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1. Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations

Author

Bonnemaijer, Pieter, Iglesias Gonzalez, Adriana, Nadkarni, GN, Sanyiwa, AJ, Hassan, HG, Cook, C, Simcoe, M, Taylor, KD, Schurmann, C, Belbin, GM, Kenny, EE, Bottinger, EP, van de Laar, S, Wiliams, SEI, Akafo, SK, Ashaye, AO, Zangwill, LM, Girkin, CA, Ng, MCY, Rotter, JI, Weinreb, RN, Li, Z, Allingham, RR, Nag, A, Hysi, PG, Meester - Smoor, Magda, Wiggs, JL, Hauser, MA, Hammond, CJ, Lemij, HG, Loos, RJF, Duijn, Cornelia, Thiadens, Alberta, Klaver, Caroline, Bonnemaijer, Pieter, Iglesias Gonzalez, Adriana, Nadkarni, GN, Sanyiwa, AJ, Hassan, HG, Cook, C, Simcoe, M, Taylor, KD, Schurmann, C, Belbin, GM, Kenny, EE, Bottinger, EP, van de Laar, S, Wiliams, SEI, Akafo, SK, Ashaye, AO, Zangwill, LM, Girkin, CA, Ng, MCY, Rotter, JI, Weinreb, RN, Li, Z, Allingham, RR, Nag, A, Hysi, PG, Meester - Smoor, Magda, Wiggs, JL, Hauser, MA, Hammond, CJ, Lemij, HG, Loos, RJF, Duijn, Cornelia, Thiadens, Alberta, and Klaver, Caroline

Published
2018

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

Author

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

Published
2017

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

Author

Springelkamp, Henriët, Iglesias Gonzalez, Adriana, Cuellar-Partida, G, Amin, Najaf, Burdon, KP, Leeuwen, Elisa, Gharahkhani, P, Mishra, A, van der Lee, Sven, Hewitt, AW, Rivadeneira, Fernando, Viswanathan, AC, Wolfs, R.C.W., Martin, NG, Ramdas, Wishal, van Koolwijk, LM, Pennell, CE, Vingerling, Hans, Mountain, JE, Uitterlinden, André, Hofman, Bert, Mitchell, P, Lemij, HG, Wang, JJ, Klaver, Caroline, Mackey, DA, Craig, JE, Duijn, Cornelia, Macgregor, S, Springelkamp, Henriët, Iglesias Gonzalez, Adriana, Cuellar-Partida, G, Amin, Najaf, Burdon, KP, Leeuwen, Elisa, Gharahkhani, P, Mishra, A, van der Lee, Sven, Hewitt, AW, Rivadeneira, Fernando, Viswanathan, AC, Wolfs, R.C.W., Martin, NG, Ramdas, Wishal, van Koolwijk, LM, Pennell, CE, Vingerling, Hans, Mountain, JE, Uitterlinden, André, Hofman, Bert, Mitchell, P, Lemij, HG, Wang, JJ, Klaver, Caroline, Mackey, DA, Craig, JE, Duijn, Cornelia, and Macgregor, S

Abstract

Primary open-angle glaucoma (POAG) is a blinding disease. Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly heritable. Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7 and TMCO1. However, these genes explain only a small part of the heritability of IOP and POAG. We performed a genome-wide association study of IOP in the population-based Rotterdam Study I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a new locus associated with IOP. The most significantly associated SNP was rs58073046 (beta = 0.44, P-value = 1.87 x 10(-8), minor allele frequency = 0.12), within the gene ARHGEF12. Independent replication in five population-based studies (n = 7471) resulted in an effect size in the same direction that was significantly associated (beta = 0.16, P-value = 0.04). The SNP was also significantly associated with POAG in two independent case-control studies [n = 1225 cases and n = 4117 controls; odds ratio (OR) = 1.53, P-value = 1.99 x 10(-)8], especially with high-tension glaucoma (OR = 1.66, P-value = 2.81 x 10(-9); for normal-tension glaucoma OR = 1.29, P-value = 4.23 x 10(-2)). ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in IOP regulation. Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2 and GAS7 pathway to Mendelian POAG genes (MYOC, OPTN, WDR36). In conclusion, this study identified a novel association between IOP and ARHGEF12.

Published
2015

7. The Effect of Cataract on Eye Movement Perimetry

Author

Thepass, G, Pel, Johan, Vermeer, Koenraad, Creten, O, Bryan, SR, Lemij, HG (Hans), Steen, Hans, Thepass, G, Pel, Johan, Vermeer, Koenraad, Creten, O, Bryan, SR, Lemij, HG (Hans), and Steen, Hans

Abstract

Purpose. To determine how different grades of cataract affect sensitivity threshold and saccadic reaction time (SRT) in eye movement perimetry (EMP). Methods. In EMP, the visual field is tested by assessing the saccades that a subject makes towards peripheral stimuli using an eye tracker. Forty-eight cataract patients underwent pre- and postoperative EMP examination in both eyes. The subjects had to fix a central stimulus presented on the eye tracker monitor and to look at any detected peripheral stimulus upon its appearance. A multilevel mixed model was used to determine the factors that affected the sensitivity threshold and the SRT as a function of cataract grade. Results. We found no effect of cataract severity (LOCS III grades I through IV) on SRT and the sensitivity thresholds. In cataract of LOCS III grade V, however, we found an increase by 27% and 21% (P < 0.001), respectively, compared to the SRT and the sensitivity threshold in LOCS III grade I. Eyes that underwent cataract surgery showed no change in mean SRTs and sensitivity thresholds after surgery in LOCS III grade IV and lower. Conclusion. The present study shows that EMP can be readily used in patients with cataract with LOCS III grade IV and below.

Published
2015

8. 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

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

Author

Springelkamp, H, Hoehn, R, Mishra, A, Hysi, PG, Khor, C-C, Loomis, SJ, Bailey, JNC, Gibson, J, Thorleifsson, G, Janssen, SF, Luo, X, Ramdas, WD, Vithana, E, Nongpiur, ME, Montgomery, G, Xu, L, Mountain, JE, Gharahkhani, P, Lu, Y, Amin, N, Karssen, LC, Sim, K-S, van Leeuwen, EM, Iglesias, AI, Verhoeven, VJM, Hauser, MA, Loon, S-C, 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, Weinreb, RN, de Jong, PTVM, Oostra, BA, Uitterlinden, AG, Hofman, A, Ennis, S, Thorsteinsdottir, U, Burdon, KP, Spector, TD, Mirshahi, A, Saw, S-M, Vingerling, JR, Teo, Y-Y, Haines, JL, Wolfs, RCW, Lemij, HG, Tai, E-S, Jansonius, NM, Jonas, JB, Cheng, C-Y, Aung, T, Viswanathan, AC, Klaver, CCW, Craig, JE, Macgregor, S, Mackey, DA, Lotery, AJ, Stefansson, K, Bergen, AAB, Young, TL, Wiggs, JL, Pfeiffer, N, Wong, T-Y, Pasquale, LR, Hewitt, AW, van Duijn, CM, Hammond, CJ, Springelkamp, H, Hoehn, R, Mishra, A, Hysi, PG, Khor, C-C, Loomis, SJ, Bailey, JNC, Gibson, J, Thorleifsson, G, Janssen, SF, Luo, X, Ramdas, WD, Vithana, E, Nongpiur, ME, Montgomery, G, Xu, L, Mountain, JE, Gharahkhani, P, Lu, Y, Amin, N, Karssen, LC, Sim, K-S, van Leeuwen, EM, Iglesias, AI, Verhoeven, VJM, Hauser, MA, Loon, S-C, 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, Weinreb, RN, de Jong, PTVM, Oostra, BA, Uitterlinden, AG, Hofman, A, Ennis, S, Thorsteinsdottir, U, Burdon, KP, Spector, TD, Mirshahi, A, Saw, S-M, Vingerling, JR, Teo, Y-Y, Haines, JL, Wolfs, RCW, Lemij, HG, Tai, E-S, Jansonius, NM, Jonas, JB, Cheng, C-Y, Aung, T, Viswanathan, AC, Klaver, CCW, Craig, JE, Macgregor, S, Mackey, DA, Lotery, AJ, Stefansson, K, Bergen, AAB, Young, TL, Wiggs, JL, Pfeiffer, N, Wong, T-Y, Pasquale, LR, Hewitt, AW, van Duijn, CM, and Hammond, CJ

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

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

Author

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

Abstract

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

Published
2014

12. Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma

Author

Gibson, G, van Koolwijk, LME, Ramdas, WD, Ikram, MK, Jansonius, NM, Pasutto, F, Hysi, PG, Macgregor, S, Janssen, SF, Hewitt, AW, Viswanathan, AC, ten Brink, JB, Hosseini, SM, Amin, N, Despriet, DDG, Willemse-Assink, JJM, Kramer, R, Rivadeneira, F, Struchalin, M, Aulchenko, YS, Weisschuh, N, Zenkel, M, Mardin, CY, Gramer, E, Welge-Luessen, U, Montgomery, GW, Carbonaro, F, Young, TL, Bellenguez, C, McGuffin, P, Foster, PJ, Topouzis, F, Mitchell, P, Wang, JJ, Wong, TY, Czudowska, MA, Hofman, A, Uitterlinden, AG, Wolfs, RCW, de Jong, PTVM, Oostra, BA, Paterson, AD, Mackey, DA, Bergen, AAB, Reis, A, Hammond, CJ, Vingerling, JR, Lemij, HG, Klaver, CCW, van Duijn, CM, Gibson, G, van Koolwijk, LME, Ramdas, WD, Ikram, MK, Jansonius, NM, Pasutto, F, Hysi, PG, Macgregor, S, Janssen, SF, Hewitt, AW, Viswanathan, AC, ten Brink, JB, Hosseini, SM, Amin, N, Despriet, DDG, Willemse-Assink, JJM, Kramer, R, Rivadeneira, F, Struchalin, M, Aulchenko, YS, Weisschuh, N, Zenkel, M, Mardin, CY, Gramer, E, Welge-Luessen, U, Montgomery, GW, Carbonaro, F, Young, TL, Bellenguez, C, McGuffin, P, Foster, PJ, Topouzis, F, Mitchell, P, Wang, JJ, Wong, TY, Czudowska, MA, Hofman, A, Uitterlinden, AG, Wolfs, RCW, de Jong, PTVM, Oostra, BA, Paterson, AD, Mackey, DA, Bergen, AAB, Reis, A, Hammond, CJ, Vingerling, JR, Lemij, HG, Klaver, CCW, and van Duijn, CM

Abstract

Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p=1.4×10(-8)), and with rs7555523, located in TMCO1 at 1q24.1 (p=1.6×10(-8)). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p=2.4×10(-2) for rs11656696 and p=9.1×10(-4) for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.

Published
2012

13. Common Genetic Determinants of Intraocular Pressure and Primary Open-Angle Glaucoma

Author

Koolwijk, Leonieke, Ramdas, Wishal, Ikram, Kamran, Jansonius, NM (Nomdo), Pasutto, F, Hysi, PG, Macgregor, S, Janssen, SF, Hewitt, AW, Viswanathan, AC, Brink, JB, Hosseini, SM, Amin, Najaf, Despriet, Dominiek, Willemse-Assink, JJM, Kramer, R, Rivadeneira, Fernando, Struchalin, M, Aulchenko, YS, Weisschuh, N, Zenkel, M, Mardin, CY, Gramer, E, Welge-Lussen, U, Montgomery, GW, Carbonaro, F, Young, TL, Bellenguez, C, McGuffin, P, Foster, PJ, Topouzis, F, Mitchell, P, Wang, JJ, Wong, TY, Czudowska, Monika, Hofman, Bert, Uitterlinden, André, Wolfs, R.C.W., de Jong, PTVM (Paulus), Oostra, Ben, Paterson, AD, Mackey, DA, Bergen, Arthur, Reis, A, Hammond, CJ, Vingerling, Hans, Lemij, HG, Klaver, Caroline, Duijn, Cornelia, Koolwijk, Leonieke, Ramdas, Wishal, Ikram, Kamran, Jansonius, NM (Nomdo), Pasutto, F, Hysi, PG, Macgregor, S, Janssen, SF, Hewitt, AW, Viswanathan, AC, Brink, JB, Hosseini, SM, Amin, Najaf, Despriet, Dominiek, Willemse-Assink, JJM, Kramer, R, Rivadeneira, Fernando, Struchalin, M, Aulchenko, YS, Weisschuh, N, Zenkel, M, Mardin, CY, Gramer, E, Welge-Lussen, U, Montgomery, GW, Carbonaro, F, Young, TL, Bellenguez, C, McGuffin, P, Foster, PJ, Topouzis, F, Mitchell, P, Wang, JJ, Wong, TY, Czudowska, Monika, Hofman, Bert, Uitterlinden, André, Wolfs, R.C.W., de Jong, PTVM (Paulus), Oostra, Ben, Paterson, AD, Mackey, DA, Bergen, Arthur, Reis, A, Hammond, CJ, Vingerling, Hans, Lemij, HG, Klaver, Caroline, and Duijn, Cornelia

Abstract

Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p = 1.4 x 10(-8)), and with rs7555523, located in TMCO1 at 1q24.1 (p = 1.6 x 10(-8)). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p = 2.4 x 10(-2) for rs11656696 and p = 9.1 x 10(-4) for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.

Published
2012

14. A Genome-Wide Association Study of Optic Disc Parameters

Author

Ramdas, Wishal, Koolwijk, Leonieke, Ikram, Kamran, Jansonius, NM (Nomdo), de Jong, PTVM (Paulus), Bergen, Arthur, Isaacs, Aaron, Amin, Najaf, Aulchenko, YS, Wolfs, R.C.W., Hofman, Bert, Rivadeneira, Fernando, Oostra, Ben, Uitterlinden, André, Hysi, P, Hammond, CJ, Lemij, HG (Hans), Vingerling, Hans, Klaver, Caroline, Duijn, Cornelia, Ramdas, Wishal, Koolwijk, Leonieke, Ikram, Kamran, Jansonius, NM (Nomdo), de Jong, PTVM (Paulus), Bergen, Arthur, Isaacs, Aaron, Amin, Najaf, Aulchenko, YS, Wolfs, R.C.W., Hofman, Bert, Rivadeneira, Fernando, Oostra, Ben, Uitterlinden, André, Hysi, P, Hammond, CJ, Lemij, HG (Hans), Vingerling, Hans, Klaver, Caroline, and Duijn, Cornelia

Abstract

The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p = 6.72 x 10(-19)) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67 x 10(-33)) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15610 211) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93 x 10(-10)) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N = 3,612), and the TwinsUK cohort (N = 843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin.

Published
2010

16. Monitoring of stable glaucoma patients

Author

Holtzer - Goor, KM (Kim Marleine), Klazinga, NS (Niek), Koopmanschap, Marc, Lemij, HG (Hans), Plochg, T, van Sprundel, E, Holtzer - Goor, KM (Kim Marleine), Klazinga, NS (Niek), Koopmanschap, Marc, Lemij, HG (Hans), Plochg, T, and van Sprundel, E

Published
2010

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