miR-323b-5p-mediated regulation of CDKN2B. Conclusions: We identified a number of miRNAs that are associated with POAG endophenotypes. The identified miRNAs and their target genes are candidates for future studies on miRNA-related therapies for POAG.
Published: 2017

13. Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future

Author: Colijn, J.M. (Johanna), Buitendijk, G.H.S. (Gabrielle), Prokofyeva, E. (Elena), Alves, D. (Dalila), Cachulo, M.L. (Maria L.), Khawaja, A.P. (Anthony), Cougnard-Grégoire, A. (Audrey), Merle, B.M.J. (Bénédicte M.J.), Korb, C. (Christina), Erke, M.G. (Maja Gran), Bron, A. (Alain), Anastasopoulos, E. (Eleftherios), Meester-Smoor, M.A. (Magda), Segato, T. (Tatiana), Piermarocchi, S. (Stefano), Jong, P.T.V.M. (Paulus) de, Vingerling, J.R. (Hans), Topouzis, F. (Fotis), Creuzot-Garcher, C. (Catherine), Bertelsen, G. (Geir), Pfeiffer, A.F.H. (Andreas), Fletcher, A.E. (Astrid E.), Foster, P.J. (Paul), Silva, R. (Rufino), Korobelnik, J.-F. (Jean-François), Delcourt, C. (Cécile), Klaver, C.C.W. (Caroline), Ajana, S. (Soufiane), Arango-Gonzalez, B. (Blanca), Arndt, V. (Verena), Bhatia, V. (Vaibhav), Bhattacharya, S.S. (Shomi S.), Biarnés, M. (Marc), Borrell, A. (Anna), Bühren, S. (Sebastian), Calado, S.M. (Sofia M.), Colijn, J.M. (Johanna M.), Dammeier, S. (Sascha), Jong, E.K. (Eiko) de, De la Cerda, B. (Berta), den Hollander, A.I. (Anneke I.), Diaz-Corrales, F.J. (Francisco J.), Diether, S. (Sigrid), Emri, E. (Eszter), Endermann, T. (Tanja), Ferraro, L.L. (Lucia L.), Garcia, M. (Míriam), Heesterbeek, T.J. (Thomas J.), Honisch, S. (Sabina), Hoyng, C.B. (Carel B.), Kersten, E. (Eveline), Kilger, E. (Ellen), Klaver, C.C.W. (Caroline C.W.), Langen, H. (Hanno), Lengyel, I. (Imre), Luthert, P. (Phil), Maugeais, C. (Cyrille), Meester-Smoor, M. (Magda), Monés, J. (Jordi), Nogoceke, E. (Everson), Peto, T. (Tunde), Pool, F.M. (Frances M.), Rodríguez, E. (Eduardo), Ueffing, M. (Marius), Ulrich Bartz-Schmidt, K.U. (Karl U.), van Leeuwen, E.M. (Elisabeth M.), Verzijden, T. (Timo), Zumbansen, M. (Markus), Acar, N. (Niyazi), Anastosopoulos, E. (Eleftherios), Azuara-Blanco, A. (Augusto), Bergen, A.A.B. (Arthur), Binquet, C. (Christine), Bird, A.C. (Alan), Bretillon, L. (Lionel), Buitendijk, G. (Gabrielle), Cachulo, M.L. (Maria Luz), Chakravarthy, U. (Usha), Chan, M. (Michelle), Chang, P. (Petrus), Colijn, J. (Johanna), Cumberland, P. (Phillippa), Cunha-Vaz, J. (José), Daien, V. (Vincent), Deak, G. (Gabor), Delyfer, M.-N. (Marie-Noëlle), Hollander, A.I. (Anneke), Dietzel, M. (Martha), Fauser, S. (Sascha), Finger, R. (Robert), Fletcher, A. (Astrid), Foster, P.J. (Paul J.), Founti, P. (Panayiota), Göbel, A. (Arno), Gorgels, T.G.M.F. (Theo), Grauslund, J. (Jakob), Grus, F. (Franz), Hammond, C.J. (Christopher), Helmer, C. (Catherine), Hense, H.-W. (Hans-Werner), Hermann, M. (Manuel), Hoehn, R. (René), Hogg, R. (Ruth), Holz, F.G. (Frank), Hoyng, C.B. (Carel), Jansonius, N.M. (Nomdo), Janssen, S.F. (Sarah), Khawaja, A. (Anthony), Lamparter, J. (Julia), Le Goff, M. (Mélanie), Leal, S. (Sergio), Lechanteur, Y.T.E. (Yara T. E.), Lehtimäki, T. (Terho), Lotery, A.J. (Andrew), Leung, I. (Irene), Mauschitz, M. (Matthias), Merle, B. (Bénédicte), Meyer zu Westrup, V. (Verena), Midena, E. (Edoardo), Miotto, S. (Stefania), Mirshahi, A. (Alireza), Mohan-Saïd, S. (Sadek), Mueller, M. (Michael), Muldrew, A. (Alyson), Nunes, S. (Sandrina), Oexle, K. (Konrad), Peto, T. (Tünde), Rahi, J. (Jugnoo), Raitakari, O. (Olli), Ribeiro, L. (Luisa), Rougier, M.-B. (Marie-Bénédicte), Sahel, J.-A. (José-Alain), Salonikiou, A. (Aggeliki), Sanchez, C. (Clarisa), Schmitz-Valckenberg, S. (Steffen), Schweitzer, C.M.C. (C. M C), Shehata, J. (Jasmin), Silvestri, G. (Giuliana), Simader, C. (Christian), Souied, E.H. (Eric), Springelkamp, H. (Henriët), Tapp, R. (Robyn), Verhoeven, V. (Virginie), Von Hanno, T. (Therese), Vujosevic, S. (Stela), Williams, K. (Katie), Wolfram, C. (Christian), Yip, J. (Jennifer), Zerbib, J. (Jennyfer), Zwiener, I. (Isabella), Colijn, J.M. (Johanna), Buitendijk, G.H.S. (Gabrielle), Prokofyeva, E. (Elena), Alves, D. (Dalila), Cachulo, M.L. (Maria L.), Khawaja, A.P. (Anthony), Cougnard-Grégoire, A. (Audrey), Merle, B.M.J. (Bénédicte M.J.), Korb, C. (Christina), Erke, M.G. (Maja Gran), Bron, A. (Alain), Anastasopoulos, E. (Eleftherios), Meester-Smoor, M.A. (Magda), Segato, T. (Tatiana), Piermarocchi, S. (Stefano), Jong, P.T.V.M. (Paulus) de, Vingerling, J.R. (Hans), Topouzis, F. (Fotis), Creuzot-Garcher, C. (Catherine), Bertelsen, G. (Geir), Pfeiffer, A.F.H. (Andreas), Fletcher, A.E. (Astrid E.), Foster, P.J. (Paul), Silva, R. (Rufino), Korobelnik, J.-F. (Jean-François), Delcourt, C. (Cécile), Klaver, C.C.W. (Caroline), Ajana, S. (Soufiane), Arango-Gonzalez, B. (Blanca), Arndt, V. (Verena), Bhatia, V. (Vaibhav), Bhattacharya, S.S. (Shomi S.), Biarnés, M. (Marc), Borrell, A. (Anna), Bühren, S. (Sebastian), Calado, S.M. (Sofia M.), Colijn, J.M. (Johanna M.), Dammeier, S. (Sascha), Jong, E.K. (Eiko) de, De la Cerda, B. (Berta), den Hollander, A.I. (Anneke I.), Diaz-Corrales, F.J. (Francisco J.), Diether, S. (Sigrid), Emri, E. (Eszter), Endermann, T. (Tanja), Ferraro, L.L. (Lucia L.), Garcia, M. (Míriam), Heesterbeek, T.J. (Thomas J.), Honisch, S. (Sabina), Hoyng, C.B. (Carel B.), Kersten, E. (Eveline), Kilger, E. (Ellen), Klaver, C.C.W. (Caroline C.W.), Langen, H. (Hanno), Lengyel, I. (Imre), Luthert, P. (Phil), Maugeais, C. (Cyrille), Meester-Smoor, M. (Magda), Monés, J. (Jordi), Nogoceke, E. (Everson), Peto, T. (Tunde), Pool, F.M. (Frances M.), Rodríguez, E. (Eduardo), Ueffing, M. (Marius), Ulrich Bartz-Schmidt, K.U. (Karl U.), van Leeuwen, E.M. (Elisabeth M.), Verzijden, T. (Timo), Zumbansen, M. (Markus), Acar, N. (Niyazi), Anastosopoulos, E. (Eleftherios), Azuara-Blanco, A. (Augusto), Bergen, A.A.B. (Arthur), Binquet, C. (Christine), Bird, A.C. (Alan), Bretillon, L. (Lionel), Buitendijk, G. (Gabrielle), Cachulo, M.L. (Maria Luz), Chakravarthy, U. (Usha), Chan, M. (Michelle), Chang, P. (Petrus), Colijn, J. (Johanna), Cumberland, P. (Phillippa), Cunha-Vaz, J. (José), Daien, V. (Vincent), Deak, G. (Gabor), Delyfer, M.-N. (Marie-Noëlle), Hollander, A.I. (Anneke), Dietzel, M. (Martha), Fauser, S. (Sascha), Finger, R. (Robert), Fletcher, A. (Astrid), Foster, P.J. (Paul J.), Founti, P. (Panayiota), Göbel, A. (Arno), Gorgels, T.G.M.F. (Theo), Grauslund, J. (Jakob), Grus, F. (Franz), Hammond, C.J. (Christopher), Helmer, C. (Catherine), Hense, H.-W. (Hans-Werner), Hermann, M. (Manuel), Hoehn, R. (René), Hogg, R. (Ruth), Holz, F.G. (Frank), Hoyng, C.B. (Carel), Jansonius, N.M. (Nomdo), Janssen, S.F. (Sarah), Khawaja, A. (Anthony), Lamparter, J. (Julia), Le Goff, M. (Mélanie), Leal, S. (Sergio), Lechanteur, Y.T.E. (Yara T. E.), Lehtimäki, T. (Terho), Lotery, A.J. (Andrew), Leung, I. (Irene), Mauschitz, M. (Matthias), Merle, B. (Bénédicte), Meyer zu Westrup, V. (Verena), Midena, E. (Edoardo), Miotto, S. (Stefania), Mirshahi, A. (Alireza), Mohan-Saïd, S. (Sadek), Mueller, M. (Michael), Muldrew, A. (Alyson), Nunes, S. (Sandrina), Oexle, K. (Konrad), Peto, T. (Tünde), Rahi, J. (Jugnoo), Raitakari, O. (Olli), Ribeiro, L. (Luisa), Rougier, M.-B. (Marie-Bénédicte), Sahel, J.-A. (José-Alain), Salonikiou, A. (Aggeliki), Sanchez, C. (Clarisa), Schmitz-Valckenberg, S. (Steffen), Schweitzer, C.M.C. (C. M C), Shehata, J. (Jasmin), Silvestri, G. (Giuliana), Simader, C. (Christian), Souied, E.H. (Eric), Springelkamp, H. (Henriët), Tapp, R. (Robyn), Verhoeven, V. (Virginie), Von Hanno, T. (Therese), Vujosevic, S. (Stela), Williams, K. (Katie), Wolfram, C. (Christian), Yip, J. (Jennifer), Zerbib, J. (Jennyfer), and Zwiener, I. (Isabella)
Abstract: Purpose Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future. Design Meta-analysis of prevalence data. Participants A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe. Methods AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV). Main Outcome Measures Prevalence of early and late AMD, BCVA, and number of AMD cases. Results Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%–5.0%) in those aged 55–59 years to 17.6% (95% C
Published: 2017
Full Text: View/download PDF

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

Author: Springelkamp, H. (Henriët), Iglesias, A.I. (Adriana), Mishra, A. (Aniket), Höhn, R. (René), Wojciechowski, R. (Robert), Khawaja, A.P. (Anthony), Nag, A. (Abhishek), Wang, Y.X. (Ya Xing), Wang, J.J. (Jie Jin), Cuellar-Partida, G. (Gabriel), Gibson, J. (Jane), Cooke Bailey, J.N. (Jessica), Vithana, E.N. (Eranga), Gharahkhani, P. (Puya), Boutin, T. (Thibaud), Ramdas, W.D. (Wishal), Zeller, T. (Tanja), Luben, R.N. (Robert), Yonova-Doing, E. (Ekaterina), Viswanathan, A.C. (Ananth), Yazar, S. (Seyhan), Cree, A.J. (Angela), Haines, J.L. (Jonathan), Koh, J.Y. (Jia Yu), Souzeau, E. (Emmanuelle), Wilson, J.F. (James), Amin, N. (Najaf), Müller, C. (Christian), Venturini, C. (Cristina), Kearns, L.S. (Lisa), Hee Kang, J. (Jae), Consortium, N. (Neighborhood), Tham, Y.C. (Yih Chung), Zhou, T. (Tiger), van Leeuwen, E.M. (Elisabeth), Nickels, S. (Stefan), Sanfilippo, P. (Paul), Liao, J. (Jiemin), Linde, H.V. (Herma van der), Zhao, W. (Wanting), van Koolwijk, L.M. (Leonieke), Zheng, L. (Li), Rivadeneira, F. (Fernando), Baskaran, M. (Mani), van der Lee, S.J. (Sven), Perera, S. (Shamira), de Jong, P.T. (Paulus), Oostra, B.A. (Ben), Uitterlinden, A.G. (André), Fan, Q. (Qiao), Hofman, A. (Albert), Shyong Tai, E. (E-), Vingerling, J.R. (Johannes), Sim, X. (Xueling), Wolfs, R.C. (Roger), Teo, Y.Y. (Yik Ying), Lemij, H.G. (Hans), Khor, C.C. (Chiea Chuen), Willemsen, R. (Rob), Lackner, K.J. (Karl), Aung, T. (Tin), Jansonius, N.M. (Nomdo), Montgomery, G. (Grant), Wild, P.S. (Philipp), Young, T.L. (Terri), Burdon, K.P. (Kathryn), Hysi, P.G. (Pirro), Pasquale, L.R. (Louis), Wong, T.Y. (Tien Yin), Klaver, C.C. (Caroline), Hewitt, A.W. (Alex), Jonas, J.B. (Jost), Mitchell, P. (Paul), Lotery, A.J. (Andrew), Foster, P.J. (Paul), Vitart, V. (Veronique), Pfeiffer, N. (Norbert), Craig, J.E. (Jamie), Mackey, D.A. (David), Hammond, C.J. (Christopher), Wiggs, J.L. (Janey), Cheng, C.Y. (Ching-Yu), van Duijn, C.M. (Cornelia), MacGregor, S. (Stuart), Springelkamp, H. (Henriët), Iglesias, A.I. (Adriana), Mishra, A. (Aniket), Höhn, R. (René), Wojciechowski, R. (Robert), Khawaja, A.P. (Anthony), Nag, A. (Abhishek), Wang, Y.X. (Ya Xing), Wang, J.J. (Jie Jin), Cuellar-Partida, G. (Gabriel), Gibson, J. (Jane), Cooke Bailey, J.N. (Jessica), Vithana, E.N. (Eranga), Gharahkhani, P. (Puya), Boutin, T. (Thibaud), Ramdas, W.D. (Wishal), Zeller, T. (Tanja), Luben, R.N. (Robert), Yonova-Doing, E. (Ekaterina), Viswanathan, A.C. (Ananth), Yazar, S. (Seyhan), Cree, A.J. (Angela), Haines, J.L. (Jonathan), Koh, J.Y. (Jia Yu), Souzeau, E. (Emmanuelle), Wilson, J.F. (James), Amin, N. (Najaf), Müller, C. (Christian), Venturini, C. (Cristina), Kearns, L.S. (Lisa), Hee Kang, J. (Jae), Consortium, N. (Neighborhood), Tham, Y.C. (Yih Chung), Zhou, T. (Tiger), van Leeuwen, E.M. (Elisabeth), Nickels, S. (Stefan), Sanfilippo, P. (Paul), Liao, J. (Jiemin), Linde, H.V. (Herma van der), Zhao, W. (Wanting), van Koolwijk, L.M. (Leonieke), Zheng, L. (Li), Rivadeneira, F. (Fernando), Baskaran, M. (Mani), van der Lee, S.J. (Sven), Perera, S. (Shamira), de Jong, P.T. (Paulus), Oostra, B.A. (Ben), Uitterlinden, A.G. (André), Fan, Q. (Qiao), Hofman, A. (Albert), Shyong Tai, E. (E-), Vingerling, J.R. (Johannes), Sim, X. (Xueling), Wolfs, R.C. (Roger), Teo, Y.Y. (Yik Ying), Lemij, H.G. (Hans), Khor, C.C. (Chiea Chuen), Willemsen, R. (Rob), Lackner, K.J. (Karl), Aung, T. (Tin), Jansonius, N.M. (Nomdo), Montgomery, G. (Grant), Wild, P.S. (Philipp), Young, T.L. (Terri), Burdon, K.P. (Kathryn), Hysi, P.G. (Pirro), Pasquale, L.R. (Louis), Wong, T.Y. (Tien Yin), Klaver, C.C. (Caroline), Hewitt, A.W. (Alex), Jonas, J.B. (Jost), Mitchell, P. (Paul), Lotery, A.J. (Andrew), Foster, P.J. (Paul), Vitart, V. (Veronique), Pfeiffer, N. (Norbert), Craig, J.E. (Jamie), Mackey, D.A. (David), Hammond, C.J. (Christopher), Wiggs, J.L. (Janey), Cheng, C.Y. (Ching-Yu), van Duijn, C.M. (Cornelia), and MacGregor, S. (Stuart)
Abstract: Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increase 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
Full Text: View/download PDF

15. Incidence of glaucomatous visual field loss after two decades of follow-up: the Rotterdam Study

Author: Springelkamp, H. (Henriët), Wolfs, R.C.W. (Roger), Ramdas, W.D. (Wishal), Hofman, A. (Albert), Vingerling, J.R. (Hans), Klaver, C.C.W. (Caroline), Jansonius, N.M. (Nomdo), Springelkamp, H. (Henriët), Wolfs, R.C.W. (Roger), Ramdas, W.D. (Wishal), Hofman, A. (Albert), Vingerling, J.R. (Hans), Klaver, C.C.W. (Caroline), and Jansonius, N.M. (Nomdo)
Abstract: To determine the incidence of glaucomatous visual field loss (GVFL) two decades after the start of the Rotterdam Study, and to compare known risk factors for open-angle glaucoma (OAG) between different clinical manifestations of OAG. Of 6806 participants aged 55 years and older from the population-based Rotterdam Study, 3939 underwent visual field testing at baseline and at least one follow-up round. The ophthalmic examinations included optic disc assessment and measurements of intraocular pressure (IOP), refractive error, diastolic blood pressure (DBP), and height and weight. The incidence rate of GVFL was calculated. Associations with the risk factors age, gender, baseline IOP, family history, myopia, DBP, and body-mass index [BMI] were assessed using Cox regression, with different clinical manifestations of OAG as outcome measure (glaucomatous optic neuropathy (GON), GVFL, GVFL and GON, GVFL without GON, and GON without GVFL). Median follow-up was 11.1 (IQR 6.8–17.2; range 5.0–20.3) years. The incidence rate of GVFL was 2.9 (95% confidence interval 2.4–3.4) per 1000 person years (140 case
Published: 2017
Full Text: View/download PDF

16. 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

17. Identification of plasma metabolites associated with intraocular pressure in a Dutch family-based study

Author: Iglesias, A.I., Springelkamp, H., Lee, S. van der, Demirkan, A., Verhoeven, A., Schmitz, G., Dijk, K.W. van, Hankemeier, T., Klaver, C.C.W., and Duijn, C.M. van
Published: 2015

18. Meta-analysis of Genome-Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology

Author: Springelkamp, H, Mishra, A, Hysi, PG, Gharahkhani, P, Höhn, R, Khor, CC, Cooke Bailey, JN, Luo, X, Ramdas, WD, Vithana, E, Koh, V, Yazar, S, Xu, L, Forward, H, Kearns, LS, Amin, N, Iglesias, AI, Sim, KS, van Leeuwen, EM, Demirkan, A, van der Lee, S, Loon, SC, Rivadeneira, F, Nag, A, Sanfilippo, PG, Schillert, A, de Jong, PTVM, Oostra, BA, Uitterlinden, AG, Hofman, A, Zhou, T, Burdon, KP, Spector, TD, Lackner, KJ, Saw, SM, Vingerling, JR, Teo, YY, Pasquale, LR, Wolfs, RCW, Lemij, HG, Tai, ES, Jonas, JB, Cheng, CY, Aung, T, Jansonius, NM, Klaver, CCW, Craig, JE, Young, TL, Haines, JL, Macgregor, S, Mackey, DA, Pfeiffer, N, Wong, TY, Wiggs, JL, Hewitt, AW, van Duijn, CM, Hammond, CJ, Allingham, RR, Brilliant, MH, Budenz, DL, Bailey, JNC, Christen, WG, and Fingert, J
Subjects: genetic structures, sense organs, eye diseases
Abstract: © 2015 Wiley Periodicals, Inc. Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma.
Published: 2015

19. Automated Segmentability Index for Layer Segmentation of Macular SD-OCT Images

Author: Lee, K., Buitendijk, G.H., Bogunovic, H., Springelkamp, H., Hofman, A., Wahle, A., Sonka, M., Vingerling, J.R., Klaver, C.C.W., Abramoff, M.D., Lee, K., Buitendijk, G.H., Bogunovic, H., Springelkamp, H., Hofman, A., Wahle, A., Sonka, M., Vingerling, J.R., Klaver, C.C.W., and Abramoff, M.D.
Abstract: Contains fulltext : 168318.pdf (publisher's version ) (Open Access), PURPOSE: To automatically identify which spectral-domain optical coherence tomography (SD-OCT) scans will provide reliable automated layer segmentations for more accurate layer thickness analyses in population studies. METHODS: Six hundred ninety macular SD-OCT image volumes (6.0 x 6.0 x 2.3 mm3) were obtained from one eyes of 690 subjects (74.6 +/- 9.7 [mean +/- SD] years, 37.8% of males) randomly selected from the population-based Rotterdam Study. The dataset consisted of 420 OCT volumes with successful automated retinal nerve fiber layer (RNFL) segmentations obtained from our previously reported graph-based segmentation method and 270 volumes with failed segmentations. To evaluate the reliability of the layer segmentations, we have developed a new metric, segmentability index SI, which is obtained from a random forest regressor based on 12 features using OCT voxel intensities, edge-based costs, and on-surface costs. The SI was compared with well-known quality indices, quality index (QI), and maximum tissue contrast index (mTCI), using receiver operating characteristic (ROC) analysis. RESULTS: The 95% confidence interval (CI) and the area under the curve (AUC) for the QI are 0.621 to 0.805 with AUC 0.713, for the mTCI 0.673 to 0.838 with AUC 0.756, and for the SI 0.784 to 0.920 with AUC 0.852. The SI AUC is significantly larger than either the QI or mTCI AUC (P < 0.01). CONCLUSIONS: The segmentability index SI is well suited to identify SD-OCT scans for which successful automated intraretinal layer segmentations can be expected. TRANSLATIONAL RELEVANCE: Interpreting the quantification of SD-OCT images requires the underlying segmentation to be reliable, but standard SD-OCT quality metrics do not predict which segmentations are reliable and which are not. The segmentability index SI presented in this study does allow reliable segmentations to be identified, which is important for more accurate layer thickness analyses in research and population studies.
Published: 2016

20. Associations with intraocular pressure across Europe: The European Eye Epidemiology (E3) Consortium

Author: Khawaja, A.P. (Anthony), Springelkamp, H. (Henriët), Creuzot-Garcher, C. (Catherine), Delcourt, C. (Cécile), Hofman, A. (Albert), Höhn, R. (René), Iglesias González, A.I. (Adriana), Wolfs, R.C.W. (Roger), Korobelnik, J.-F. (Jean-François), Silva, R. (Rufino), Topouzis, F. (Fotis), Williams, K.M. (Katie M.), Bron, A. (Alain), Buitendijk, G.H.S. (Gabrielle), Cachulo, M.L. (Maria da Luz), Cougnard-Grégoire, A. (Audrey), Dartigues, J.-F., Hammond, C.J. (Christopher J.), Pfeiffer, A.F.H. (Andreas), Salonikiou, A. (Angeliki), van Duijn, C.M. (Cornelia M.), Vingerling, J.R. (Hans), Luben, R.N. (Robert), Mirshahi, A. (Alireza), Lamparter, J. (Julia), Klaver, C.C.W. (Caroline), Jansonius, N.M. (Nomdo M.), Foster, P.J. (Paul), Khawaja, A.P. (Anthony), Springelkamp, H. (Henriët), Creuzot-Garcher, C. (Catherine), Delcourt, C. (Cécile), Hofman, A. (Albert), Höhn, R. (René), Iglesias González, A.I. (Adriana), Wolfs, R.C.W. (Roger), Korobelnik, J.-F. (Jean-François), Silva, R. (Rufino), Topouzis, F. (Fotis), Williams, K.M. (Katie M.), Bron, A. (Alain), Buitendijk, G.H.S. (Gabrielle), Cachulo, M.L. (Maria da Luz), Cougnard-Grégoire, A. (Audrey), Dartigues, J.-F., Hammond, C.J. (Christopher J.), Pfeiffer, A.F.H. (Andreas), Salonikiou, A. (Angeliki), van Duijn, C.M. (Cornelia M.), Vingerling, J.R. (Hans), Luben, R.N. (Robert), Mirshahi, A. (Alireza), Lamparter, J. (Julia), Klaver, C.C.W. (Caroline), Jansonius, N.M. (Nomdo M.), and Foster, P.J. (Paul)
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 (E3) 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/m2; 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
Full Text: View/download PDF

21. Open-angle glaucoma

Author: Springelkamp, H. (Henriët) and Springelkamp, H. (Henriët)
Abstract: Open-angle glaucoma (OAG) is an important cause of irreversible blindness. In OAG, loss of retinal ganglion cells leads to damage of the optic nerve. This causes visual field loss and eventually blindness. Changes in the optic nerve head (ONH) can be examined with confocal scanning laser ophthalmoscopy (Heidelberg Retina Tomograph [HRT]), scanning laser polarimetry (GDx) or Optical Coherence Tomography (OCT). Important risk factors for OAG are elevated intraocular pressure (IOP), high age, myopia, ethnicity, thin central corneal thickness, and a positive family history for OAG. However, the pathophysiology still remains largely unknown. In order to improve the diagnosis and learn more about the pathophysiology of this blinding disease, the main objectives of the research described in this thesis were to: 1) address the diagnostic utility of the OCT scan for OAG, 2) elucidate new risk factors for OAG or IOP, 3) identify novel genetic variants associated with OAG or its endophenotypes, and 4) assess the functional consequences of genetic variants associated with OAG. Our study populations included the population-based Rotterdam Study, the Erasmus Rucphen Family (ERF) Study, population-based studies from the European Eye Epidemiology (E3) Consortium and population-based and OAG case-control studies from the International Glaucoma Genetics Consortium (IGGC).
Published: 2016

22. Associations with intraocular pressure across Europe: The European Eye Epidemiology (E3) Consortium.

Author: Khawaja, AP, Springelkamp, H, Creuzot-Garcher, C, Delcourt, C, Hofman, A, Höhn, R, Iglesias, AI, Wolfs, RCW, Korobelnik, J-F, Silva, R, Topouzis, F, Williams, KM, Bron, AM, Buitendijk, GHS, Cachulo, MDL, Cougnard-Grégoire, A, Dartigues, J-F, Hammond, CJ, Pfeiffer, N, Salonikiou, A, van Duijn, CM, Vingerling, JR, Luben, RN, Mirshahi, A, Lamparter, J, Klaver, CCW, Jansonius, NM, Foster, PJ, European Eye Epidemiology (E³) Consortium, Khawaja, AP, Springelkamp, H, Creuzot-Garcher, C, Delcourt, C, Hofman, A, Höhn, R, Iglesias, AI, Wolfs, RCW, Korobelnik, J-F, Silva, R, Topouzis, F, Williams, KM, Bron, AM, Buitendijk, GHS, Cachulo, MDL, Cougnard-Grégoire, A, Dartigues, J-F, Hammond, CJ, Pfeiffer, N, Salonikiou, A, van Duijn, CM, Vingerling, JR, Luben, RN, Mirshahi, A, Lamparter, J, Klaver, CCW, Jansonius, NM, Foster, PJ, and European Eye Epidemiology (E³) Consortium
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 (E3) 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/m2; 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. 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

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

Author: Springelkamp, H, Höhn, R, Mishra, A, Hysi, PG, Khor, CC, Loomis, SJ, Bailey, JNC, Gibson, J, Thorleifsson, G, Janssen, SF, Luo, X, Ramdas, WD, Vithana, E, Nongpiur, ME, Montgomery, GW, Xu, L, Mountain, JE, Gharahkhani, P, Lu, Y, Amin, N, Karssen, LC, Sim, KS, Van Leeuwen, EM, Iglesias, AI, Verhoeven, VJM, Hauser, MA, Loon, SC, Despriet, DDG, Nag, A, Venturini, C, Sanfilippo, PG, Schillert, A, Kang, JH, Landers, J, Jonasson, F, Cree, AJ, Van Koolwijk, LME, Rivadeneira, F, Souzeau, E, Jonsson, V, Menon, G, Mitchell, P, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Weinreb, RN, De Jong, PTVM, Oostra, BA, Uitterlinden, AG, Hofman, A, Ennis, S, Thorsteinsdottir, U, Burdon, KP, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Haines, JL, Kraft, P, Lee, RK, Lichter, PR, and Liu, Y
Subjects: genetic structures, sense organs, eye diseases
Abstract: © 2014 Macmillan Publishers Limited. All rights reserved. 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

25. Meta-analysis of Genome-Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology

Author: Springelkamp, H. (Henriët), Mishra, A. (Aniket), Hysi, P.G. (Pirro), Gharahkhani, P. (Puya), Höhn, R. (René), Khor, C.C., Cooke Bailey, J.N. (Jessica N.), Luo, X. (Xiaoyan), Ramdas, W.D. (Wishal), Vithana, E.N. (Eranga), Koh, V. (Victor), Yazar, S. (Seyhan), Xu, L. (Liang), Forward, H. (Hannah), Kearns, L.S. (Lisa S.), Amin, N. (Najaf), Iglesias González, A.I. (Adriana), Sim, K.S., Leeuwen, E.M. (Elisa) van, Demirkan, A. (Ayşe), Lee, S.J. (Sven) van der, Loon, S.-C. (Seng-Chee), Rivadeneira Ramirez, F. (Fernando), Nag, A. (Abhishek), Sanfilippo, P.G. (Paul G.), Schillert, A. (Arne), Jong, P.T.V.M. (Paulus) de, Oostra, B.A. (Ben), Uitterlinden, A.G. (André), Hofman, A. (Albert), Zhou, T. (Tiger), Burdon, K.P. (Kathryn), Spector, T.D. (Timothy), Lackner, K.J. (Karl), Saw, S-M. (Seang-Mei), Vingerling, J.R. (Hans), Teo, Y.Y. (Yik Ying), Pasquale, L.R. (Louis), Wolfs, R.C.W. (Roger), Lemij, H.G. (Hans), Tai, E.S. (Shyong), Jonas, J.B. (Jost B.), Cheng, C-Y. (Ching-Yu), Aung, T. (Tin), Jansonius, N.M. (Nomdo), Klaver, C.C.W. (Caroline), Craig, J.E. (Jamie), Young, T.L. (Terri), Haines, J.L. (Jonathan), MacGregor, S. (Stuart), Mackey, D.A. (David), Pfeiffer, A.F.H. (Andreas), Wong, T.Y. (Tien Yin), Wiggs, J.L. (Janey), Hewit, A.W. (Alex), Duijn, C.M. (Cornelia) van, Hammond, C.J. (Christopher), Springelkamp, H. (Henriët), Mishra, A. (Aniket), Hysi, P.G. (Pirro), Gharahkhani, P. (Puya), Höhn, R. (René), Khor, C.C., Cooke Bailey, J.N. (Jessica N.), Luo, X. (Xiaoyan), Ramdas, W.D. (Wishal), Vithana, E.N. (Eranga), Koh, V. (Victor), Yazar, S. (Seyhan), Xu, L. (Liang), Forward, H. (Hannah), Kearns, L.S. (Lisa S.), Amin, N. (Najaf), Iglesias González, A.I. (Adriana), Sim, K.S., Leeuwen, E.M. (Elisa) van, Demirkan, A. (Ayşe), Lee, S.J. (Sven) van der, Loon, S.-C. (Seng-Chee), Rivadeneira Ramirez, F. (Fernando), Nag, A. (Abhishek), Sanfilippo, P.G. (Paul G.), Schillert, A. (Arne), Jong, P.T.V.M. (Paulus) de, Oostra, B.A. (Ben), Uitterlinden, A.G. (André), Hofman, A. (Albert), Zhou, T. (Tiger), Burdon, K.P. (Kathryn), Spector, T.D. (Timothy), Lackner, K.J. (Karl), Saw, S-M. (Seang-Mei), Vingerling, J.R. (Hans), Teo, Y.Y. (Yik Ying), Pasquale, L.R. (Louis), Wolfs, R.C.W. (Roger), Lemij, H.G. (Hans), Tai, E.S. (Shyong), Jonas, J.B. (Jost B.), Cheng, C-Y. (Ching-Yu), Aung, T. (Tin), Jansonius, N.M. (Nomdo), Klaver, C.C.W. (Caroline), Craig, J.E. (Jamie), Young, T.L. (Terri), Haines, J.L. (Jonathan), MacGregor, S. (Stuart), Mackey, D.A. (David), Pfeiffer, A.F.H. (Andreas), Wong, T.Y. (Tien Yin), Wiggs, J.L. (Janey), Hewit, A.W. (Alex), Duijn, C.M. (Cornelia) van, and Hammond, C.J. (Christopher)
Abstract: Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed
Published: 2015
Full Text: View/download PDF

26. Validity of automated choroidal segmentation in SS-OCT and SD-OCT

Author: Zhang, L. (Li), Buitendijk, G.H.S. (Gabrielle), Lee, K. (Kyungmoo), Sonka, M. (Milan), Springelkamp, H. (Henriët), Hofman, A. (Albert), Vingerling, J.R. (Hans), Mullins, R.F. (Robert F.), Klaver, C.C.W. (Caroline), Abràmoff, M.D. (Michael), Zhang, L. (Li), Buitendijk, G.H.S. (Gabrielle), Lee, K. (Kyungmoo), Sonka, M. (Milan), Springelkamp, H. (Henriët), Hofman, A. (Albert), Vingerling, J.R. (Hans), Mullins, R.F. (Robert F.), Klaver, C.C.W. (Caroline), and Abràmoff, M.D. (Michael)
Abstract: PURPOSE. To evaluate the validity of a novel fully automated three-dimensional (3D) method capable of segmenting the choroid from two different optical coherence tomography scanners: swept-source OCT (SS-OCT) and spectral-domain OCT (SD-OCT). METHODS. One hundred eight subjects were imaged using SS-OCT and SD-OCT. A 3D method was used to segment the choroid and quantify the choroidal thickness along each A-scan. The segmented choroidal posterior boundary was evaluated by comparing to manual segmentation. Differences were assessed to test the agreement between segmentation results of the same subject. Choroidal thickness was defined as the Euclidian distance between Bruch’s membrane and the choroidal posterior boundary, and reproducibility was analyzed using automatically and manually determined choroidal thicknesses. RESULTS. For SS-OCT, the average choroidal thickness of the entire 6-by 6-mm2 macular region was 219.5 lm (95% confidence interval [CI], 204.9–234.2 µm), and for SD-OCT it was 209.5 µm (95% CI, 197.9–221.0 µm). The agreement between automated and manual segmentations was high: Average relative difference was less than 5 lm, and average absolute difference was less than 15 µm. Reproducibility of choroidal thickness between repeated SS-OCT scans was high (coefficient of variation [CV] of 3.3%, intraclass correlation coefficient [ICC] of 0.98), and differences between SS-OCT and SD-OCT results were small (CV of 11.0%, ICC of 0.73). CONCLUSIONS. We have developed a fully automated 3D method for segmenting the choroid and quantifying choroidal thickness along each A-scan. The method yielded high validity. Our method can be used reliably to study local choroidal changes and may improve the diagnosis and management of patients with ocular diseases in which the choroid is affected.
Published: 2015
Full Text: View/download PDF

27. Genes, pathways, and animal models in primary open-angle glaucoma

Author: Iglesias, A I, primary, Springelkamp, H, additional, Ramdas, W D, additional, Klaver, C C W, additional, Willemsen, R, additional, and van Duijn, C M, additional
Published: 2015
Full Text: View/download PDF

28. ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure

Author: Springelkamp, H., primary, Iglesias, A. I., additional, Cuellar-Partida, G., additional, Amin, N., additional, Burdon, K. P., additional, van Leeuwen, E. M., additional, Gharahkhani, P., additional, Mishra, A., additional, van der Lee, S. J., additional, Hewitt, A. W., additional, Rivadeneira, F., additional, Viswanathan, A. C., additional, Wolfs, R. C. W., additional, Martin, N. G., additional, Ramdas, W. D., additional, van Koolwijk, L. M., additional, Pennell, C. E., additional, Vingerling, J. R., additional, Mountain, J. E., additional, Uitterlinden, A. G., additional, Hofman, A., additional, Mitchell, P., additional, Lemij, H. G., additional, Wang, J. J., additional, Klaver, C. C. W., additional, Mackey, D. A., additional, Craig, J. E., additional, van Duijn, C. M., additional, and MacGregor, S., additional
Published: 2015
Full Text: View/download PDF

29. Population-based evaluation of retinal nerve fiber layer, Retinal ganglion cell layer, And inner plexiform layer as a diagnostic tool for glaucoma

Author: Springelkamp, H. (Henriët), Lee, K. (Kyungmoo), Wolfs, R.C.W. (Roger), Buitendijk, G.H.S. (Gabrielle), Ramdas, W.D. (Wishal), Hofman, A. (Albert), Vingerling, J.R. (Hans), Klaver, C.C.W. (Caroline), Abràmoff, M.D. (Michael), Jansonius, N.M. (Nomdo), Springelkamp, H. (Henriët), Lee, K. (Kyungmoo), Wolfs, R.C.W. (Roger), Buitendijk, G.H.S. (Gabrielle), Ramdas, W.D. (Wishal), Hofman, A. (Albert), Vingerling, J.R. (Hans), Klaver, C.C.W. (Caroline), Abràmoff, M.D. (Michael), and Jansonius, N.M. (Nomdo)
Abstract: PURPOSE. We determined the glaucoma screening performance of regional optical coherence tomography (OCT) layer thickness measurements in the peripapillary and macular region, in a population-based setting.METHODS. Subjects (n = 1224) in the Rotterdam Study underwent visual field testing (Humphrey Field Analyzer) and OCT of the macula and optic nerve head (Topcon 3-D OCT- 1000). We determined the mean thi
Published: 2014
Full Text: View/download PDF

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

Author: Hysi, P.G. (Pirro), Cheng, C-Y. (Ching-Yu), Springelkamp, H. (Henriët), MacGregor, S. (Stuart), Bailey, J.N.C. (Jessica N. Cooke), Wojciechowski, R. (Robert), Vitart, V. (Veronique), Nag, A. (Abhishek), Hewit, A.W. (Alex), Höhn, R. (René), Venturini, C. (Cristina), Mirshahi, A. (Alireza), Ramdas, W.D. (Wishal), Thorleifsson, G. (Gudmar), Vithana, E.N. (Eranga), Khor, C.C., Stefansson, A.B. (Arni B.), Liao, J. (Jie), Haines, J.L. (Jonathan), Amin, N. (Najaf), Wang, Y. (Ying), Wild, P.S. (Philipp S.), Ozel, A.B. (Ayse), Li, J., Fleck, B.W. (Brian W.), Zeller, T. (Tanja), Staffieri, S.E. (Sandra E.), Teo, Y.Y. (Yik Ying), Cuellar-Partida, G. (Gabriel), Luo, X. (Xiaoyan), Allingham, R.R. (R Rand), Richards, J.E. (Julia), Senft, A. (Andrea), Karssen, L.C. (Lennart), Zheng, Y. (Yingfeng), Bellenguez, C. (Céline), Xu, L. (Liang), Iglesias González, A.I. (Adriana), Wilson, J.F. (James F), Kang, J.H. (Jae), Leeuwen, E.M. (Elisa) van, Jonsson, V. (Vesteinn), Thorsteinsdottir, U. (Unnur), Despriet, D.D.G. (Dominique), Ennis, S. (Sarah), Moroi, S.E. (Sayoko), Martin, N.G. (Nicholas), Jansonius, N.M. (Nomdo), Yazar, S. (Seyhan), Tai, E.S. (Shyong), Amouyel, P. (Philippe), Kirwan, J. (James), Koolwijk, L.M.E. (Leonieke) van, Hauser, M.A. (Michael), Jonasson, F. (Fridbert), Leo, P.J. (Paul), Loomis, S.J. (Stephanie J.), Fogarty, R. (Rhys), Rivadeneira Ramirez, F. (Fernando), Kearns, L.S. (Lisa S.), Lackner, K.J. (Karl), Jong, P.T.V.M. (Paulus) de, Simpson, C.L. (Claire), Pennell, C.E. (Craig), Oostra, B.A. (Ben), Uitterlinden, A.G. (André), Saw, S-M. (Seang-Mei), Lotery, A.J. (Andrew), Bailey-Wilson, J.E. (Joan E.), Hofman, A. (Albert), Vingerling, J.R. (Hans), Maubaret, C. (Cécilia), Pfeiffer, A.F.H. (Andreas), Wolfs, R.C.W. (Roger), Lemij, H.G. (Hans), Young, T.L. (Terri), Pasquale, L.R. (Louis), Delcourt, C. (Cécile), Spector, T.D. (Timothy), Klaver, C.C.W. (Caroline), Small, K.S. (Kerrin), Burdon, K.P. (Kathryn), Zwart, J-A. (John-Anker), Wong, T.Y. (Tien Yin), Viswanathan, A.C. (Ananth), Mackey, D.A. (David), Craig, J.E. (Jamie), Wiggs, J.L. (Janey), Duijn, C.M. (Cornelia) van, Hammond, C.J. (Christopher), Aung, T. (Tin), Hysi, P.G. (Pirro), Cheng, C-Y. (Ching-Yu), Springelkamp, H. (Henriët), MacGregor, S. (Stuart), Bailey, J.N.C. (Jessica N. Cooke), Wojciechowski, R. (Robert), Vitart, V. (Veronique), Nag, A. (Abhishek), Hewit, A.W. (Alex), Höhn, R. (René), Venturini, C. (Cristina), Mirshahi, A. (Alireza), Ramdas, W.D. (Wishal), Thorleifsson, G. (Gudmar), Vithana, E.N. (Eranga), Khor, C.C., Stefansson, A.B. (Arni B.), Liao, J. (Jie), Haines, J.L. (Jonathan), Amin, N. (Najaf), Wang, Y. (Ying), Wild, P.S. (Philipp S.), Ozel, A.B. (Ayse), Li, J., Fleck, B.W. (Brian W.), Zeller, T. (Tanja), Staffieri, S.E. (Sandra E.), Teo, Y.Y. (Yik Ying), Cuellar-Partida, G. (Gabriel), Luo, X. (Xiaoyan), Allingham, R.R. (R Rand), Richards, J.E. (Julia), Senft, A. (Andrea), Karssen, L.C. (Lennart), Zheng, Y. (Yingfeng), Bellenguez, C. (Céline), Xu, L. (Liang), Iglesias González, A.I. (Adriana), Wilson, J.F. (James F), Kang, J.H. (Jae), Leeuwen, E.M. (Elisa) van, Jonsson, V. (Vesteinn), Thorsteinsdottir, U. (Unnur), Despriet, D.D.G. (Dominique), Ennis, S. (Sarah), Moroi, S.E. (Sayoko), Martin, N.G. (Nicholas), Jansonius, N.M. (Nomdo), Yazar, S. (Seyhan), Tai, E.S. (Shyong), Amouyel, P. (Philippe), Kirwan, J. (James), Koolwijk, L.M.E. (Leonieke) van, Hauser, M.A. (Michael), Jonasson, F. (Fridbert), Leo, P.J. (Paul), Loomis, S.J. (Stephanie J.), Fogarty, R. (Rhys), Rivadeneira Ramirez, F. (Fernando), Kearns, L.S. (Lisa S.), Lackner, K.J. (Karl), Jong, P.T.V.M. (Paulus) de, Simpson, C.L. (Claire), Pennell, C.E. (Craig), Oostra, B.A. (Ben), Uitterlinden, A.G. (André), Saw, S-M. (Seang-Mei), Lotery, A.J. (Andrew), Bailey-Wilson, J.E. (Joan E.), Hofman, A. (Albert), Vingerling, J.R. (Hans), Maubaret, C. (Cécilia), Pfeiffer, A.F.H. (Andreas), Wolfs, R.C.W. (Roger), Lemij, H.G. (Hans), Young, T.L. (Terri), Pasquale, L.R. (Louis), Delcourt, C. (Cécile), Spector, T.D. (Timothy), Klaver, C.C.W. (Caroline), Small, K.S. (Kerrin), Burdon, K.P. (Kathryn), Zwart, J-A. (John-Anker), Wong, T.Y. (Tien Yin), Viswanathan, A.C. (Ananth), Mackey, D.A. (David), Craig, J.E. (Jamie), Wiggs, J.L. (Janey), Duijn, C.M. (Cornelia) van, Hammond, C.J. (Christopher), and Aung, T. (Tin)
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
Full Text: View/download PDF

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

Author: Springelkamp, H. (Henriët), Höhn, R. (René), Mishra, A. (Aniket), Hysi, P.G. (Pirro), Khor, C.C., Loomis, S.J. (Stephanie J.), Bailey, J.N.C. (Jessica N. Cooke), Gibson, J. (Jane), Thorleifsson, G. (Gudmar), Janssen, S.F. (Sarah), Luo, X. (Xiaoyan), Ramdas, W.D. (Wishal), Vithana, E.N. (Eranga), Nongpiur, M.E. (Monisha E.), Montgomery, G.W. (Grant), Xu, L. (Liang), Mountain, J.E. (Jenny E.), Gharahkhani, P. (Puya), Lu, Y. (Yi), Amin, N. (Najaf), Karssen, L.C. (Lennart), Sim, K.S., Leeuwen, E.M. (Elisa) van, Iglesias González, A.I. (Adriana), Verhoeven, V.J.M. (Virginie), Hauser, M.A. (Michael), Loon, S.-C. (Seng-Chee), Despriet, D.D.G. (Dominique), Nag, A. (Abhishek), Venturini, C. (Cristina), Sanfilippo, P.G. (Paul G.), Schillert, A. (Arne), Kang, J.H. (Jae), Landers, J. (John), Jonasson, F. (Fridbert), Cree, A.J. (Angela), Koolwijk, L.M.E. (Leonieke) van, Rivadeneira Ramirez, F. (Fernando), Souzeau, E. (Emmanuelle), Jonsson, V. (Vesteinn), Menon, G. (Geeta), Mitchell, P. (Paul), Wang, J.J. (Jie Jin), Rochtchina, E. (Elena), Attia, J. (John), Scott, R. (Rodney), Holliday, E.G. (Elizabeth), Baird, P.N. (Paul), Xie, J. (Jing), Inouye, M. (Michael), Viswanathan, A.C. (Ananth), Sim, X. (Xueling), Weinreb, R.N. (Robert N.), Jong, P.T.V.M. (Paulus) de, Oostra, B.A. (Ben), Uitterlinden, A.G. (André), Hofman, A. (Albert), Ennis, S. (Sarah), Thorsteinsdottir, U. (Unnur), Burdon, K.P. (Kathryn), Spector, T.D. (Timothy), Mirshahi, A. (Alireza), Saw, S-M. (Seang-Mei), Vingerling, J.R. (Hans), Teo, Y.Y. (Yik Ying), Wolfs, R.C.W. (Roger), Lemij, H.G. (Hans), Tai, E.S. (Shyong), Jansonius, N.M. (Nomdo), Jonas, J.B. (Jost B.), Cheng, C-Y. (Ching-Yu), Aung, T. (Tin), Klaver, C.C.W. (Caroline), Craig, J.E. (Jamie), MacGregor, S. (Stuart), Mackey, D.A. (David), Lotery, A.J. (Andrew), Zwart, J-A. (John-Anker), Bergen, A.A.B. (Arthur), Young, T.L. (Terri), Wiggs, J.L. (Janey), Pfeiffer, A.F.H. (Andreas), Wong, T.Y. (Tien Yin), Pasquale, L.R. (Louis), Hewit, A.W. (Alex), Duijn, C.M. (Cornelia) van, Hammond, C.J. (Christopher), Springelkamp, H. (Henriët), Höhn, R. (René), Mishra, A. (Aniket), Hysi, P.G. (Pirro), Khor, C.C., Loomis, S.J. (Stephanie J.), Bailey, J.N.C. (Jessica N. Cooke), Gibson, J. (Jane), Thorleifsson, G. (Gudmar), Janssen, S.F. (Sarah), Luo, X. (Xiaoyan), Ramdas, W.D. (Wishal), Vithana, E.N. (Eranga), Nongpiur, M.E. (Monisha E.), Montgomery, G.W. (Grant), Xu, L. (Liang), Mountain, J.E. (Jenny E.), Gharahkhani, P. (Puya), Lu, Y. (Yi), Amin, N. (Najaf), Karssen, L.C. (Lennart), Sim, K.S., Leeuwen, E.M. (Elisa) van, Iglesias González, A.I. (Adriana), Verhoeven, V.J.M. (Virginie), Hauser, M.A. (Michael), Loon, S.-C. (Seng-Chee), Despriet, D.D.G. (Dominique), Nag, A. (Abhishek), Venturini, C. (Cristina), Sanfilippo, P.G. (Paul G.), Schillert, A. (Arne), Kang, J.H. (Jae), Landers, J. (John), Jonasson, F. (Fridbert), Cree, A.J. (Angela), Koolwijk, L.M.E. (Leonieke) van, Rivadeneira Ramirez, F. (Fernando), Souzeau, E. (Emmanuelle), Jonsson, V. (Vesteinn), Menon, G. (Geeta), Mitchell, P. (Paul), Wang, J.J. (Jie Jin), Rochtchina, E. (Elena), Attia, J. (John), Scott, R. (Rodney), Holliday, E.G. (Elizabeth), Baird, P.N. (Paul), Xie, J. (Jing), Inouye, M. (Michael), Viswanathan, A.C. (Ananth), Sim, X. (Xueling), Weinreb, R.N. (Robert N.), Jong, P.T.V.M. (Paulus) de, Oostra, B.A. (Ben), Uitterlinden, A.G. (André), Hofman, A. (Albert), Ennis, S. (Sarah), Thorsteinsdottir, U. (Unnur), Burdon, K.P. (Kathryn), Spector, T.D. (Timothy), Mirshahi, A. (Alireza), Saw, S-M. (Seang-Mei), Vingerling, J.R. (Hans), Teo, Y.Y. (Yik Ying), Wolfs, R.C.W. (Roger), Lemij, H.G. (Hans), Tai, E.S. (Shyong), Jansonius, N.M. (Nomdo), Jonas, J.B. (Jost B.), Cheng, C-Y. (Ching-Yu), Aung, T. (Tin), Klaver, C.C.W. (Caroline), Craig, J.E. (Jamie), MacGregor, S. (Stuart), Mackey, D.A. (David), Lotery, A.J. (Andrew), Zwart, J-A. (John-Anker), Bergen, A.A.B. (Arthur), Young, T.L. (Terri), Wiggs, J.L. (Janey), Pfeiffer, A.F.H. (Andreas), Wong, T.Y. (Tien Yin), Pasquale, L.R. (Louis), Hewit, A.W. (Alex), Duijn, C.M. (Cornelia) van, and Hammond, C.J. (Christopher)
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
Full Text: View/download PDF

32. 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

33. Population-Based Evaluation of Retinal Nerve Fiber Layer, Retinal Ganglion Cell Layer, and Inner Plexiform Layer as a Diagnostic Tool For Glaucoma

Author: Springelkamp, H., primary, Lee, K., additional, Wolfs, R. C. W., additional, Buitendijk, G. H. S., additional, Ramdas, W. D., additional, Hofman, A., additional, Vingerling, J. R., additional, Klaver, C. C. W., additional, Abramoff, M. D., additional, and Jansonius, N. M., additional
Published: 2014
Full Text: View/download PDF

34. Optimizing the information yield of 3-D OCT in glaucoma

Author: Springelkamp, H. (Henriët), Lee, K. (Kyungmoo), Ramdas, W.D. (Wishal), Vingerling, J.R. (Hans), Hofman, A. (Albert), Klaver, C.C.W. (Caroline), Sonka, M. (Milan), Abràmoff, M.D. (Michael), Jansonius, N.M. (Nomdo), Springelkamp, H. (Henriët), Lee, K. (Kyungmoo), Ramdas, W.D. (Wishal), Vingerling, J.R. (Hans), Hofman, A. (Albert), Klaver, C.C.W. (Caroline), Sonka, M. (Milan), Abràmoff, M.D. (Michael), and Jansonius, N.M. (Nomdo)
Abstract: Purpose. To determine, first, which regions of 3-D optical coherence tomography (OCT) volumes can be segmented completely in the majority of subjects and, second, the relationship between analyzed area and thickness measurement test-retest variability. Methods. Three-dimensional OCT volumes (6 × 6 mm) centered around the fovea and optic nerve head (ONH) of 925 Rotterdam Study participants were analyzed; 44 participants were scanned twice. Volumes were segmented into 10 layers, and we determined the area where all layers could be identified in at least 95% (macula) or 90% (ONH) of subjects. Macular volumes were divided in 2 × 2, 4 × 4, 6 × 6, 8 × 8, or 68 blocks. We placed two circles around the ONH; the ONH had to fit into the smaller circle, and the larger circle had to fit into the segmentable part of the volume. The area between the circles was divided in 3 to 12 segments. We determined the test-retest variability (coefficient of repeatability) of the retinal nerve fiber layer (RNFL) and ganglion cell layer (RGCL) thickness measurements as a function of size of blocks/segments. Results. Eighty-two percent of the macular volume could be segmented in at least 95% of subjects; for the ONH, this was 65% in at least 90%. The radii of the circles were 1.03 and 1.84 mm. Depending on the analyzed area, median test-retest variability ranged from 8% to 15% for macular RNFL, 11% to 22% for macular RGCL, 5% to 11% for the two together, and 18% to 22% for ONH RNFL. Conclusions. Test-retest variability hampers a detailed analysis of 3-D OCT data. Combined macular RNFL and RGCL thickness averaged over larger areas had the best test-retest variability.
Published: 2012
Full Text: View/download PDF

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

Author: Ap, Khawaja, Springelkamp H, Creuzot-Garcher C, Delcourt C, Hofman A, Höhn R, Ai, Iglesias, Rc, Wolfs, Jf, Korobelnik, Silva R, Topouzis F, Km, Williams, Am, Bron, Gh, Buitendijk, Md, Cachulo, Cougnard-Grégoire A, Jf, Dartigues, Christopher Hammond, Pfeiffer N, and Salonikiou A

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

Author: Iglesias AI, Mishra A, Vitart V, Bykhovskaya Y, Höhn R, Springelkamp H, Cuellar-Partida G, Gharahkhani P, Bailey JNC, Willoughby CE, Li X, Yazar S, Nag A, Khawaja AP, Polašek O, Siscovick D, Mitchell P, Tham YC, Haines JL, Kearns LS, Hayward C, Shi Y, van Leeuwen EM, Taylor KD, Bonnemaijer P, Rotter JI, Martin NG, Zeller T, Mills RA, Souzeau E, Staffieri SE, Jonas JB, Schmidtmann I, Boutin T, Kang JH, Lucas SEM, Wong TY, Beutel ME, Wilson JF, Uitterlinden AG, Vithana EN, Foster PJ, Hysi PG, Hewitt AW, Khor CC, Pasquale LR, Montgomery GW, Klaver CCW, Aung T, Pfeiffer N, Mackey DA, Hammond CJ, Cheng CY, Craig JE, Rabinowitz YS, Wiggs JL, Burdon KP, van Duijn CM, and MacGregor S
Subjects: ADAMTS Proteins genetics, ADAMTS Proteins metabolism, Asian People, Cornea abnormalities, Cornea pathology, Corneal Diseases ethnology, Corneal Diseases genetics, Corneal Diseases metabolism, Corneal Diseases pathology, Corneal Dystrophies, Hereditary ethnology, Corneal Dystrophies, Hereditary genetics, Corneal Dystrophies, Hereditary metabolism, Corneal Dystrophies, Hereditary pathology, Decorin genetics, Decorin metabolism, Ehlers-Danlos Syndrome ethnology, Ehlers-Danlos Syndrome genetics, Ehlers-Danlos Syndrome metabolism, Ehlers-Danlos Syndrome pathology, Eye Diseases, Hereditary ethnology, Eye Diseases, Hereditary genetics, Eye Diseases, Hereditary metabolism, Eye Diseases, Hereditary pathology, Fibrillin-1 genetics, Fibrillin-1 metabolism, Gene Expression, Genome-Wide Association Study, Glaucoma, Open-Angle ethnology, Glaucoma, Open-Angle metabolism, Glaucoma, Open-Angle pathology, Humans, Keratoconus ethnology, Keratoconus metabolism, Keratoconus pathology, Loeys-Dietz Syndrome ethnology, Loeys-Dietz Syndrome genetics, Loeys-Dietz Syndrome metabolism, Loeys-Dietz Syndrome pathology, Lumican genetics, Lumican metabolism, Marfan Syndrome ethnology, Marfan Syndrome genetics, Marfan Syndrome metabolism, Marfan Syndrome pathology, Mendelian Randomization Analysis, Myopia ethnology, Myopia genetics, Myopia metabolism, Myopia pathology, Proteoglycans genetics, Proteoglycans metabolism, Quantitative Trait Loci, Transforming Growth Factor beta2 genetics, Transforming Growth Factor beta2 metabolism, White People, Cornea metabolism, Genome, Human, Glaucoma, Open-Angle genetics, Keratoconus genetics, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable
Abstract: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10 -5 ) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
Published: 2018
Full Text: View/download PDF

37. A Genome-Wide Scan for MicroRNA-Related Genetic Variants Associated With Primary Open-Angle Glaucoma.

Author: Ghanbari M, Iglesias AI, Springelkamp H, van Duijn CM, Ikram MA, Dehghan A, Erkeland SJ, Klaver CCW, and Meester-Smoor MA
Subjects: Base Sequence, Binding Sites, Genetic Predisposition to Disease, Humans, Intraocular Pressure, Molecular Sequence Data, Phenotype, Polymorphism, Single Nucleotide, Genetic Variation, Genome-Wide Association Study, Glaucoma, Open-Angle genetics, MicroRNAs genetics
Abstract: Purpose: To identify microRNAs (miRNAs) involved in primary open-angle glaucoma (POAG), using genetic data. MiRNAs are small noncoding RNAs that posttranscriptionally regulate gene expression. Genetic variants in miRNAs or miRNA-binding sites within gene 3'-untranslated regions (3'UTRs) are expected to affect miRNA function and contribute to disease risk., Methods: Data from the recent genome-wide association studies on intraocular pressure, vertical cup-to-disc ratio (VCDR), cupa area and disc area were used to investigate the association of miRNAs with POAG endophenotypes. Putative targets of the associated miRNAs were studied according to their association with POAG and tested in cell line by transfection experiments for regulation by the miRNAs., Results: Of 411 miRNA variants, rs12803915:A/G in the terminal loop of pre-miR-612 and rs2273626:A/C in the seed sequence of miR-4707 were significantly associated with VCDR and cup area (P values < 1.2 × 10-4). The first variant is demonstrated to increase the miR-612 expression. We showed that the second variant does not affect the miR-4707 biogenesis, but reduces the binding of miR-4707-3p to CARD10, a gene known to be involved in glaucoma. Moreover, of 72,052 miRNA-binding-site variants, 47 were significantly associated with four POAG endophenotypes (P value < 6.9 × 10-6). Of these, we highlighted 10 variants that are more likely to affect miRNA-mediated gene regulation in POAG. These include rs3217992 and rs1063192, which have been shown experimentally to affect miR-138-3p- and miR-323b-5p-mediated regulation of CDKN2B., Conclusions: We identified a number of miRNAs that are associated with POAG endophenotypes. The identified miRNAs and their target genes are candidates for future studies on miRNA-related therapies for POAG.
Published: 2017
Full Text: View/download PDF

38. Incidence of glaucomatous visual field loss after two decades of follow-up: the Rotterdam Study.

Author: Springelkamp H, Wolfs RC, Ramdas WD, Hofman A, Vingerling JR, Klaver CC, and Jansonius NM
Subjects: Adult, Age Distribution, Aged, Aged, 80 and over, Blood Pressure physiology, Female, Follow-Up Studies, Glaucoma, Open-Angle diagnosis, Humans, Incidence, Male, Middle Aged, Myopia epidemiology, Netherlands epidemiology, Optic Nerve Diseases epidemiology, Population Surveillance, Risk Factors, Sex Distribution, Tonometry, Ocular, Vision Disorders diagnosis, Visual Field Tests, Glaucoma, Open-Angle epidemiology, Intraocular Pressure, Vision Disorders epidemiology, Visual Fields
Abstract: To determine the incidence of glaucomatous visual field loss (GVFL) two decades after the start of the Rotterdam Study, and to compare known risk factors for open-angle glaucoma (OAG) between different clinical manifestations of OAG. Of 6806 participants aged 55 years and older from the population-based Rotterdam Study, 3939 underwent visual field testing at baseline and at least one follow-up round. The ophthalmic examinations included optic disc assessment and measurements of intraocular pressure (IOP), refractive error, diastolic blood pressure (DBP), and height and weight. The incidence rate of GVFL was calculated. Associations with the risk factors age, gender, baseline IOP, family history, myopia, DBP, and body-mass index [BMI] were assessed using Cox regression, with different clinical manifestations of OAG as outcome measure (glaucomatous optic neuropathy (GON), GVFL, GVFL and GON, GVFL without GON, and GON without GVFL). Median follow-up was 11.1 (IQR 6.8-17.2; range 5.0-20.3) years. The incidence rate of GVFL was 2.9 (95% confidence interval 2.4-3.4) per 1000 person years (140 cases with incident GVFL in one (n = 113) or both (n = 27) eyes). Baseline IOP and age were significantly associated with all OAG outcomes (all p < 0.001); BMI showed a non-significant protective effect in all outcomes (p = 0.01 to p = 0.09). Gender, myopia, and DBP were not associated with any outcome. Our study provides an estimate of the long-term incidence of GVFL in a predominantly white population. The development of GVFL was strongly associated with baseline IOP and age. Risk factor profiles were similar for the different outcomes.
Published: 2017
Full Text: View/download PDF

39. 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 AI, Mishra A, Höhn R, Wojciechowski R, Khawaja AP, Nag A, Wang YX, Wang JJ, Cuellar-Partida G, Gibson J, Bailey JN, Vithana EN, Gharahkhani P, Boutin T, Ramdas WD, Zeller T, Luben RN, Yonova-Doing E, Viswanathan AC, Yazar S, Cree AJ, Haines JL, Koh JY, Souzeau E, Wilson JF, Amin N, Müller C, Venturini C, Kearns LS, Kang JH, Tham YC, Zhou T, van Leeuwen EM, Nickels S, Sanfilippo P, Liao J, van der Linde H, Zhao W, van Koolwijk LM, Zheng L, Rivadeneira F, Baskaran M, van der Lee SJ, Perera S, de Jong PT, Oostra BA, Uitterlinden AG, Fan Q, Hofman A, Tai ES, Vingerling JR, Sim X, Wolfs RC, Teo YY, Lemij HG, Khor CC, Willemsen R, Lackner KJ, Aung T, Jansonius NM, Montgomery G, Wild PS, Young TL, Burdon KP, Hysi PG, Pasquale LR, Wong TY, Klaver CC, Hewitt AW, Jonas JB, Mitchell P, Lotery AJ, Foster PJ, Vitart V, Pfeiffer N, Craig JE, Mackey DA, Hammond CJ, Wiggs JL, Cheng CY, van Duijn CM, and MacGregor S
Subjects: Female, Genome, Human, Genome-Wide Association Study, Glaucoma, Open-Angle pathology, Humans, Intraocular Pressure genetics, Male, Middle Aged, Optic Disk pathology, Optic Nerve Diseases pathology, Tonometry, Ocular, Cyclin-Dependent Kinase Inhibitor p21 genetics, Glaucoma, Open-Angle genetics, Homeodomain Proteins genetics, Optic Nerve Diseases genetics, Zebrafish Proteins genetics
Abstract: 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., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Published: 2017
Full Text: View/download PDF

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

Author: Khawaja AP, Springelkamp H, Creuzot-Garcher C, Delcourt C, Hofman A, Höhn R, Iglesias AI, Wolfs RC, Korobelnik JF, Silva R, Topouzis F, Williams KM, Bron AM, Buitendijk GH, Cachulo MD, Cougnard-Grégoire A, Dartigues JF, Hammond CJ, Pfeiffer N, Salonikiou A, van Duijn CM, Vingerling JR, Luben RN, Mirshahi A, Lamparter J, Klaver CC, Jansonius NM, and Foster PJ
Subjects: Age Factors, Aged, Aged, 80 and over, Cohort Studies, Cross-Sectional Studies, Europe epidemiology, Female, Humans, Male, Middle Aged, Intraocular Pressure physiology, Ocular Hypertension epidemiology
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., Competing Interests: None.
Published: 2016
Full Text: View/download PDF

41. Automated Segmentability Index for Layer Segmentation of Macular SD-OCT Images.

Author: Lee K, Buitendijk GH, Bogunovic H, Springelkamp H, Hofman A, Wahle A, Sonka M, Vingerling JR, Klaver CC, and Abràmoff MD
Abstract: Purpose: To automatically identify which spectral-domain optical coherence tomography (SD-OCT) scans will provide reliable automated layer segmentations for more accurate layer thickness analyses in population studies., Methods: Six hundred ninety macular SD-OCT image volumes (6.0 × 6.0 × 2.3 mm 3 ) were obtained from one eyes of 690 subjects (74.6 ± 9.7 [mean ± SD] years, 37.8% of males) randomly selected from the population-based Rotterdam Study. The dataset consisted of 420 OCT volumes with successful automated retinal nerve fiber layer (RNFL) segmentations obtained from our previously reported graph-based segmentation method and 270 volumes with failed segmentations. To evaluate the reliability of the layer segmentations, we have developed a new metric, segmentability index SI, which is obtained from a random forest regressor based on 12 features using OCT voxel intensities, edge-based costs, and on-surface costs. The SI was compared with well-known quality indices, quality index (QI), and maximum tissue contrast index (mTCI), using receiver operating characteristic (ROC) analysis., Results: The 95% confidence interval (CI) and the area under the curve (AUC) for the QI are 0.621 to 0.805 with AUC 0.713, for the mTCI 0.673 to 0.838 with AUC 0.756, and for the SI 0.784 to 0.920 with AUC 0.852. The SI AUC is significantly larger than either the QI or mTCI AUC ( P < 0.01)., Conclusions: The segmentability index SI is well suited to identify SD-OCT scans for which successful automated intraretinal layer segmentations can be expected., Translational Relevance: Interpreting the quantification of SD-OCT images requires the underlying segmentation to be reliable, but standard SD-OCT quality metrics do not predict which segmentations are reliable and which are not. The segmentability index SI presented in this study does allow reliable segmentations to be identified, which is important for more accurate layer thickness analyses in research and population studies.
Published: 2016
Full Text: View/download PDF

42. WNT10A exonic variant increases the risk of keratoconus by decreasing corneal thickness.

Author: Cuellar-Partida G, Springelkamp H, Lucas SE, Yazar S, Hewitt AW, Iglesias AI, Montgomery GW, Martin NG, Pennell CE, van Leeuwen EM, Verhoeven VJ, Hofman A, Uitterlinden AG, Ramdas WD, Wolfs RC, Vingerling JR, Brown MA, Mills RA, Craig JE, Klaver CC, van Duijn CM, Burdon KP, MacGregor S, and Mackey DA
Subjects: Adult, Aged, Australia epidemiology, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genotype, Humans, Keratoconus epidemiology, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Risk, Young Adult, Cornea metabolism, Cornea pathology, Exons, Genetic Variation, Keratoconus genetics, Keratoconus pathology, Wnt Proteins genetics
Abstract: Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross-linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency (MAF) >5%). However, these studies typically ignore the large set of exonic variants whose MAF is usually low. In this study, we performed a CCT exome-wide association analysis in a sample of 1029 individuals from a population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P = 6.63 × 10(-10)) in WNT10A. This gene is 437 kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent samples from the Brisbane Adolescent Twin Study, Twin Eye Study in Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a sample of 1680 unscreened controls from the Queensland Twin Registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P = 5.41 × 10(-5))., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Published: 2015
Full Text: View/download PDF

43. Validity of Automated Choroidal Segmentation in SS-OCT and SD-OCT.

Author: Zhang L, Buitendijk GH, Lee K, Sonka M, Springelkamp H, Hofman A, Vingerling JR, Mullins RF, Klaver CC, and Abràmoff MD
Subjects: Adult, Aged, Female, Humans, Imaging, Three-Dimensional methods, Male, Middle Aged, Netherlands, Prospective Studies, Reproducibility of Results, Choroid Diseases diagnosis, Tomography, Optical Coherence methods
Abstract: Purpose: To evaluate the validity of a novel fully automated three-dimensional (3D) method capable of segmenting the choroid from two different optical coherence tomography scanners: swept-source OCT (SS-OCT) and spectral-domain OCT (SD-OCT)., Methods: One hundred eight subjects were imaged using SS-OCT and SD-OCT. A 3D method was used to segment the choroid and quantify the choroidal thickness along each A-scan. The segmented choroidal posterior boundary was evaluated by comparing to manual segmentation. Differences were assessed to test the agreement between segmentation results of the same subject. Choroidal thickness was defined as the Euclidian distance between Bruch's membrane and the choroidal posterior boundary, and reproducibility was analyzed using automatically and manually determined choroidal thicknesses., Results: For SS-OCT, the average choroidal thickness of the entire 6- by 6-mm2 macular region was 219.5 μm (95% confidence interval [CI], 204.9-234.2 μm), and for SD-OCT it was 209.5 μm (95% CI, 197.9-221.0 μm). The agreement between automated and manual segmentations was high: Average relative difference was less than 5 μm, and average absolute difference was less than 15 μm. Reproducibility of choroidal thickness between repeated SS-OCT scans was high (coefficient of variation [CV] of 3.3%, intraclass correlation coefficient [ICC] of 0.98), and differences between SS-OCT and SD-OCT results were small (CV of 11.0%, ICC of 0.73)., Conclusions: We have developed a fully automated 3D method for segmenting the choroid and quantifying choroidal thickness along each A-scan. The method yielded high validity. Our method can be used reliably to study local choroidal changes and may improve the diagnosis and management of patients with ocular diseases in which the choroid is affected.
Published: 2015
Full Text: View/download PDF

44. Meta-analysis of Genome-Wide Association Studies Identifies Novel Loci Associated With Optic Disc Morphology.

Author: Springelkamp H, Mishra A, Hysi PG, Gharahkhani P, Höhn R, Khor CC, Cooke Bailey JN, Luo X, Ramdas WD, Vithana E, Koh V, Yazar S, Xu L, Forward H, Kearns LS, Amin N, Iglesias AI, Sim KS, van Leeuwen EM, Demirkan A, van der Lee S, Loon SC, Rivadeneira F, Nag A, Sanfilippo PG, Schillert A, de Jong PT, Oostra BA, Uitterlinden AG, Hofman A, Zhou T, Burdon KP, Spector TD, Lackner KJ, Saw SM, Vingerling JR, Teo YY, Pasquale LR, Wolfs RC, Lemij HG, Tai ES, Jonas JB, Cheng CY, Aung T, Jansonius NM, Klaver CC, Craig JE, Young TL, Haines JL, MacGregor S, Mackey DA, Pfeiffer N, Wong TY, Wiggs JL, Hewitt AW, van Duijn CM, and Hammond CJ
Subjects: Asian People genetics, Glaucoma ethnology, Glaucoma pathology, Humans, Optic Nerve Diseases ethnology, Optic Nerve Diseases pathology, White People genetics, Genome-Wide Association Study, Glaucoma genetics, Optic Disk pathology, Optic Nerve Diseases genetics, Quantitative Trait Loci genetics
Abstract: Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma., (© 2015 Wiley Periodicals, Inc.)
Published: 2015
Full Text: View/download PDF

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

Author: Hysi PG, Cheng CY, Springelkamp H, Macgregor S, Bailey JNC, Wojciechowski R, Vitart V, Nag A, Hewitt AW, Höhn R, Venturini C, Mirshahi A, Ramdas WD, Thorleifsson G, Vithana E, Khor CC, Stefansson AB, Liao J, Haines JL, Amin N, Wang YX, Wild PS, Ozel AB, Li JZ, Fleck BW, Zeller T, Staffieri SE, Teo YY, 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 ES, 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 SM, 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 TY, Viswanathan A, Mackey DA, Craig JE, Wiggs JL, van Duijn CM, Hammond CJ, and Aung T
Subjects: ABO Blood-Group System genetics, ATP Binding Cassette Transporter 1 genetics, Adult, Aged, Aged, 80 and over, Chromosomes, Human, Pair 11 genetics, Chromosomes, Human, Pair 3 genetics, Chromosomes, Human, Pair 9 genetics, Cohort Studies, Female, Fibronectins genetics, Genotype, Glaucoma, Open-Angle genetics, Humans, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Young Adult, Genetic Loci genetics, Genetic Predisposition to Disease genetics, Genome-Wide Association Study, Glaucoma genetics, Intraocular Pressure genetics
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
Full Text: View/download PDF

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

Author: Springelkamp H, Höhn R, Mishra A, Hysi PG, Khor CC, Loomis SJ, Bailey JN, Gibson J, Thorleifsson G, Janssen SF, Luo X, Ramdas WD, Vithana E, Nongpiur ME, Montgomery GW, Xu L, Mountain JE, Gharahkhani P, Lu Y, Amin N, Karssen LC, Sim KS, van Leeuwen EM, Iglesias AI, Verhoeven VJ, Hauser MA, Loon SC, Despriet DD, Nag A, Venturini C, Sanfilippo PG, Schillert A, Kang JH, Landers J, Jonasson F, Cree AJ, van Koolwijk LM, Rivadeneira F, Souzeau E, Jonsson V, Menon G, Weinreb RN, de Jong PT, Oostra BA, Uitterlinden AG, Hofman A, Ennis S, Thorsteinsdottir U, Burdon KP, Spector TD, Mirshahi A, Saw SM, Vingerling JR, Teo YY, Haines JL, Wolfs RC, Lemij HG, Tai ES, Jansonius NM, Jonas JB, Cheng CY, Aung T, Viswanathan AC, Klaver CC, Craig JE, Macgregor S, Mackey DA, Lotery AJ, Stefansson K, Bergen AA, Young TL, Wiggs JL, Pfeiffer N, Wong TY, Pasquale LR, Hewitt AW, van Duijn CM, and Hammond CJ
Subjects: Asian People genetics, Case-Control Studies, Gene Expression Profiling, Gene Frequency, Genotype, Glaucoma ethnology, Humans, Optic Disk pathology, Optic Nerve pathology, Phenotype, Polymorphism, Single Nucleotide, White People genetics, Genome-Wide Association Study, Glaucoma genetics, Glaucoma physiopathology
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
Full Text: View/download PDF

47. Exome sequencing and functional analyses suggest that SIX6 is a gene involved in an altered proliferation-differentiation balance early in life and optic nerve degeneration at old age.

Author: Iglesias AI, Springelkamp H, van der Linde H, Severijnen LA, Amin N, Oostra B, Kockx CE, van den Hout MC, van Ijcken WF, Hofman A, Uitterlinden AG, Verdijk RM, Klaver CC, Willemsen R, and van Duijn CM
Subjects: Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Animals, Cell Proliferation, Chromosome Mapping, Exome, Eye embryology, Eye metabolism, Gene Expression Profiling, Genome-Wide Association Study, Glaucoma, Open-Angle genetics, Glaucoma, Open-Angle metabolism, Glaucoma, Open-Angle pathology, High-Throughput Nucleotide Sequencing, Homeodomain Proteins metabolism, Humans, Middle Aged, Models, Biological, Organogenesis genetics, Phenotype, Quantitative Trait Loci, Trans-Activators metabolism, Young Adult, Zebrafish, Cell Differentiation genetics, Homeodomain Proteins genetics, Nerve Degeneration genetics, Optic Nerve metabolism, Optic Nerve pathology, Trans-Activators genetics
Abstract: Primary open-angle glaucoma (POAG) is a hereditary neurodegenerative disease, characterized by optic nerve changes including increased excavation, notching and optic disc hemorrhages. The excavation can be described by the vertical cup-disc ratio (VCDR). Previously, genome-wide significant evidence for the association of rs10483727 in SIX1-SIX6 locus with VCDR and subsequent POAG was found. Using 1000 genomes-based imputation of four independent population-based cohorts in the Netherlands, we identified a missense variant rs33912345 (His141Asn) in SIX6 associated with VCDR (Pmeta = 7.74 × 10(-7), n = 11 473) and POAG (Pmeta = 6.09 × 10(-3), n = 292). Exome sequencing analysis revealed another missense variant rs146737847 (Glu129Lys) also in SIX6 associated with VCDR (P = 5.09 × 10(-3), n = 1208). These two findings point to SIX6 as the responsible gene for the previously reported association signal. Functional characterization of SIX6 in zebrafish revealed that knockdown of six6b led to a small eye phenotype. Histological analysis showed retinal lamination, implying an apparent normal development of the eye, but an underdeveloped lens, and reduced optic nerve diameter. Expression analysis of morphants at 3 dpf showed a 5.5-fold up-regulation of cdkn2b, a cyclin-dependent kinase inhibitor, involved in cell cycle regulation and previously associated with VCDR and POAG in genome-wide association studies (GWASs). Since both six6b and cdkn2b play a key role in cell proliferation, we assessed the proliferative activity in the eye of morphants and found an alteration in the proliferative pattern of retinal cells. Our findings in humans and zebrafish suggest a functional involvement of six6b in early eye development, and open new insights into the genetic architecture of POAG.
Published: 2014
Full Text: View/download PDF

48. Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus.

Author: Lu Y, Vitart V, Burdon KP, Khor CC, Bykhovskaya Y, Mirshahi A, Hewitt AW, Koehn D, Hysi PG, Ramdas WD, Zeller T, Vithana EN, Cornes BK, Tay WT, Tai ES, Cheng CY, Liu J, Foo JN, Saw SM, Thorleifsson G, Stefansson K, Dimasi DP, Mills RA, Mountain J, Ang W, Hoehn R, Verhoeven VJ, Grus F, Wolfs R, Castagne R, Lackner KJ, Springelkamp H, Yang J, Jonasson F, Leung DY, Chen LJ, Tham CC, Rudan I, Vatavuk Z, Hayward C, Gibson J, Cree AJ, MacLeod A, Ennis S, Polasek O, Campbell H, Wilson JF, Viswanathan AC, Fleck B, Li X, Siscovick D, Taylor KD, Rotter JI, Yazar S, Ulmer M, Li J, Yaspan BL, Ozel AB, Richards JE, Moroi SE, Haines JL, Kang JH, Pasquale LR, Allingham RR, Ashley-Koch A, Mitchell P, Wang JJ, Wright AF, Pennell C, Spector TD, Young TL, Klaver CC, Martin NG, Montgomery GW, Anderson MG, Aung T, Willoughby CE, Wiggs JL, Pang CP, Thorsteinsdottir U, Lotery AJ, Hammond CJ, van Duijn CM, Hauser MA, Rabinowitz YS, Pfeiffer N, Mackey DA, Craig JE, Macgregor S, and Wong TY
Subjects: Asian People genetics, Corneal Pachymetry, Forkhead Box Protein O1, Genome-Wide Association Study, Glaucoma genetics, Humans, Microarray Analysis, Odds Ratio, Real-Time Polymerase Chain Reaction, White People genetics, Cornea anatomy & histology, Fibronectins genetics, Forkhead Transcription Factors genetics, Genetic Loci genetics, Keratoconus genetics
Abstract: Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10(-8)). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4-1.88, P = 2.7 × 10(-10), and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29-1.68, P = 4.9 × 10(-9)). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10(-4); tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.
Published: 2013
Full Text: View/download PDF

49. Optimizing the information yield of 3-D OCT in glaucoma.

Author: Springelkamp H, Lee K, Ramdas WD, Vingerling JR, Hofman A, Klaver CC, Sonka M, Abràmoff MD, and Jansonius NM
Subjects: Algorithms, Female, Fovea Centralis pathology, Humans, Intraocular Pressure, Male, Middle Aged, Optic Disk pathology, Reproducibility of Results, Axons pathology, Glaucoma, Open-Angle diagnosis, Imaging, Three-Dimensional, Retinal Ganglion Cells pathology, Tomography, Optical Coherence
Abstract: Purpose: To determine, first, which regions of 3-D optical coherence tomography (OCT) volumes can be segmented completely in the majority of subjects and, second, the relationship between analyzed area and thickness measurement test-retest variability., Methods: Three-dimensional OCT volumes (6 × 6 mm) centered around the fovea and optic nerve head (ONH) of 925 Rotterdam Study participants were analyzed; 44 participants were scanned twice. Volumes were segmented into 10 layers, and we determined the area where all layers could be identified in at least 95% (macula) or 90% (ONH) of subjects. Macular volumes were divided in 2 × 2, 4 × 4, 6 × 6, 8 × 8, or 68 blocks. We placed two circles around the ONH; the ONH had to fit into the smaller circle, and the larger circle had to fit into the segmentable part of the volume. The area between the circles was divided in 3 to 12 segments. We determined the test-retest variability (coefficient of repeatability) of the retinal nerve fiber layer (RNFL) and ganglion cell layer (RGCL) thickness measurements as a function of size of blocks/segments., Results: Eighty-two percent of the macular volume could be segmented in at least 95% of subjects; for the ONH, this was 65% in at least 90%. The radii of the circles were 1.03 and 1.84 mm. Depending on the analyzed area, median test-retest variability ranged from 8% to 15% for macular RNFL, 11% to 22% for macular RGCL, 5% to 11% for the two together, and 18% to 22% for ONH RNFL., Conclusions: Test-retest variability hampers a detailed analysis of 3-D OCT data. Combined macular RNFL and RGCL thickness averaged over larger areas had the best test-retest variability.
Published: 2012
Full Text: View/download PDF

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Region

Database

Publisher

49 results on '"Springelkamp, H"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources