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

Author

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

Abstract

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

Published
2021

2. Gene-specific facial dysmorphism in Axenfeld-Rieger syndrome caused by FOXC1 and PITX2 variants

Author

Souzeau, E, Siggs, OM, Pasutto, F, Knight, LSW, Perez-Jurado, LA, McGregor, L, Le Blanc, S, Barnett, CP, Liebelt, J, Craig, JE, Souzeau, E, Siggs, OM, Pasutto, F, Knight, LSW, Perez-Jurado, LA, McGregor, L, Le Blanc, S, Barnett, CP, Liebelt, J, and Craig, JE

Abstract

Axenfeld-Rieger syndrome is a genetic condition characterized by ocular and systemic features and is most commonly caused by variants in the FOXC1 or PITX2 genes. Facial dysmorphism is part of the syndrome but the differences between both genes have never been systematically assessed. Here, 11 facial traits commonly reported in Axenfeld-Rieger syndrome were assessed by five clinical geneticists blinded to the molecular diagnosis. Individuals were drawn from the Australian and New Zealand Registry of Advanced Glaucoma in Australia or recruited through the Genetic and Ophthalmology Unit of l'Azienda Socio-Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Italy. Thirty-four individuals from 18 families were included. FOXC1 variants were present in 64.7% of individuals and PITX2 variants in 35.3% of individuals. A thin upper lip (55.9%) and a prominent forehead (41.2%) were common facial features shared between both genes. Hypertelorism/telecanthus (81.8% vs 25.0%, p = 0.002) and low-set ears (31.8% vs 0.0%, p = 0.036) were significantly more prevalent in individuals with FOXC1 variants compared with PITX2 variants. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling.

Published
2021

3. An Assessment of GUCA1C Variants in Primary Congenital Glaucoma

Author

Souzeau, E, Weisschuh, N, Craig, JE, Pasutto, F, Koch, K-W, Souzeau, E, Weisschuh, N, Craig, JE, Pasutto, F, and Koch, K-W

Abstract

In the special issue "Molecular Genetics of Retinal Dystrophies", Morales-Cámara and colleagues reported the association of a new candidate gene with primary congenital glaucoma (PCG) [...].

Published
2021

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

Author

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

Abstract

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

Published
2021

5. Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression

Author

Craig, J.E., Han, X., Qassim, A., Hassall, M., Bailey, J.N., Kinzy, T.G., Khawaja, A.P., An, J., Marshall, H., Gharahkhani, P., Igo, R.P., Jr., Graham, S.L., Healey, P.R., Ong, J.S., Zhou, T., Siggs, O., Law, M.H., Souzeau, E., Ridge, B., Hysi, P.G., Burdon, K.P., Mills, R.A., Landers, J., Ruddle, J.B., Agar, A., Galanopoulos, A., White, A.J.R., Willoughby, C.E., Andrew, N.H., Best, S., Vincent, A.L., Goldberg, I., Radford-Smith, G., Martin, N.G., Montgomery, G.W., Vitart, V., Hoehn, R., Wojciechowski, R., Jonas, J.B., Aung, T., Pasquale, L.R., Cree, A.J., Sivaprasad, S., Vallabh, N.A., Viswanathan, A.C., Pasutto, F., Haines, J.L., Klaver, C.C.W., Duijn, C.M. van, Casson, R.J., Foster, P.J., Khaw, P.T., Hammond, C.J., Mackey, D.A., Mitchell, P., Lotery, A.J., Wiggs, J.L., Hewitt, A.W., MacGregor, S., Craig, J.E., Han, X., Qassim, A., Hassall, M., Bailey, J.N., Kinzy, T.G., Khawaja, A.P., An, J., Marshall, H., Gharahkhani, P., Igo, R.P., Jr., Graham, S.L., Healey, P.R., Ong, J.S., Zhou, T., Siggs, O., Law, M.H., Souzeau, E., Ridge, B., Hysi, P.G., Burdon, K.P., Mills, R.A., Landers, J., Ruddle, J.B., Agar, A., Galanopoulos, A., White, A.J.R., Willoughby, C.E., Andrew, N.H., Best, S., Vincent, A.L., Goldberg, I., Radford-Smith, G., Martin, N.G., Montgomery, G.W., Vitart, V., Hoehn, R., Wojciechowski, R., Jonas, J.B., Aung, T., Pasquale, L.R., Cree, A.J., Sivaprasad, S., Vallabh, N.A., Viswanathan, A.C., Pasutto, F., Haines, J.L., Klaver, C.C.W., Duijn, C.M. van, Casson, R.J., Foster, P.J., Khaw, P.T., Hammond, C.J., Mackey, D.A., Mitchell, P., Lotery, A.J., Wiggs, J.L., Hewitt, A.W., and MacGregor, S.

Abstract

Contains fulltext : 218893.pdf (Publisher’s version ) (Closed access), Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 x 10(-)(6)). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.

Published
2020

6. Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression

Author

Craig, JE, Han, X, Qassim, A, Hassall, M, Bailey, JNC, Kinzy, TG, Khawaja, AP, An, J, Marshall, H, Gharahkhani, P, Igo, RP, Graham, SL, Healey, PR, Ong, J-S, Zhou, T, Siggs, O, Law, MH, Souzeau, E, Ridge, B, Hysi, PG, Burdon, KP, Mills, RA, Landers, J, Ruddle, JB, Agar, A, Galanopoulos, A, White, AJR, Willoughby, CE, Andrew, NH, Best, S, Vincent, AL, Goldberg, I, Radford-Smith, G, Martin, NG, Montgomery, GW, Vitart, V, Hoehn, R, Wojciechowski, R, Jonas, JB, Aung, T, Pasquale, LR, Cree, AJ, Sivaprasad, S, Vallabh, NA, Viswanathan, AC, Pasutto, F, Haines, JL, Klaver, CCW, van Duijn, CM, Casson, RJ, Foster, PJ, Khaw, PT, Hammond, CJ, Mackey, DA, Mitchell, P, Lotery, AJ, Wiggs, JL, Hewitt, AW, MacGregor, S, Craig, JE, Han, X, Qassim, A, Hassall, M, Bailey, JNC, Kinzy, TG, Khawaja, AP, An, J, Marshall, H, Gharahkhani, P, Igo, RP, Graham, SL, Healey, PR, Ong, J-S, Zhou, T, Siggs, O, Law, MH, Souzeau, E, Ridge, B, Hysi, PG, Burdon, KP, Mills, RA, Landers, J, Ruddle, JB, Agar, A, Galanopoulos, A, White, AJR, Willoughby, CE, Andrew, NH, Best, S, Vincent, AL, Goldberg, I, Radford-Smith, G, Martin, NG, Montgomery, GW, Vitart, V, Hoehn, R, Wojciechowski, R, Jonas, JB, Aung, T, Pasquale, LR, Cree, AJ, Sivaprasad, S, Vallabh, NA, Viswanathan, AC, Pasutto, F, Haines, JL, Klaver, CCW, van Duijn, CM, Casson, RJ, Foster, PJ, Khaw, PT, Hammond, CJ, Mackey, DA, Mitchell, P, Lotery, AJ, Wiggs, JL, Hewitt, AW, and MacGregor, S

Abstract

Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10-6). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.

Published
2020

9. POSITIONAL CLONING OF THE CMT2B2 GENE AND ITS IMPLICATIONS FOR CMT1A

Author

Rautenstrauss, B, Leal, A, Huehne, K, Bauer, F, Sticht, H, Berger, P, Suter, U, Ekici, A, Pasutto, F, Endele, S, Saifi, M, Lupski, J R, Morera, B, Del Valle, G, Barrantes, R, Heuss, D, Berghoff, C, Berghoff, M, Neundörfer, B, Uhlmann, T, Meisterernst, M, Sereda, M W, zu Horste, G M, Nave, K-A, and Reis, A

Published
2005

10. 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
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11. 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

12. 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
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13. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Author

Aung, T., Ozaki, M., Lee, M.C., Schlotzer-Schrehardt, U., Thorleifsson, G., Mizoguchi, T., Igo, R.P., Jr., Haripriya, A., Williams, S.E., Astakhov, Y.S., Orr, A.C., Burdon, K.P., Nakano, S., Mori, K., Abu-Amero, K., Hauser, M., Li, Z., Prakadeeswari, G., Bailey, J.N., Cherecheanu, A.P., Kang, J.H., Nelson, S., Hayashi, K., Manabe, S.I., Kazama, S., Zarnowski, T., Inoue, K., Irkec, M., Coca-Prados, M., Sugiyama, K., Jarvela, I., Schlottmann, P., Lerner, S.F., Lamari, H., Nilgun, Y., Bikbov, M., Park, K.H., Cha, S.C., Yamashiro, K., Zenteno, J.C., Jonas, J.B., Kumar, R.S.S., Perera, S.A., Chan, A.S.Y., Kobakhidze, N., George, R., Vijaya, L., Do, T., Edward, D.P., Juan Marcos, L. de, Pakravan, M., Moghimi, S., Ideta, R., Bach-Holm, D., Kappelgaard, P., Wirostko, B., Thomas, S., Gaston, D., Bedard, K., Greer, W.L., Yang, Z, Chen, X., Huang, L., Sang, J., Jia, H., Jia, L., Qiao, C., Zhang, H., Liu, X., Zhao, B., Wang, Y.X., Xu, L., Leruez, S., Reynier, P., Chichua, G., Tabagari, S., Uebe, S., Zenkel, M., Berner, D., Mossbock, G., Weisschuh, N., Hoja, U., Welge-Luessen, U.C., Mardin, C., Founti, P., Chatzikyriakidou, A., Pappas, T., Anastasopoulos, E., Lambropoulos, A., Ghosh, A., Shetty, R., Porporato, N., Saravanan, V., Venkatesh, R., Shivkumar, C., Kalpana, N., Sarangapani, S., Kanavi, M.R., Beni, A.N., Yazdani, S., Hollander, A.I. den, Pasutto, F., Khor, C.C., Aung, T., Ozaki, M., Lee, M.C., Schlotzer-Schrehardt, U., Thorleifsson, G., Mizoguchi, T., Igo, R.P., Jr., Haripriya, A., Williams, S.E., Astakhov, Y.S., Orr, A.C., Burdon, K.P., Nakano, S., Mori, K., Abu-Amero, K., Hauser, M., Li, Z., Prakadeeswari, G., Bailey, J.N., Cherecheanu, A.P., Kang, J.H., Nelson, S., Hayashi, K., Manabe, S.I., Kazama, S., Zarnowski, T., Inoue, K., Irkec, M., Coca-Prados, M., Sugiyama, K., Jarvela, I., Schlottmann, P., Lerner, S.F., Lamari, H., Nilgun, Y., Bikbov, M., Park, K.H., Cha, S.C., Yamashiro, K., Zenteno, J.C., Jonas, J.B., Kumar, R.S.S., Perera, S.A., Chan, A.S.Y., Kobakhidze, N., George, R., Vijaya, L., Do, T., Edward, D.P., Juan Marcos, L. de, Pakravan, M., Moghimi, S., Ideta, R., Bach-Holm, D., Kappelgaard, P., Wirostko, B., Thomas, S., Gaston, D., Bedard, K., Greer, W.L., Yang, Z, Chen, X., Huang, L., Sang, J., Jia, H., Jia, L., Qiao, C., Zhang, H., Liu, X., Zhao, B., Wang, Y.X., Xu, L., Leruez, S., Reynier, P., Chichua, G., Tabagari, S., Uebe, S., Zenkel, M., Berner, D., Mossbock, G., Weisschuh, N., Hoja, U., Welge-Luessen, U.C., Mardin, C., Founti, P., Chatzikyriakidou, A., Pappas, T., Anastasopoulos, E., Lambropoulos, A., Ghosh, A., Shetty, R., Porporato, N., Saravanan, V., Venkatesh, R., Shivkumar, C., Kalpana, N., Sarangapani, S., Kanavi, M.R., Beni, A.N., Yazdani, S., Hollander, A.I. den, Pasutto, F., and Khor, C.C.

Abstract

Item does not contain fulltext, Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 x 10-14) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10-8). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Published
2017

14. Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility

Author

Chintalapudi, S.R. (Sumana R.), Maria, D. (Doaa), Di Wang, X. (Xiang), Bailey, J.N.C. (Jessica N. Cooke), Allingham, R. (Rand), Brilliant, M.H. (Murray H.), Budenz, D.L. (Donald L.), Fingert, J. (John), Gaasterland, D. (Douglas), Gaasterland, T. (Terry), Haines, J.L. (Jonathan), Hark, L. (Lisa), Hauser, M.A. (Michael), Igo Jr., R.P. (Robert), Hee Kang, J. (Jae), Kraft, P. (Peter), Lee, R.K. (Richard K.), Lichter, P.A. (Paul A.), Liu, Y. (Yutao), Moroi, S. (Syoko), Pasquale, L.R. (Louis), Pericak-Vance, M.A. (Margaret), Realini, A. (Anthony), Rhee, D. (Doug), Richards, J.R. (Julia R.), Ritch, R. (Robert), Schuman, J.S. (Joel S.), Scott, W.K. (William), Singh, K. (Kuldev), Sit, A.J. (Arthur J.), Vollrath, D. (Douglas), Wollstein, G. (Gadi), Zack, D.J. (Donald), Aung, T. (Tin), Bonnemaijer, P. (Peter), Cheng, C.-Y. (Cheng-Yu), Craig, J.E. (Jamie), Duijn, C.M. (Cornelia) van, Gharahkhani, P. (Puya), Iglesias Gonzalez, A. (Adriana), Hammond, C.J. (Christopher J.), Hewitt, A. (Alex), Hoehn, R. (Rene), Jonansson, F. (Fridbert), Khawaja, A.P. (Anthony), Chuen Khor, C. (Chiea), Klaver, C.C.W. (Caroline), Lotery, A.J. (Andrew), Mackey, D.A. (David), MacGregor, S. (Stuart), Pang, C. (Calvin), Pasutto, F. (Francesca), Zwart, J-A. (John-Anker), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnar), Vitart, V. (Veronique), Vithana, E.N. (Eranga), Young, T.L. (Terri L.), Zeller, T. (Tanja), Hysi, P.G. (Pirro), Wiggs, J.L. (Janey L.), Williams, R.W. (Robert W.), Jablonski, M.M. (Monica M.), Chintalapudi, S.R. (Sumana R.), Maria, D. (Doaa), Di Wang, X. (Xiang), Bailey, J.N.C. (Jessica N. Cooke), Allingham, R. (Rand), Brilliant, M.H. (Murray H.), Budenz, D.L. (Donald L.), Fingert, J. (John), Gaasterland, D. (Douglas), Gaasterland, T. (Terry), Haines, J.L. (Jonathan), Hark, L. (Lisa), Hauser, M.A. (Michael), Igo Jr., R.P. (Robert), Hee Kang, J. (Jae), Kraft, P. (Peter), Lee, R.K. (Richard K.), Lichter, P.A. (Paul A.), Liu, Y. (Yutao), Moroi, S. (Syoko), Pasquale, L.R. (Louis), Pericak-Vance, M.A. (Margaret), Realini, A. (Anthony), Rhee, D. (Doug), Richards, J.R. (Julia R.), Ritch, R. (Robert), Schuman, J.S. (Joel S.), Scott, W.K. (William), Singh, K. (Kuldev), Sit, A.J. (Arthur J.), Vollrath, D. (Douglas), Wollstein, G. (Gadi), Zack, D.J. (Donald), Aung, T. (Tin), Bonnemaijer, P. (Peter), Cheng, C.-Y. (Cheng-Yu), Craig, J.E. (Jamie), Duijn, C.M. (Cornelia) van, Gharahkhani, P. (Puya), Iglesias Gonzalez, A. (Adriana), Hammond, C.J. (Christopher J.), Hewitt, A. (Alex), Hoehn, R. (Rene), Jonansson, F. (Fridbert), Khawaja, A.P. (Anthony), Chuen Khor, C. (Chiea), Klaver, C.C.W. (Caroline), Lotery, A.J. (Andrew), Mackey, D.A. (David), MacGregor, S. (Stuart), Pang, C. (Calvin), Pasutto, F. (Francesca), Zwart, J-A. (John-Anker), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnar), Vitart, V. (Veronique), Vithana, E.N. (Eranga), Young, T.L. (Terri L.), Zeller, T. (Tanja), Hysi, P.G. (Pirro), Wiggs, J.L. (Janey L.), Williams, R.W. (Robert W.), and Jablonski, M.M. (Monica M.)

Abstract

Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with know

Published
2017
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15. Angiopoietin-1 is required for Schlemm's canal development in mice and humans

Author

Thomson, BR, Souma, T, Tompson, SW, Onay, T, Kizhatil, K, Siggs, OM, Feng, L, Whisenhunt, KN, Yanovitch, TL, Kalaydjieva, L, Azmanov, DN, Finzi, S, Tanna, CE, Hewitt, AW, Mackey, DA, Bradfield, YS, Souzeau, E, Javadiyan, S, Wiggs, JL, Pasutto, F, Liu, X, John, SWM, Craig, JE, Jin, J, Young, TL, Quaggin, SE, Thomson, BR, Souma, T, Tompson, SW, Onay, T, Kizhatil, K, Siggs, OM, Feng, L, Whisenhunt, KN, Yanovitch, TL, Kalaydjieva, L, Azmanov, DN, Finzi, S, Tanna, CE, Hewitt, AW, Mackey, DA, Bradfield, YS, Souzeau, E, Javadiyan, S, Wiggs, JL, Pasutto, F, Liu, X, John, SWM, Craig, JE, Jin, J, Young, TL, and Quaggin, SE

Abstract

Primary congenital glaucoma (PCG) is a leading cause of blindness in children worldwide and is caused by developmental defects in 2 aqueous humor outflow structures, Schlemm's canal (SC) and the trabecular meshwork. We previously identified loss-of-function mutations in the angiopoietin (ANGPT) receptor TEK in families with PCG and showed that ANGPT/TEK signaling is essential for SC development. Here, we describe roles for the major ANGPT ligands in the development of the aqueous outflow pathway. We determined that ANGPT1 is essential for SC development, and that Angpt1-knockout mice form a severely hypomorphic canal with elevated intraocular pressure. By contrast, ANGPT2 was dispensable, although mice deficient in both Angpt1 and Angpt2 completely lacked SC, indicating that ANGPT2 compensates for the loss of ANGPT1. In addition, we identified 3 human subjects with rare ANGPT1 variants within an international cohort of 284 PCG patients. Loss of function in 2 of the 3 patient alleles was observed by functional analysis of ANGPT1 variants in a combined in silico, in vitro, and in vivo approach, supporting a causative role for ANGPT1 in disease. By linking ANGPT1 with PCG, these results highlight the importance of ANGPT/TEK signaling in glaucoma pathogenesis and identify a candidate target for therapeutic development.

Published
2017

22. Common genetic determinants of intraocular pressure and primary open-angle Glaucoma

Author

Koolwijk, L.M.E. (Leonieke) van, Ramdas, W.D. (Wishal), Ikram, M.K. (Kamran), Jansonius, N.M. (Nomdo), Pasutto, F. (Francesca), Hysi, P.G. (Pirro), MacGregor, S. (Stuart), Janssen, S.F. (Sarah), Hewit, A.W. (Alex), Viswanathan, A.C. (Ananth), Brink, J.B. (Jacoline) ten, Hosseini, M. (Mehran), Amin, N. (Najaf), Despriet, D.D.G. (Dominique), Willemse-Assink, J.J.M. (Jacqueline), Kramer, R. (Rogier), Rivadeneira Ramirez, F. (Fernando), Struchalin, M.V. (Maksim), Aulchenko, Y.S. (Yurii), Weisschuh, N. (Nicole), Zenkel, M. (Matthias), Mardin, C.Y. (Christian), Gramer, E. (Eugen), Welge-Lüssen, U. (Ulrich), Montgomery, G.W. (Grant), Carbonaro, F. (Francis), Young, T.L. (Terri), Bellenguez, C. (Céline), Mcguffin, P. (Peter), Foster, P.J. (Paul), Topouzis, F. (Fotis), Mitchell, P. (Paul), Wang, J.J. (Jie Jin), Wong, T.Y. (Tien Yin), Czudowska, M.A. (Monika), Hofman, A. (Albert), Uitterlinden, A.G. (André), Wolfs, R.C.W. (Roger), Jong, P.T.V.M. (Paulus) de, Oostra, B.A. (Ben), Paterson, A.D. (Andrew), Mackey, D.A. (David), Bergen, A.A.B. (Arthur), Reis, A. (André), Hammond, C.J. (Christopher), Vingerling, J.R. (Hans), Lemij, H.G. (Hans), Klaver, C.C.W. (Caroline), Duijn, C.M. (Cornelia) van, Koolwijk, L.M.E. (Leonieke) van, Ramdas, W.D. (Wishal), Ikram, M.K. (Kamran), Jansonius, N.M. (Nomdo), Pasutto, F. (Francesca), Hysi, P.G. (Pirro), MacGregor, S. (Stuart), Janssen, S.F. (Sarah), Hewit, A.W. (Alex), Viswanathan, A.C. (Ananth), Brink, J.B. (Jacoline) ten, Hosseini, M. (Mehran), Amin, N. (Najaf), Despriet, D.D.G. (Dominique), Willemse-Assink, J.J.M. (Jacqueline), Kramer, R. (Rogier), Rivadeneira Ramirez, F. (Fernando), Struchalin, M.V. (Maksim), Aulchenko, Y.S. (Yurii), Weisschuh, N. (Nicole), Zenkel, M. (Matthias), Mardin, C.Y. (Christian), Gramer, E. (Eugen), Welge-Lüssen, U. (Ulrich), Montgomery, G.W. (Grant), Carbonaro, F. (Francis), Young, T.L. (Terri), Bellenguez, C. (Céline), Mcguffin, P. (Peter), Foster, P.J. (Paul), Topouzis, F. (Fotis), Mitchell, P. (Paul), Wang, J.J. (Jie Jin), Wong, T.Y. (Tien Yin), Czudowska, M.A. (Monika), Hofman, A. (Albert), Uitterlinden, A.G. (André), Wolfs, R.C.W. (Roger), Jong, P.T.V.M. (Paulus) de, Oostra, B.A. (Ben), Paterson, A.D. (Andrew), Mackey, D.A. (David), Bergen, A.A.B. (Arthur), Reis, A. (André), Hammond, C.J. (Christopher), Vingerling, J.R. (Hans), Lemij, H.G. (Hans), Klaver, C.C.W. (Caroline), and Duijn, C.M. (Cornelia) van

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 geno

Published
2012
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23. 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

24. 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

25. Evidence for RPGRIP1 gene as risk factor for primary open angle glaucoma

Author

Fernandez-Martinez, L., Letteboer, S.J.F., Mardin, C.Y., Weisschuh, N., Gramer, E., Weber, B.H., Rautenstrauss, B., Ferreira, P.A., Kruse, F.E., Reis, A., Roepman, R., Pasutto, F., Fernandez-Martinez, L., Letteboer, S.J.F., Mardin, C.Y., Weisschuh, N., Gramer, E., Weber, B.H., Rautenstrauss, B., Ferreira, P.A., Kruse, F.E., Reis, A., Roepman, R., and Pasutto, F.

Abstract

Item does not contain fulltext, Glaucoma is a genetically heterogeneous disorder and is the second cause of blindness worldwide owing to the progressive degeneration of retinal ganglion neurons. Very few genes causing glaucoma were identified to this date. In this study, we screened 10 candidate genes of glaucoma between the D14S261 and D14S121 markers of chromosome 14q11, a critical region previously linked to primary open-angle glaucoma (POAG). Mutation analyses of two large cohorts of patients with POAG, normal tension glaucoma (NTG) and juvenile open-angle glaucoma (JOAG), and control subjects, found only association of non-synonymous heterozygous variants of the retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1) with POAG, NTG and JOAG. The 20 non-synonymous variants identified in RPGRIP1 were all distinct from variants causing photoreceptor dystrophies and were found throughout all but one domain (RPGR-interacting domain) of RPGRIP1. Among them, 14 missense variants clustered within or around the C2 domains of RPGRIP1. Yeast two-hybrid analyses of a subset of the missense mutations within the C2 domains of RPGRIP1 shows that five of them (p.R598Q, p.A635G, p.T806I, p.A837G and p.I838V) decrease the association of the C2 domains with nephrocystin-4 (NPHPH). When considering only these five confirmed C2-domain mutations, the association remains statistically significant (P=0.001). Altogether, the data support that heterozygous non-synonymous variants of RPGRIP1 may cause or increase the susceptibility to various forms of glaucoma and that among other factors, physical impairment of the interaction of RPGRIP1with different proteins may contribute to the pathogenesis of forms of glaucoma.

Published
2011

26. Common genetic variants associated with open-angle glaucoma.

Author

Ramdas, W.D., van Koolwijk, L.M., Lemij, H.G., Pasutto, F., Cree, A.J., Thorleifsson, G., Janssen, S.F., Jacoline, T.B., Amin, N., Rivadeneira, F., Wolfs, R.C., Walters, G.B., Jonasson, F., Weisschuh, N., Mardin, C.Y., Gibson, J., Zegers, R.H., Hofman, A., de Jong, P.T.V.M., Uitterlinden, A.G., Oostra, B.A., Thorsteinsdottir, U., Gramer, E., Welgen-Lussen, U.C., Kirwan, J.F., Bergen, A.A.B., Reis, A., Stefansson, K., Lotery, A.J., Vingerling, J.R., Jansonius, N.M., Klaver, C.C., Van Duijn, C.M., Ramdas, W.D., van Koolwijk, L.M., Lemij, H.G., Pasutto, F., Cree, A.J., Thorleifsson, G., Janssen, S.F., Jacoline, T.B., Amin, N., Rivadeneira, F., Wolfs, R.C., Walters, G.B., Jonasson, F., Weisschuh, N., Mardin, C.Y., Gibson, J., Zegers, R.H., Hofman, A., de Jong, P.T.V.M., Uitterlinden, A.G., Oostra, B.A., Thorsteinsdottir, U., Gramer, E., Welgen-Lussen, U.C., Kirwan, J.F., Bergen, A.A.B., Reis, A., Stefansson, K., Lotery, A.J., Vingerling, J.R., Jansonius, N.M., Klaver, C.C., and Van Duijn, C.M.

Published
2011

28. Variants in ASB10 are associated with open-angle glaucoma

Author

Pasutto, F., primary, Keller, K. E., additional, Weisschuh, N., additional, Sticht, H., additional, Samples, J. R., additional, Yang, Y.-F., additional, Zenkel, M., additional, Schlotzer-Schrehardt, U., additional, Mardin, C. Y., additional, Frezzotti, P., additional, Edmunds, B., additional, Kramer, P. L., additional, Gramer, E., additional, Reis, A., additional, Acott, T. S., additional, and Wirtz, M. K., additional

Published
2011
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33. Substitution and Michael reactions of bicyclic tetronic, tetramic and thiotetronic esters

Author

Bertucco, A, Brennen, J, Fachini, M, Kluge, S, Murphy, Pj, Pasutto, F, Signorini, Raffaella, Williams, Hl, J. C. h. e. m. S. o. c. Perkin T. r. a. n. s. 1., and 1831, 1833

Subjects
chemistry.chemical_classification, Acetic anhydride, chemistry.chemical_compound, chemistry, Nucleophile, Bicyclic molecule, Furan, Heteroatom, Thiolactone, Michael reaction, Organic chemistry, Lactone
Abstract

The 1,4-addition of several heteroatom and carbon nucleophiles to the bicyclic structures 1, 2, 3 and 13 are reported along with the conversion of the resultant adducts to substituted tetronic, tetramic, thiotetronic acids and butenolides; a novel reaction mechanism has been observed for the iodotrimethylsilane (TMSI) or acetic anhydride/magnesium bromide-mediated furan ring-opening reactions of the bicyclic tetronate 1.

Published
1993
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37. Stereoselective metabolism of rac-mexiletine by the fungus Cunninghamella echinulata yields the major human metabolites hydroxymethylmexiletine and p-hydroxymexiletine.

Author

G, Freitag D, T, Foster R, T, Coutts R, A, Pickard M, and M, Pasutto F

Abstract

rac-Mexiletine is an orally effective class 1b antiarrhythmic agent used to treat ventricular arrhythmias. In vivo experiments have demonstrated. It is predominantly metabolized by the liver with < 10% excreted as unchanged drug. The major mammalian metabolites have been identified as p-hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM). The purpose of our study was to determine whether the fungus Cunninghamella echinulata, which possesses a cytochrome P450 system analogous to that found in humans, could be used as a suitable in vitro model for studying the oxidative metabolism of rac-mexiletine. To accomplish this, a high performance liquid chromatographic assay was used that was capable of simultaneously quantifying the enantiomers of mexiletine, HMM, and PHM. Utilizing this procedure, it was demonstrated that C. echinulata stereoselectively converted rac-mexiletine into HMM (4% of added drug) and PHM (32% of added drug) after an incubation period of 50 hr. In addition, metabolite biosynthesis could be optimized by altering fermentation media components. Seven media values and seven pH values were evaluated. It was determined that a medium at pH 7.0 containing yeast extract and sucrose yielded optimal amounts of metabolites.

Published
1997

39. The metabolism of selected organic compounds by microorganisms in the Athabasca River

Author

Westlake, D. W. S., Coutts, R. T., Nix, P. G., and Pasutto, F. M.

Subjects
Oil Sands, Tar Sands, Organics, AOSERP, AOSERP Report 121, Athabasca River, AOSERP WS 2.3.1, Microbiology, Alberta
Abstract

In this study, the ability of microorganisms to degrade selected organic substrates in samples of Athabasca River water and water-sediment has been determined. Analysis of laboratory-incubated samples using gas chromatography/ mass spectrometry has shown that trace amounts (100 µg/L) of m-cresol and camphor can be quantified and a \"50% depletion time\" determined. Sites both above the oil sands region and downstream from the area of mining activity had a noticeably high level of activity regarding the degradation of these compounds. In addition, the incubation of samples taken along a transect of the river just downstream from the oil sands plants showed higher rates of microbial degradation on the west bank where effluents and drainage would likely be concentrated. Other substrates, 2,6-xylenol and methylsalicylate, were not suitable for degradation studies due to depletion caused by non-biological processes. Analysis of 14C-labelled substrates indicated that \"natural\" compounds (amino acids and starch) were degraded more quickly than hydrocarbons and that significant degradation of hydrocarbons occurred only after nutrient supplementation.

Published
1981
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