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2. Structure of the Hir histone chaperone complex

Author

Kim, Hee Jong, Szurgot, Mary R., van Eeuwen, Trevor, Ricketts, M. Daniel, Basnet, Pratik, Zhang, Athena L., Vogt, Austin, Sharmin, Samah, Kaplan, Craig D., Garcia, Benjamin A., Marmorstein, Ronen, and Murakami, Kenji

Published
2024
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3. Sleep-Related Hypoxia, Right Ventricular Dysfunction, and Survival in Patients With Group 1 Pulmonary Arterial Hypertension

Author

Lowery, Megan M., primary, Hill, Nicholas S., additional, Wang, Lu, additional, Rosenzweig, Erika B., additional, Bhat, Aparna, additional, Erzurum, Serpil, additional, Finet, J. Emanuel, additional, Jellis, Christine L., additional, Kaur, Sunjeet, additional, Kwon, Deborah H., additional, Nawabit, Rawan, additional, Radeva, Milena, additional, Beck, Gerald J., additional, Frantz, Robert P., additional, Hassoun, Paul M., additional, Hemnes, Anna R., additional, Horn, Evelyn M., additional, Leopold, Jane A., additional, Rischard, Franz P., additional, Mehra, Reena, additional, Hill, N., additional, Xiao, L., additional, Fu, Y.-P., additional, Postow, L., additional, Schmetter, B., additional, Stanton, K., additional, Tian, X., additional, Gray, M., additional, Wong, B., additional, Leopold, J., additional, Waxman, A., additional, DiCarli, M., additional, Lawler, L., additional, Maron, B., additional, Segrera, S., additional, Systrom, D., additional, Yu, P., additional, Rosenzweig, E.B., additional, Arcasoy, S., additional, Brady, D., additional, Chung, W., additional, Payne, D., additional, Grunig, G., additional, Haythe, J., additional, Krishnan, U., additional, Horn, E., additional, Akat, K., additional, Borczuk, A., additional, Devereux, R., additional, Gordon, J., additional, Kaner, R., additional, Karas, M., additional, Min, J., additional, Narula, N., additional, Ricketts, M., additional, Sobol, I., additional, Spiera, R., additional, Singh, H., additional, Tuschl, T., additional, Weinsaft, J., additional, Hassoun, P., additional, Mathai, S., additional, Barnes, K., additional, Damico, R., additional, Enobun, B., additional, Gao, L., additional, Halushka, M., additional, Kass, D., additional, Kolb, T., additional, Lin, T., additional, Tedford, R., additional, Zimmerman, S., additional, Frantz, R., additional, Behfar, A., additional, Block, L., additional, Borlaug, B., additional, Durst, L., additional, Foley, T., additional, Hammer, T., additional, Johnson, B., additional, Johnson, G., additional, Kane, G., additional, Krowka, M., additional, McNallan, A., additional, Olson, T., additional, Redfield, M., additional, Rohwer, K., additional, Terzic, A., additional, Williamson, E., additional, Rischard, F., additional, Yuan, J., additional, Abidov, A., additional, Garcia, J., additional, Cordery, A., additional, Desai, A., additional, Erickson, H., additional, Hansen, L., additional, Khalpey, Z., additional, Knox, K., additional, Lussier, Y., additional, Simon, M., additional, Vanderpool, R., additional, Hemnes, A., additional, Newman, J., additional, Austin, E., additional, Brittain, E., additional, Cunningham, J., additional, LaRochelle, C., additional, Pugh, M., additional, Robbins, I., additional, Wheeler, L., additional, Beck, G., additional, Erzurum, S., additional, Aldred, M., additional, Asosingh, K., additional, Barnard, J., additional, Collart, C., additional, Comhair, S., additional, DiFilippo, F., additional, Drinko, J., additional, Dweik, R., additional, Flinn, A., additional, Geraci, M., additional, Hu, B., additional, Jaber, W., additional, Jacob, M., additional, Jellis, C., additional, Kalhan, S., additional, Kassimatis, K., additional, Kirsop, J., additional, Koo, M., additional, Kwon, D., additional, Larive, B., additional, Lempel, J., additional, Li, M., additional, MacKrell, J., additional, Matuska, B., additional, McCarthy, K., additional, Mehra, R., additional, Neumann, D., additional, Nawabit, R., additional, Olman, M., additional, Park, M., additional, Radeva, M., additional, Sharp, J., additional, Sherer, S., additional, Tang, W., additional, Thomas, J., additional, Wiggins, K., additional, Willard, B., additional, Rounds, S., additional, Benza, R., additional, Bull, T., additional, Cadigan, J., additional, Fang, J., additional, Gomberg-Maitland, M., additional, and Page, G., additional

Published
2023
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7. Public Health and the BSE Epidemic

Author

Ricketts, M. N., Compans, R. W., editor, Cooper, M. D., editor, Honjo, T., editor, Koprowski, H., editor, Melchers, F., editor, Oldstone, M. B. A., editor, Olsnes, S., editor, Potter, M., editor, Vogt, P. K., editor, Wagner, H., editor, and Harris, David A., editor

Published
2004
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8. Autophagy mediates degradation of nuclear lamina

Author

Dou, Zhixun, Xu, Caiyue, Donahue, Greg, Shimi, Takeshi, Pan, Ji-An, Zhu, Jiajun, Ivanov, Andrejs, Capell, Brian C., Drake, Adam M., Shah, Parisha P., Catanzaro, Joseph M., Ricketts, M. Daniel, Lamark, Trond, Adam, Stephen A., Marmorstein, Ronen, Zong, Wei-Xing, Johansen, Terje, Goldman, Robert D., Adams, Peter D., and Berger, Shelley L.

Subjects
Carcinogenesis -- Genetic aspects, Autophagy (Cytology) -- Genetic aspects -- Health aspects, Cellular proteins -- Properties, Disease susceptibility -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Macroautophagy (hereafter referred to as autophagy) is a catabolic membrane trafficking process that degrades a variety of cellular constituents and is associated with human diseases (1-3). Although extensive studies have [...]

Published
2015

9. THE GEOSTATIONARY EARTH RADIATION BUDGET PROJECT

Author

Harries, J. E., Russell, J. E., Hanafin, J. A., Brindley, H., Futyan, J., Rufus, J., Kellock, S., Matthews, G., Wrigley, R., Last, A., Mueller, J., Mossavati, R., Ashmall, J., Sawyer, E., Parker, D., Caldwell, M., Allan, P. M., Smith, A., Bates, M. J., Coan, B., Stewart, B. C., Lepine, D. R., Cornwall, L. A., Corney, D. R., Ricketts, M. J., Drummond, D., Smart, D., Cutler, R., Dewitte, S., Clerbaux, N., Gonzalez, L., Ipe, A., Bertrand, C., Joukoff, A., Crommelynck, D., Nelms, N., Llewellyn-Jones, D. T., Butcher, G., Smith, G. L., Szewczyk, Z. P., Mlynczak, P. E., Slingo, A., Allan, R. P., and Ringer, M. A.

Published
2005

10. Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data

Author

Romagnoni, A., Jegou, S., Van Steen, K., Wainrib, G., Hugot, J. -P., Peyrin-Biroulet, L., Chamaillard, M., Colombel, J. -F., Cottone, M., D'Amato, M., D'Inca, R., Halfvarson, J., Henderson, P., Karban, A., Kennedy, N. A., Khan, M. A., Lemann, M., Levine, A., Massey, D., Milla, M., S. M. E., Ng, Oikonomou, I., Peeters, H., Proctor, D. D., Rahier, J. -F., Rutgeerts, P., Seibold, F., Stronati, L., Taylor, K. M., Torkvist, L., Ublick, K., Van Limbergen, J., Van Gossum, A., Vatn, M. H., Zhang, H., Zhang, W., Andrews, J. M., Bampton, P. A., Barclay, M., Florin, T. H., Gearry, R., Krishnaprasad, K., Lawrance, I. C., Mahy, G., Montgomery, G. W., Radford-Smith, G., Roberts, R. L., Simms, L. A., Hanigan, K., Croft, A., Amininijad, L., Cleynen, I., Dewit, O., Franchimont, D., Georges, M., Laukens, D., Theatre, E., Vermeire, S., Aumais, G., Baidoo, L., Barrie, A. M., Beck, K., Bernard, E. -J., Binion, D. G., Bitton, A., Brant, S. R., Cho, J. H., Cohen, A., Croitoru, K., Daly, M. J., Datta, L. W., Deslandres, C., Duerr, R. H., Dutridge, D., Ferguson, J., Fultz, J., Goyette, P., Greenberg, G. R., Haritunians, T., Jobin, G., Katz, S., Lahaie, R. G., Mcgovern, D. P., Nelson, L., S. M., Ng, Ning, K., Pare, P., Regueiro, M. D., Rioux, J. D., Ruggiero, E., Schumm, L. P., Schwartz, M., Scott, R., Sharma, Y., Silverberg, M. S., Spears, D., Steinhart, A. H., Stempak, J. M., Swoger, J. M., Tsagarelis, C., Zhang, C., Zhao, H., Aerts, J., Ahmad, T., Arbury, H., Attwood, A., Auton, A., Ball, S. G., Balmforth, A. J., Barnes, C., Barrett, J. C., Barroso, I., Barton, A., Bennett, A. J., Bhaskar, S., Blaszczyk, K., Bowes, J., Brand, O. J., Braund, P. S., Bredin, F., Breen, G., Brown, M. J., Bruce, I. N., Bull, J., Burren, O. S., Burton, J., Byrnes, J., Caesar, S., Cardin, N., Clee, C. M., Coffey, A. J., MC Connell, J., Conrad, D. F., Cooper, J. D., Dominiczak, A. F., Downes, K., Drummond, H. E., Dudakia, D., Dunham, A., Ebbs, B., Eccles, D., Edkins, S., Edwards, C., Elliot, A., Emery, P., Evans, D. M., Evans, G., Eyre, S., Farmer, A., Ferrier, I. N., Flynn, E., Forbes, A., Forty, L., Franklyn, J. A., Frayling, T. M., Freathy, R. M., Giannoulatou, E., Gibbs, P., Gilbert, P., Gordon-Smith, K., Gray, E., Green, E., Groves, C. J., Grozeva, D., Gwilliam, R., Hall, A., Hammond, N., Hardy, M., Harrison, P., Hassanali, N., Hebaishi, H., Hines, S., Hinks, A., Hitman, G. A., Hocking, L., Holmes, C., Howard, E., Howard, P., Howson, J. M. M., Hughes, D., Hunt, S., Isaacs, J. D., Jain, M., Jewell, D. P., Johnson, T., Jolley, J. D., Jones, I. R., Jones, L. A., Kirov, G., Langford, C. F., Lango-Allen, H., Lathrop, G. M., Lee, J., Lee, K. L., Lees, C., Lewis, K., Lindgren, C. M., Maisuria-Armer, M., Maller, J., Mansfield, J., Marchini, J. L., Martin, P., Massey, D. C., Mcardle, W. L., Mcguffin, P., Mclay, K. E., Mcvean, G., Mentzer, A., Mimmack, M. L., Morgan, A. E., Morris, A. P., Mowat, C., Munroe, P. B., Myers, S., Newman, W., Nimmo, E. R., O'Donovan, M. C., Onipinla, A., Ovington, N. R., Owen, M. J., Palin, K., Palotie, A., Parnell, K., Pearson, R., Pernet, D., Perry, J. R., Phillips, A., Plagnol, V., Prescott, N. J., Prokopenko, I., Quail, M. A., Rafelt, S., Rayner, N. W., Reid, D. M., Renwick, A., Ring, S. M., Robertson, N., Robson, S., Russell, E., Clair, D. S., Sambrook, J. G., Sanderson, J. D., Sawcer, S. J., Schuilenburg, H., Scott, C. E., Seal, S., Shaw-Hawkins, S., Shields, B. M., Simmonds, M. J., Smyth, D. J., Somaskantharajah, E., Spanova, K., Steer, S., Stephens, J., Stevens, H. E., Stirrups, K., Stone, M. A., Strachan, D. P., Su, Z., Symmons, D. P. M., Thompson, J. R., Thomson, W., Tobin, M. D., Travers, M. E., Turnbull, C., Vukcevic, D., Wain, L. V., Walker, M., Walker, N. M., Wallace, C., Warren-Perry, M., Watkins, N. A., Webster, J., Weedon, M. N., Wilson, A. G., Woodburn, M., Wordsworth, B. P., Yau, C., Young, A. H., Zeggini, E., Brown, M. A., Burton, P. R., Caulfield, M. J., Compston, A., Farrall, M., Gough, S. C. L., Hall, A. S., Hattersley, A. T., Hill, A. V. S., Mathew, C. G., Pembrey, M., Satsangi, J., Stratton, M. R., Worthington, J., Hurles, M. E., Duncanson, A., Ouwehand, W. H., Parkes, M., Rahman, N., Todd, J. A., Samani, N. J., Kwiatkowski, D. P., Mccarthy, M. I., Craddock, N., Deloukas, P., Donnelly, P., Blackwell, J. M., Bramon, E., Casas, J. P., Corvin, A., Jankowski, J., Markus, H. S., Palmer, C. N., Plomin, R., Rautanen, A., Trembath, R. C., Viswanathan, A. C., Wood, N. W., Spencer, C. C. A., Band, G., Bellenguez, C., Freeman, C., Hellenthal, G., Pirinen, M., Strange, A., Blackburn, H., Bumpstead, S. J., Dronov, S., Gillman, M., Jayakumar, A., Mccann, O. T., Liddle, J., Potter, S. C., Ravindrarajah, R., Ricketts, M., Waller, M., Weston, P., Widaa, S., Whittaker, P., Romagnoni, A., Jegou, S., Van Steen, K., Wainrib, G., Hugot, J. -P., Peyrin-Biroulet, L., Chamaillard, M., Colombel, J. -F., Cottone, M., D'Amato, M., D'Inca, R., Halfvarson, J., Henderson, P., Karban, A., Kennedy, N. A., Khan, M. A., Lemann, M., Levine, A., Massey, D., Milla, M., Ng, S. M. E., Oikonomou, I., Peeters, H., Proctor, D. D., Rahier, J. -F., Rutgeerts, P., Seibold, F., Stronati, L., Taylor, K. M., Torkvist, L., Ublick, K., Van Limbergen, J., Van Gossum, A., Vatn, M. H., Zhang, H., Zhang, W., Andrews, J. M., Bampton, P. A., Barclay, M., Florin, T. H., Gearry, R., Krishnaprasad, K., Lawrance, I. C., Mahy, G., Montgomery, G. W., Radford-Smith, G., Roberts, R. L., Simms, L. A., Hanigan, K., Croft, A., Amininijad, L., Cleynen, I., Dewit, O., Franchimont, D., Georges, M., Laukens, D., Theatre, E., Vermeire, S., Aumais, G., Baidoo, L., Barrie, A. M., Beck, K., Bernard, E. -J., Binion, D. G., Bitton, A., Brant, S. R., Cho, J. H., Cohen, A., Croitoru, K., Daly, M. J., Datta, L. W., Deslandres, C., Duerr, R. H., Dutridge, D., Ferguson, J., Fultz, J., Goyette, P., Greenberg, G. R., Haritunians, T., Jobin, G., Katz, S., Lahaie, R. G., Mcgovern, D. P., Nelson, L., Ng, S. M., Ning, K., Pare, P., Regueiro, M. D., Rioux, J. D., Ruggiero, E., Schumm, L. P., Schwartz, M., Scott, R., Sharma, Y., Silverberg, M. S., Spears, D., Steinhart, A. H., Stempak, J. M., Swoger, J. M., Tsagarelis, C., Zhang, C., Zhao, H., Aerts, J., Ahmad, T., Arbury, H., Attwood, A., Auton, A., Ball, S. G., Balmforth, A. J., Barnes, C., Barrett, J. C., Barroso, I., Barton, A., Bennett, A. J., Bhaskar, S., Blaszczyk, K., Bowes, J., Brand, O. J., Braund, P. S., Bredin, F., Breen, G., Brown, M. J., Bruce, I. N., Bull, J., Burren, O. S., Burton, J., Byrnes, J., Caesar, S., Cardin, N., Clee, C. M., Coffey, A. J., MC Connell, J., Conrad, D. F., Cooper, J. D., Dominiczak, A. F., Downes, K., Drummond, H. E., Dudakia, D., Dunham, A., Ebbs, B., Eccles, D., Edkins, S., Edwards, C., Elliot, A., Emery, P., Evans, D. M., Evans, G., Eyre, S., Farmer, A., Ferrier, I. N., Flynn, E., Forbes, A., Forty, L., Franklyn, J. A., Frayling, T. M., Freathy, R. M., Giannoulatou, E., Gibbs, P., Gilbert, P., Gordon-Smith, K., Gray, E., Green, E., Groves, C. J., Grozeva, D., Gwilliam, R., Hall, A., Hammond, N., Hardy, M., Harrison, P., Hassanali, N., Hebaishi, H., Hines, S., Hinks, A., Hitman, G. A., Hocking, L., Holmes, C., Howard, E., Howard, P., Howson, J. M. M., Hughes, D., Hunt, S., Isaacs, J. D., Jain, M., Jewell, D. P., Johnson, T., Jolley, J. D., Jones, I. R., Jones, L. A., Kirov, G., Langford, C. F., Lango-Allen, H., Lathrop, G. M., Lee, J., Lee, K. L., Lees, C., Lewis, K., Lindgren, C. M., Maisuria-Armer, M., Maller, J., Mansfield, J., Marchini, J. L., Martin, P., Massey, D. C., Mcardle, W. L., Mcguffin, P., Mclay, K. E., Mcvean, G., Mentzer, A., Mimmack, M. L., Morgan, A. E., Morris, A. P., Mowat, C., Munroe, P. B., Myers, S., Newman, W., Nimmo, E. R., O'Donovan, M. C., Onipinla, A., Ovington, N. R., Owen, M. J., Palin, K., Palotie, A., Parnell, K., Pearson, R., Pernet, D., Perry, J. R., Phillips, A., Plagnol, V., Prescott, N. J., Prokopenko, I., Quail, M. A., Rafelt, S., Rayner, N. W., Reid, D. M., Renwick, A., Ring, S. M., Robertson, N., Robson, S., Russell, E., Clair, D. S., Sambrook, J. G., Sanderson, J. D., Sawcer, S. J., Schuilenburg, H., Scott, C. E., Seal, S., Shaw-Hawkins, S., Shields, B. M., Simmonds, M. J., Smyth, D. J., Somaskantharajah, E., Spanova, K., Steer, S., Stephens, J., Stevens, H. E., Stirrups, K., Stone, M. A., Strachan, D. P., Su, Z., Symmons, D. P. M., Thompson, J. R., Thomson, W., Tobin, M. D., Travers, M. E., Turnbull, C., Vukcevic, D., Wain, L. V., Walker, M., Walker, N. M., Wallace, C., Warren-Perry, M., Watkins, N. A., Webster, J., Weedon, M. N., Wilson, A. G., Woodburn, M., Wordsworth, B. P., Yau, C., Young, A. H., Zeggini, E., Brown, M. A., Burton, P. R., Caulfield, M. J., Compston, A., Farrall, M., Gough, S. C. L., Hall, A. S., Hattersley, A. T., Hill, A. V. S., Mathew, C. G., Pembrey, M., Satsangi, J., Stratton, M. R., Worthington, J., Hurles, M. E., Duncanson, A., Ouwehand, W. H., Parkes, M., Rahman, N., Todd, J. A., Samani, N. J., Kwiatkowski, D. P., Mccarthy, M. I., Craddock, N., Deloukas, P., Donnelly, P., Blackwell, J. M., Bramon, E., Casas, J. P., Corvin, A., Jankowski, J., Markus, H. S., Palmer, C. N., Plomin, R., Rautanen, A., Trembath, R. C., Viswanathan, A. C., Wood, N. W., Spencer, C. C. A., Band, G., Bellenguez, C., Freeman, C., Hellenthal, G., Pirinen, M., Strange, A., Blackburn, H., Bumpstead, S. J., Dronov, S., Gillman, M., Jayakumar, A., Mccann, O. T., Liddle, J., Potter, S. C., Ravindrarajah, R., Ricketts, M., Waller, M., Weston, P., Widaa, S., Whittaker, P., Daly, Mark J. [0000-0002-0949-8752], Apollo - University of Cambridge Repository, Hugot, Jean-Pierre [0000-0002-8446-6056], UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (MGD) Service de gastro-entérologie, Romagnoni, A, Jegou, S, VAN STEEN, Kristel, Wainrib, G, Hugot, JP, Peyrin-Biroulet, L, Chamaillard, M, Colombel, JF, Cottone, M, D'Amato, M, D'Inca, R, Halfvarson, J, Henderson, P, Karban, A, Kennedy, NA, Khan, MA, Lemann, M, Levine, A, Massey, D, Milla, M, Ng, SME, Oikonomou, I, Peeters, H, Proctor, DD, Rahier, JF, Rutgeerts, P, Seibold, F, Stronati, L, Taylor, KM, Torkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, MH, Zhang, H, Zhang, W, Andrews, JM, Bampton, PA, Barclay, M, Florin, TH, Gearry, R, Krishnaprasad, K, Lawrance, IC, Mahy, G, Montgomery, GW, Radford-Smith, G, Roberts, RL, Simms, LA, Hanigan, K, Croft, A, Amininijad, L, Cleynen, I, Dewit, O, Franchimont, D, Georges, M, Laukens, D, Theatre, E, Vermeire, S, Aumais, G, Baidoo, L, Barrie, AM, Beck, K, Bernard, EJ, Binion, DG, Bitton, A, Brant, SR, Cho, JH, Cohen, A, Croitoru, K, Daly, MJ, Datta, LW, Deslandres, C, Duerr, RH, Dutridge, D, Ferguson, J, Fultz, J, Goyette, P, Greenberg, GR, Haritunians, T, Jobin, G, Katz, S, Lahaie, RG, McGovern, DP, Nelson, L, Ng, SM, Ning, K, Pare, P, Regueiro, MD, Rioux, JD, Ruggiero, E, Schumm, LP, Schwartz, M, Scott, R, Sharma, Y, Silverberg, MS, Spears, D, Steinhart, AH, Stempak, JM, Swoger, JM, Tsagarelis, C, Zhang, C, Zhao, HY, AERTS, Jan, Ahmad, T, Arbury, H, Attwood, A, Auton, A, Ball, SG, Balmforth, AJ, Barnes, C, Barrett, JC, Barroso, I, Barton, A, Bennett, AJ, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, OJ, Braund, PS, Bredin, F, Breen, G, Brown, MJ, Bruce, IN, Bull, J, Burren, OS, Burton, J, Byrnes, J, Caesar, S, Cardin, N, Clee, CM, Coffey, AJ, Mc Connell, J, Conrad, DF, Cooper, JD, Dominiczak, AF, Downes, K, Drummond, HE, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, DM, Evans, G, Eyre, S, Farmer, A, Ferrier, IN, Flynn, E, Forbes, A, Forty, L, Franklyn, JA, Frayling, TM, Freathy, RM, Giannoulatou, E, Gibbs, P, Gilbert, P, Gordon-Smith, K, Gray, E, Green, E, Groves, CJ, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, GA, Hocking, L, Holmes, C, Howard, E, Howard, P, Howson, JMM, Hughes, D, Hunt, S, Isaacs, JD, Jain, M, Jewell, DP, Johnson, T, Jolley, JD, Jones, IR, Jones, LA, Kirov, G, Langford, CF, Lango-Allen, H, Lathrop, GM, Lee, J, Lee, KL, Lees, C, Lewis, K, Lindgren, CM, Maisuria-Armer, M, Maller, J, Mansfield, J, Marchini, JL, Martin, P, Massey, DCO, McArdle, WL, McGuffin, P, McLay, KE, McVean, G, Mentzer, A, Mimmack, ML, Morgan, AE, Morris, AP, Mowat, C, Munroe, PB, Myers, S, Newman, W, Nimmo, ER, O'Donovan, MC, Onipinla, A, Ovington, NR, Owen, MJ, Palin, K, Palotie, A, Parnell, K, Pearson, R, Pernet, D, Perry, JRB, Phillips, A, Plagnol, V, Prescott, NJ, Prokopenko, I, Quail, MA, Rafelt, S, Rayner, NW, Reid, DM, Renwick, A, Ring, SM, Robertson, N, Robson, S, Russell, E, St Clair, D, Sambrook, JG, Sanderson, JD, Sawcer, SJ, Schuilenburg, H, Scott, CE, Seal, S, Shaw-Hawkins, S, Shields, BM, Simmonds, MJ, Smyth, DJ, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, HE, Stirrups, K, Stone, MA, Strachan, DP, Su, Z, Symmons, DPM, Thompson, JR, Thomson, W, Tobin, MD, Travers, ME, Turnbull, C, Vukcevic, D, Wain, LV, Walker, M, Walker, NM, Wallace, C, Warren-Perry, M, Watkins, NA, Webster, J, Weedon, MN, Wilson, AG, Woodburn, M, Wordsworth, BP, Yau, C, Young, AH, Zeggini, E, Brown, MA, Burton, PR, Caulfield, MJ, Compston, A, Farrall, M, Gough, SCL, Hall, AS, Hattersley, AT, Hill, AVS, Mathew, CG, Pembrey, M, Satsangi, J, Stratton, MR, Worthington, J, Hurles, ME, Duncanson, A, Ouwehand, WH, Parkes, M, Rahman, N, Todd, JA, Samani, NJ, Kwiatkowski, DP, McCarthy, MI, Craddock, N, Deloukas, P, Donnelly, P, Blackwell, JM, Bramon, E, Casas, JP, Corvin, A, Jankowski, J, Markus, HS, Palmer, CNA, Plomin, R, Rautanen, A, Trembath, RC, Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Pirinen, M, Strange, A, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, and Kwiatkowski, D

Subjects
Male, 692/4020/1503/257/1402, Genotype, Genotyping Techniques, LOCI, 45/43, lcsh:Medicine, Polymorphism, Single Nucleotide, Crohn's disease, genetics, genome wide association, Article, Deep Learning, Crohn Disease, INDEL Mutation, Genetics research, Humans, genetics, Genetic Predisposition to Disease, 129, lcsh:Science, Alleles, Science & Technology, genome wide association, RISK PREDICTION, 45, Models, Genetic, lcsh:R, Decision Trees, 692/308/2056, ASSOCIATION, Multidisciplinary Sciences, Crohn's disease, Logistic Models, Nonlinear Dynamics, ROC Curve, Area Under Curve, Science & Technology - Other Topics, lcsh:Q, Female, Neural Networks, Computer, INFLAMMATORY-BOWEL-DISEASE, Genome-Wide Association Study
Abstract

Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers. Tis work was supported by Fondation pour la Recherche Médical (ref DEI20151234405) and Investissements d’Avenir programme ANR-11-IDEX-0005-02, Sorbonne Paris Cite, Laboratoire d’excellence INFLAMEX. Te authors thank the students that participated to the wisdom of the crowd exercise.

Published
2019

12. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

Author

Patsopoulos, NA, Baranzini, SE, Santaniello, A, Shoostari, P, Cotsapas, C, Wong, G, Beecham, AH, James, T, Replogle, J, Vlachos, IS, McCabe, C, Pers, TH, Brandes, A, White, C, Keenan, B, Cimpean, M, Winn, P, Panteliadis, IP, Robbins, A, Andlauer, TFM, Zarzycki, O, Dubois, B, Goris, A, Sondergaard, HB, Sellebjerg, F, Sorensen, PS, Ullum, H, Thorner, LW, Saarela, J, Cournu-Rebeix, I, Damotte, V, Fontaine, B, Guillot-Noel, L, Lathrop, M, Vukusic, S, Berthele, A, Pongratz, V, Gasperi, C, Graetz, C, Grummel, V, Hemmer, B, Hoshi, M, Knier, B, Korn, T, Lill, CM, Luessi, F, Muhlau, M, Zipp, F, Dardiotis, E, Agliardi, C, Amoroso, A, Barizzone, N, Benedetti, MD, Bernardinelli, L, Cavalla, P, Clarelli, F, Comi, G, Cusi, D, Esposito, F, Ferre, L, Galimberti, D, Guaschino, C, Leone, MA, Martinelli, V, Moiola, L, Salvetti, M, Sorosina, M, Vecchio, D, Zauli, A, Santoro, S, Mancini, N, Zuccala, M, Mescheriakova, J, van Duijn, C, Bos, SD, Celius, EG, Spurkland, A, Comabella, M, Montalban, X, Alfredsson, L, Bomfim, IL, Gomez-Cabrero, D, Hillert, J, Jagodic, M, Linden, M, Piehl, F, Jelcic, I, Martin, R, Sospedra, M, Baker, A, Ban, M, Hawkins, C, Hysi, P, Kalra, S, Karpe, F, Khadake, J, Lachance, G, Molyneux, P, Neville, M, Thorpe, J, Bradshaw, E, Caillier, SJ, Calabresi, P, Cree, BAC, Cross, A, Davis, M, de Bakker, PWI, Delgado, S, Dembele, M, Edwards, K, Fitzgerald, K, Frohlich, IY, Gourraud, PA, Haines, JL, Hakonarson, H, Kimbrough, D, Isobe, N, Konidari, I, Lathi, E, Lee, MH, Li, T, An, D, Zimmer, A, Madireddy, L, Manrique, CP, Mitrovic, M, Olah, M, Patrick, E, Pericak-Vance, MA, Piccio, L, Schaefer, C, Weiner, H, Lage, K, Scott, RJ, Lechner-Scott, J, Leal, R, Moscato, P, Booth, DR, Stewart, GJ, Vucic, S, Pame, G, BamettO, M, Mason, D, GriffithS, L, Broadley, S, Tajouri, L, Baxter, A, Slee, M, Taylor, BV, Charlesworth, J, Kilpatrick, TJ, Rubio, J, Jokubaitis, V, Wiley, J, Butzkueven, H, Leslie, S, Motyer, A, Stankovich, J, Carroll, WM, Kermode, AG, Edrin, M, Barclay, M, Peyrin-Biroulet, L, Chamaillard, M, Colombe, JF, Cottone, M, Croft, A, D'Inca, R, Halfvarson, J, Hanigan, K, Henderson, P, Hugot, JP, Karban, A, Kennedy, NA, Khan, MA, Lemann, M, Levine, A, Massey, D, Milla, M, Motoey, GW, Ng, SME, Oikonomnou, J, Peeters, H, Proctor, DD, Rahier, JF, Roberts, R, Rutgeerts, P, Seibold, F, Stronati, L, Taylor, KM, Torkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, MH, Zhang, H, Zhang, W, Donnelly, P, Barroso, I, Blackwe, 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, Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Sul, Z, Vukcevic, DA, 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, Compston, A, Hafler, D, Harbo, HF, Hauser, SL, Stewart, G, D'Alfonso, S, Hadjigeorgiou, G, Taylor, B, Barcellos, LF, Booth, D, Hintzen, R, Kockum, I, Martinelli-Boneschi, F, McCauley, JL, Oksenberg, JR, Oturai, A, Sawcer, S, Ivinson, AJ, Olsson, T, De Jager, PL, Patsopoulos, Na, Baranzini, Se, Santaniello, A, Shoostari, P, Cotsapas, C, Wong, G, Beecham, Ah, James, T, Replogle, J, Vlachos, I, Mccabe, C, Pers, Th, Brandes, A, White, C, Keenan, B, Cimpean, M, Winn, P, Panteliadis, Ip, Robbins, A, Andlauer, Tfm, Zarzycki, O, Dubois, B, Goris, A, Sondergaard, Hb, Sellebjerg, F, Sorensen, P, Ullum, H, Thorner, Lw, Saarela, J, Cournu-Rebeix, I, Damotte, V, Fontaine, B, Guillot-Noel, L, Lathrop, M, Vukusic, S, Berthele, A, Pongratz, V, Gasperi, C, Graetz, C, Grummel, V, Hemmer, B, Hoshi, M, Knier, B, Korn, T, Lill, Cm, Luessi, F, Muhlau, M, Zipp, F, Dardiotis, E, Agliardi, C, Amoroso, A, Barizzone, N, Benedetti, Md, Bernardinelli, L, Cavalla, P, Clarelli, F, Comi, G, Cusi, D, Esposito, F, Ferre, L, Galimberti, D, Guaschino, C, Leone, Ma, Martinelli, V, Moiola, L, Salvetti, M, Sorosina, M, Vecchio, D, Zauli, A, Santoro, S, Mancini, N, Zuccala, M, Mescheriakova, J, van Duijn, C, Bos, Sd, Celius, Eg, Spurkland, A, Comabella, M, Montalban, X, Alfredsson, L, Bomfim, Il, Gomez-Cabrero, D, Hillert, J, Jagodic, M, Linden, M, Piehl, F, Jelcic, I, Martin, R, Sospedra, M, Baker, A, Ban, M, Hawkins, C, Hysi, P, Kalra, S, Karpe, F, Khadake, J, Lachance, G, Molyneux, P, Neville, M, Thorpe, J, Bradshaw, E, Caillier, Sj, Calabresi, P, Cree, Bac, Cross, A, Davis, M, de Bakker, Pwi, Delgado, S, Dembele, M, Edwards, K, Fitzgerald, K, Frohlich, Iy, Gourraud, Pa, Haines, Jl, Hakonarson, H, Kimbrough, D, Isobe, N, Konidari, I, Lathi, E, Lee, Mh, Li, T, An, D, Zimmer, A, Madireddy, L, Manrique, Cp, Mitrovic, M, Olah, M, Patrick, E, Pericak-Vance, Ma, Piccio, L, Schaefer, C, Weiner, H, Lage, K, Scott, Rj, Lechner-Scott, J, Leal, R, Moscato, P, Booth, Dr, Stewart, Gj, Vucic, S, Pame, G, Bametto, M, Mason, D, Griffiths, L, Broadley, S, Tajouri, L, Baxter, A, Slee, M, Taylor, Bv, Charlesworth, J, Kilpatrick, Tj, Rubio, J, Jokubaitis, V, Wiley, J, Butzkueven, H, Leslie, S, Motyer, A, Stankovich, J, Carroll, Wm, Kermode, Ag, Edrin, M, Barclay, M, Peyrin-Biroulet, L, Chamaillard, M, Colombe, Jf, Cottone, M, Croft, A, D'Inca, R, Halfvarson, J, Hanigan, K, Henderson, P, Hugot, Jp, Karban, A, Kennedy, Na, Khan, Ma, Lemann, M, Levine, A, Massey, D, Milla, M, Motoey, Gw, Ng, Sme, Oikonomnou, J, Peeters, H, Proctor, Dd, Rahier, Jf, Roberts, R, Rutgeerts, P, Seibold, F, Stronati, L, Taylor, Km, Torkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, Mh, Zhang, H, Zhang, W, Donnelly, P, Barroso, I, Blackwe, Jm, Bramon, E, Brown, Ma, Casas, Jp, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, H, Mathew, Cg, Palmer, Cna, Plomin, R, Rautanen, A, Sawcer, Sj, Trembath, Rc, Viswanathan, Ac, Wood, Nw, Spencer, Cca, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Sul, Z, Vukcevic, Da, 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, Compston, A, Hafler, D, Harbo, Hf, Hauser, Sl, Stewart, G, D'Alfonso, S, Hadjigeorgiou, G, Taylor, B, Barcellos, Lf, Booth, D, Hintzen, R, Kockum, I, Martinelli-Boneschi, F, Mccauley, Jl, Oksenberg, Jr, Oturai, A, Sawcer, S, Ivinson, Aj, Olsson, T, De Jager, Pl, Neurology, and Immunology

Subjects
0301 basic medicine, Multiple Sclerosis, Quantitative Trait Loci, Inheritance Patterns, Cell Cycle Proteins, Genome-wide association study, Biology, Major histocompatibility complex, Polymorphism, Single Nucleotide, Major Histocompatibility Complex, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Immune system, Gene Frequency, Autoimmune Process, medicine, Humans, RNA-Seq, X chromosome, Genetics, Chromosomes, Human, X, Multidisciplinary, Microglia, Multiple sclerosis, GTPase-Activating Proteins, Chromosome Mapping, Genomics, medicine.disease, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Genetic Loci, Case-Control Studies, biology.protein, Genome-Wide Association Study, 030217 neurology & neurosurgery
Abstract

Genetic roots of multiple sclerosis The genetics underlying who develops multiple sclerosis (MS) have been difficult to work out. Examining more than 47,000 cases and 68,000 controls with multiple genome-wide association studies, the International Multiple Sclerosis Genetics Consortium identified more than 200 risk loci in MS (see the Perspective by Briggs). Focusing on the best candidate genes, including a model of the major histocompatibility complex region, the authors identified statistically independent effects at the genome level. Gene expression studies detected that every major immune cell type is enriched for MS susceptibility genes and that MS risk variants are enriched in brain-resident immune cells, especially microglia. Up to 48% of the genetic contribution of MS can be explained through this analysis. Science , this issue p. eaav7188 ; see also p. 1383

Published
2019

13. Deeper snow increases the net soil organic carbon accrual rate in moist acidic tussock tundra:²¹⁰Pb evidence from Arctic Alaska

Author

DeFranco, K. C. (Karyn C.), Ricketts, M. P. (Michael P.), Blanc-Betes, E. (Elena), Welker, J. M. (Jeffrey M.), Gonzalez-Meler, M. A. (Miquel A.), and Sturchio, N. C. (Neil C.)

Subjects
Arctic Alaska, tundra, carbon, Pb-210, snow depth
Abstract

The net change in the carbon inventory of arctic tundra remains uncertain as global warming leads to shifts in arctic water and carbon cycles. To better understand the response of arctic tundra carbon to changes in winter precipitation amount, we investigated soil depth profiles of carbon concentration and radionuclide activities (⁷Be, ¹³⁷Cs, ²¹⁰Pb, and ²⁴¹Am) in the active layer of a twenty-two-year winter snow depth manipulation experiment in moist acidic tussock tundra at Toolik Lake, Alaska. Depth correlations of cumulative carbon dry mass (g cm⁻²) vs. unsupported ²¹⁰Pb activity (mBq g⁻¹) were examined using a modified constant rate of supply (CRS) model. Results were best fit by two-slope CRS models indicating an apparent step temporal increase in the accumulation rate of soil organic carbon. Most of the best-fit model chronologies indicated that the increase in carbon accumulation rate apparently began and persisted after snow fence construction in 1994. The inhomogeneous nature of permafrost soils and their relatively low net carbon accumulation rates make it challenging to establish robust chronologic records. Nonetheless, the data obtained in this study support a decadal-scale increase in net soil organic carbon accumulation rate in the active layer of arctic moist acidic tussock tundra under conditions of increased winter precipitation.

Published
2020

15. Book reviews

Author

Nerlove, M., Yamashige, S., Magnusson, L., Baldwin, R., Ricketts, M., Güth, W., and Beckmann, M.

Published
1997
Full Text
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16. Imperial collapse or revolution? A discussion of Brian R. Hamnett’s The End of Iberian Rule on the American Continent, 1770–1830

Author

Ricketts, M, Posada-Carbó, E, Thibaud, C, and Hamnett, B

Abstract

A book forum featuring The End of Iberian Rule on the American Continent, 1770–1830 by Brian R. Hamnett. His 2017 volume argues that the origins of Ibero-American Independence must be found in the interplay between the Spanish and Lusitanian monarchies and the American empires ruled by them. It was internal conflict within these empires that led to independence, not revolution, separatist sentiment, or the emergence of American nation-states. Monica Ricketts, Eduardo Posada-Carbó, Clément Thibaud strongly commend the work while offering constructive criticism and analysis. Reviewers raise questions about socio-cultural forces and changes, the role of politics, the exclusion of an Atlantic perspective, and the lack of attention to revolutionary thought and nationalism. The book is celebrated for its breadth, its historiographical contribution, and the strength of its argument for the continuities from the Iberian monarchies and empires to the nation states that grew out of them. Hamnett responds to the reviewers.

Published
2019

17. 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

18. Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia

Author

Harold, D, Connolly, S, Riley, BP, Kendler, KS, McCarthy, SE, McCombie, WR, Richards, A, Owen, MJ, O'Donovan, MC, Walters, J, Donnelly, P, Bates, L, 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, Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Hopkins, L, 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, Ripke, S, Neale, BM, Walters, JTR, Farh, K-H, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M-L, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chan, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Giegling, I, Giusti-Rodriguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Gratten, J, de Haan, L, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, Hoffmann, P, Hofman, A, Hollegaard, MV, Hougaard, DM, Ikeda, M, Joa, I, Julia, A, Kalaydjieva, L, Karachanak-Yankova, S, Karjalainen, J, Kavanagh, D, Keller, MC, Kennedy, JL, Khrunin, A, Kim, Y, Klovins, J, Knowles, JA, Konte, B, Kucinskas, V, Kucinskiene, ZA, Kuzelova-Ptackova, H, Kahler, AK, Laurent, C, Lee, J, Lee, SH, Legge, SE, Lerer, B, Li, M, Li, T, Liang, K-Y, Lieberman, J, Limborska, S, Loughland, CM, Lubinski, J, Lonnqvist, J, Macek, M, Magnusson, PKE, Maher, BS, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, McCarley, RW, McDonald, C, McIntosh, AM, Meier, S, Meijer, CJ, Melegh, B, Melle, I, Mesholam-Gately, RI, Metspalu, A, Michie, PT, Milani, L, Milanova, V, Mokrab, Y, Morris, DW, Mors, O, Murphy, KC, Murray, RM, Myin-Germeys, I, Muller-Myhsok, B, Nelis, M, Nenadic, I, Nertney, DA, Nestadt, G, Nicodemus, KK, Nikitina-Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, FA, Oh, S-Y, Olincy, A, Olsen, L, Van Os, J, Pantelis, C, Papadimitriou, GN, Papiol, S, Parkhomenko, E, Pato, MT, Paunio, T, Pejovic-Milovancevic, M, Perkins, DO, Pietilainen, O, Pimm, J, Pocklington, AJ, Price, A, Pulver, AE, Purcell, SM, Quested, D, Rasmussen, HB, Reichenberg, A, Reimers, MA, Richards, AL, Roffman, JL, Roussos, P, Ruderfer, DM, Salomaa, V, Sanders, AR, Schall, U, Schubert, CR, Schulze, TG, Schwab, SG, Scolnick, EM, Scott, RJ, Seidman, LJ, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, JM, Sim, K, Slominsky, P, Smoller, JW, So, H-C, Stahl, EA, Stefansson, H, Steinberg, S, Stogmann, E, Straub, RE, Strengman, E, Strohmaier, J, Stroup, TS, Subramaniam, M, Suvisaari, J, Svrakic, DM, Szatkiewicz, JP, Soderman, E, Thirumalai, S, Toncheva, D, Tosato, S, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, BT, Weiser, M, Wildenauer, DB, Williams, NM, Williams, S, Witt, SH, Wolen, AR, Wong, EHM, Wormley, BK, Xi, HS, Zai, CC, Zheng, X, Zimprich, F, Wray, NR, Stefansson, K, Visscher, PM, Adolfsson, R, Andreassen, OA, Blackwood, DHR, Buxbaum, JD, Borglum, AD, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, PV, Gill, M, Gurling, H, Hultman, CM, Iwata, N, Jablensky, AV, Jonsson, EG, Kirov, G, Knight, J, Lencz, T, Levinson, DF, Li, QS, Liu, J, Malhotra, AK, McCarroll, SA, McQuillin, A, Moran, JL, Mortensen, PB, Mowry, BJ, Palotie, A, Pato, CN, Petryshen, TL, Posthuma, D, Rujescu, D, Sham, PC, Sklar, P, St Clair, D, Weinberger, DR, Wendland, JR, Werge, T, Daly, MJ, Sullivan, PF, Harold, D, Connolly, S, Riley, BP, Kendler, KS, McCarthy, SE, McCombie, WR, Richards, A, Owen, MJ, O'Donovan, MC, Walters, J, Donnelly, P, Bates, L, 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, Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Hopkins, L, 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, Ripke, S, Neale, BM, Walters, JTR, Farh, K-H, Holmans, PA, Lee, P, Bulik-Sullivan, B, Collier, DA, Huang, H, Pers, TH, Agartz, I, Agerbo, E, Albus, M, Alexander, M-L, Amin, F, Bacanu, SA, Begemann, M, Belliveau, RA, Bene, J, Bergen, SE, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Byerley, W, Cahn, W, Cai, G, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Chan, RCK, Chan, RYL, Chen, EYH, Cheng, W, Cheung, EFC, Chong, SA, Cloninger, CR, Cohen, D, Cohen, N, Cormican, P, Craddock, N, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, Demontis, D, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Durmishi, N, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedl, M, Friedman, JI, Fromer, M, Genovese, G, Georgieva, L, Giegling, I, Giusti-Rodriguez, P, Godard, S, Goldstein, JI, Golimbet, V, Gopal, S, Gratten, J, de Haan, L, Hammer, C, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, Hoffmann, P, Hofman, A, Hollegaard, MV, Hougaard, DM, Ikeda, M, Joa, I, Julia, A, Kalaydjieva, L, Karachanak-Yankova, S, Karjalainen, J, Kavanagh, D, Keller, MC, Kennedy, JL, Khrunin, A, Kim, Y, Klovins, J, Knowles, JA, Konte, B, Kucinskas, V, Kucinskiene, ZA, Kuzelova-Ptackova, H, Kahler, AK, Laurent, C, Lee, J, Lee, SH, Legge, SE, Lerer, B, Li, M, Li, T, Liang, K-Y, Lieberman, J, Limborska, S, Loughland, CM, Lubinski, J, Lonnqvist, J, Macek, M, Magnusson, PKE, Maher, BS, Maier, W, Mallet, J, Marsal, S, Mattheisen, M, Mattingsdal, M, McCarley, RW, McDonald, C, McIntosh, AM, Meier, S, Meijer, CJ, Melegh, B, Melle, I, Mesholam-Gately, RI, Metspalu, A, Michie, PT, Milani, L, Milanova, V, Mokrab, Y, Morris, DW, Mors, O, Murphy, KC, Murray, RM, Myin-Germeys, I, Muller-Myhsok, B, Nelis, M, Nenadic, I, Nertney, DA, Nestadt, G, Nicodemus, KK, Nikitina-Zake, L, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, O'Neill, FA, Oh, S-Y, Olincy, A, Olsen, L, Van Os, J, Pantelis, C, Papadimitriou, GN, Papiol, S, Parkhomenko, E, Pato, MT, Paunio, T, Pejovic-Milovancevic, M, Perkins, DO, Pietilainen, O, Pimm, J, Pocklington, AJ, Price, A, Pulver, AE, Purcell, SM, Quested, D, Rasmussen, HB, Reichenberg, A, Reimers, MA, Richards, AL, Roffman, JL, Roussos, P, Ruderfer, DM, Salomaa, V, Sanders, AR, Schall, U, Schubert, CR, Schulze, TG, Schwab, SG, Scolnick, EM, Scott, RJ, Seidman, LJ, Shi, J, Sigurdsson, E, Silagadze, T, Silverman, JM, Sim, K, Slominsky, P, Smoller, JW, So, H-C, Stahl, EA, Stefansson, H, Steinberg, S, Stogmann, E, Straub, RE, Strengman, E, Strohmaier, J, Stroup, TS, Subramaniam, M, Suvisaari, J, Svrakic, DM, Szatkiewicz, JP, Soderman, E, Thirumalai, S, Toncheva, D, Tosato, S, Veijola, J, Waddington, J, Walsh, D, Wang, D, Wang, Q, Webb, BT, Weiser, M, Wildenauer, DB, Williams, NM, Williams, S, Witt, SH, Wolen, AR, Wong, EHM, Wormley, BK, Xi, HS, Zai, CC, Zheng, X, Zimprich, F, Wray, NR, Stefansson, K, Visscher, PM, Adolfsson, R, Andreassen, OA, Blackwood, DHR, Buxbaum, JD, Borglum, AD, Darvasi, A, Domenici, E, Ehrenreich, H, Esko, T, Gejman, PV, Gill, M, Gurling, H, Hultman, CM, Iwata, N, Jablensky, AV, Jonsson, EG, Kirov, G, Knight, J, Lencz, T, Levinson, DF, Li, QS, Liu, J, Malhotra, AK, McCarroll, SA, McQuillin, A, Moran, JL, Mortensen, PB, Mowry, BJ, Palotie, A, Pato, CN, Petryshen, TL, Posthuma, D, Rujescu, D, Sham, PC, Sklar, P, St Clair, D, Weinberger, DR, Wendland, JR, Werge, T, Daly, MJ, and Sullivan, PF

Abstract

Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.

Published
2019

19. 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

20. L'activité fonctionnelle du complexe d'histone chaperon H3.3 HIRA nécessite la trimérisation de la sous-unité HIRA

Author

Ray-Gallet, Dominique, Ricketts, M. Daniel, Sato, Yukari, Gupta, Kushol, Boyarchuk, Ekaterina, Senda, Toshiya, Marmorstein, Ronen, Almouzni, Geneviève, Dynamique du noyau [Institut Curie], Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), and University of Pennsylvania [Philadelphia]

Subjects
Histone variants, [SDV]Life Sciences [q-bio], Nucleosomes
Abstract

International audience; The HIRA histone chaperone complex deposits the histone variant H3.3 onto chromatin in a DNA synthesis-independent manner. It comprises three identified subunits, HIRA, UBN1 and CABIN1, however the functional oligomerization state of the complex has not been investigated. Here we use biochemical and crystallographic analysis to show that the HIRA subunit forms a stable homotrimer that binds two subunits of CABIN1 in vitro. A HIRA mutant that is defective in homotrimer formation interacts less efficiently with CABIN1, is not enriched at DNA damage sites upon UV irradiation and cannot rescue new H3.3 deposition in HIRA knockout cells. The structural homology with the homotrimeric replisome component Ctf4/ AND-1 enables the drawing of parallels and discussion of the functional importance of the homotrimerization state of the HIRA subunit.; Le complexe d'histones chaperon HIRA dépose le variant d'histone H3.3 sur la chromatine de manière indépendante de la synthèse d'ADN. Il comprend trois sous-unités identifiées, HIRA, UBN1 et CABIN1, mais l'état d'oligomérisation fonctionnelle du complexe n'a pas été étudié. Nous utilisons ici l'analyse biochimique et cristallographique pour montrer que la sous-unité HIRA forme un homotrimère stable qui lie deux sous-unités de CABIN1 in vitro. Un mutant ARHI qui est défectueux dans la formation de l'homotrimère interagit moins efficacement avec CABIN1, n'est pas enrichi sur les sites d'endommagement de l'ADN lors de l'irradiation UV et ne peut pas sauver un nouveau dépôt de H3.3 dans les cellules knock-out ARHI. L'homologie structurelle avec le composant réplisomique homotrimérique Ctf4/ AND-1 permet d'établir des parallèles et de discuter de l'importance fonctionnelle de l'état d'homotrimérisation de la sous-unité HIRA.

Published
2018

27. 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
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34. Serum iron levels and the risk of Parkinson Disease: a Mendelian randomization study

Author

Pichler I, Del Greco M. F, Gögele M, Lill CM, Bertram L, Do CB, Eriksson N, Foroud T, Myers RH, PD GWAS Consortium, Nalls M, Keller MF, International Parkinson's Disease Genomics Consortium, Wellcome Trust Case Control Consortium 2, Benyamin B, Whitfield JB, Genetics of Iron Status Consortium, Pramstaller PP, Hicks AA, Thompson JR, Minelli C., Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, Simón Sánchez J, Schulte C, Lesage S, Arepalli S, Barker R, Ben Shlomo Y, Berendse HW, Berg D, Bhatia K, de Bie RM, Biffi A, Bloem B, Bochdanovits Z, Bonin M, Bras JM, Brockmann K, Brooks J, Burn DJ, Charlesworth G, Chen H, Chinnery PF, Chong S, Clarke CE, Cookson MR, Cooper JM, Corvol JC, Counsell C, Damier P, Dartigues JF, Deloukas P, Deuschl G, Dexter DT, van Dijk KD, Dillman A, Durif F, Dürr A, Edkins S, Evans JR, Foltynie T, Gao J, Gardner M, Gibbs JR, Goate A, Gray E, Guerreiro R, Harris C, van Hilten JJ, Hofman A, Hollenbeck A, Holton J, Hu M, Huang X, Huber H, Hudson G, Hunt SE, Illig T, Lambert JC, Langford C, Lees A, Lichtner P, Limousin P, Lopez G, Lorenz D, McNeill A, Moorby C, Moore M, Morris HR, Morrison KE, Mudanohwo E, O'Sullivan SS, Pearson J, Perlmutter JS, Pollak P, Post B, Potter S, Ravina B, Revesz T, Riess O, Rivadeneira F, Rizzu P, Ryten M, Sawcer S, Schapira A, Scheffer H, Shaw K, Shoulson I, Sidransky E, Smith C, Spencer CC, Stockton JD, Strange A, Talbot K, Tanner CM, Tashakkori Ghanbaria A, Trabzuni D, Traynor BJ, Uitterlinden AG, Velseboer D, Vidailhet M, Walker R, van de Warrenburg B, Wickremaratchi M, Williams N, Williams Gray CH, Winder Rhodes S, Martinez M, Hardy J, Heutink P, Brice A, Gasser T, Singleton AB, Wood NW, Donnelly P, Barroso I, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin A, Duncanson A, Jankowski J, Markus HS, Mathew CG, Palmer CN, Plomin R, Rautanen A, Sawcer SJ, Trembath RC, Viswanathan AC, Band G, Bellenguez C, Freeman C, Hellenthal G, Giannoulatou E, Pirinen M, Pearson R, Su Z, Vukcevic D, Gwilliam R, Blackburn H, Bumpstead SJ, Dronov S, Gillman M, Hammond N, Jayakumar A, McCann OT, Liddle J, Potter SC, Ravindrarajah R, Ricketts M, Waller M, Weston P, Widaa S, Whittaker P, McCarthy MI, Ouwehand WH, Radhakrishnan A, Sambrook J, Toniolo D, Camaschella C, Metspalu A, Esko T, Gieger C, Ried J, Meitinger T, Oexle K, Winkelmann J, Swinkels D, Vermeulen S, van Duijn C, Broer L, Beilby J, Hui J, Anderson D, Visscher P, Martin N., TRAGLIA, MICHELA, Pichler, Irene, Del Greco M, Fabiola, Gögele, Martin, Lill, Christina M, Benyamin, Beben, Minelli, Cosetta, PD GWAS Consortium, International Parkinson’s Disease Genomics Consortium, Wellcome Trust Case Control Consortium, Genetics of Iron Status Consortium, Pollak, Pierre, Functional Genomics, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Human genetics, NCA - Brain mechanisms in health and disease, ANS - Amsterdam Neuroscience, Neurology, Graduate School, Pichler, I, Del Greco M., F, Gögele, M, Lill, Cm, Bertram, L, Do, Cb, Eriksson, N, Foroud, T, Myers, Rh, PD GWAS, Consortium, Nalls, M, Keller, Mf, International Parkinson's Disease Genomics, Consortium, Wellcome Trust Case Control Consortium, 2, Benyamin, B, Whitfield, Jb, Genetics of Iron Status, Consortium, Pramstaller, Pp, Hicks, Aa, Thompson, Jr, Minelli, C., Plagnol, V, Hernandez, Dg, Sharma, M, Sheerin, Um, Saad, M, Simón Sánchez, J, Schulte, C, Lesage, S, Arepalli, S, Barker, R, Ben Shlomo, Y, Berendse, Hw, Berg, D, Bhatia, K, de Bie, Rm, Biffi, A, Bloem, B, Bochdanovits, Z, Bonin, M, Bras, Jm, Brockmann, K, Brooks, J, Burn, Dj, Charlesworth, G, Chen, H, Chinnery, Pf, Chong, S, Clarke, Ce, Cookson, Mr, Cooper, Jm, Corvol, Jc, Counsell, C, Damier, P, Dartigues, Jf, Deloukas, P, Deuschl, G, Dexter, Dt, van Dijk, Kd, Dillman, A, Durif, F, Dürr, A, Edkins, S, Evans, Jr, Foltynie, T, Gao, J, Gardner, M, Gibbs, Jr, Goate, A, Gray, E, Guerreiro, R, Harris, C, van Hilten, Jj, Hofman, A, Hollenbeck, A, Holton, J, Hu, M, Huang, X, Huber, H, Hudson, G, Hunt, Se, Illig, T, Lambert, Jc, Langford, C, Lees, A, Lichtner, P, Limousin, P, Lopez, G, Lorenz, D, Mcneill, A, Moorby, C, Moore, M, Morris, Hr, Morrison, Ke, Mudanohwo, E, O'Sullivan, S, Pearson, J, Perlmutter, J, Pollak, P, Post, B, Potter, S, Ravina, B, Revesz, T, Riess, O, Rivadeneira, F, Rizzu, P, Ryten, M, Sawcer, S, Schapira, A, Scheffer, H, Shaw, K, Shoulson, I, Sidransky, E, Smith, C, Spencer, Cc, Stockton, Jd, Strange, A, Talbot, K, Tanner, Cm, Tashakkori Ghanbaria, A, Trabzuni, D, Traynor, Bj, Uitterlinden, Ag, Velseboer, D, Vidailhet, M, Walker, R, van de Warrenburg, B, Wickremaratchi, M, Williams, N, Williams Gray, Ch, Winder Rhodes, S, Martinez, M, Hardy, J, Heutink, P, Brice, A, Gasser, T, Singleton, Ab, Wood, Nw, Donnelly, P, Barroso, I, Blackwell, Jm, Bramon, E, Brown, Ma, Casas, Jp, Corvin, A, Duncanson, A, Jankowski, J, Markus, H, Mathew, Cg, Palmer, Cn, Plomin, R, Rautanen, A, Sawcer, Sj, Trembath, Rc, Viswanathan, Ac, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Su, Z, Vukcevic, D, Gwilliam, R, Blackburn, H, Bumpstead, Sj, Dronov, S, Gillman, M, Hammond, N, Jayakumar, A, Mccann, Ot, Liddle, J, Potter, Sc, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Mccarthy, Mi, Ouwehand, Wh, Radhakrishnan, A, Sambrook, J, Toniolo, D, Traglia, Michela, Camaschella, C, Metspalu, A, Esko, T, Gieger, C, Ried, J, Meitinger, T, Oexle, K, Winkelmann, J, Swinkels, D, Vermeulen, S, van Duijn, C, Broer, L, Beilby, J, Hui, J, Anderson, D, Visscher, P, and Martin, N.

Subjects
Relative risk reduction, Iron, Mendelian randomization analysis, Physiology, Genome-wide association study, Biology, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, SDG 17 - Partnerships for the Goals, Risk Factors, Mendelian randomization, medicine, Humans, Genetic Predisposition to Disease, Iron/blood, Genetic Association Studies, 030304 developmental biology, 0303 health sciences, medicine.diagnostic_test, Parkinson Disease/blood/genetics, Confounding, Parkinson Disease, Mendelian Randomization Analysis, General Medicine, Iron metabolism, 3. Good health, ddc:616.8, Parkinson disease, Meta-analysis, Hereditary hemochromatosis, Serum iron, Medicine, 030217 neurology & neurosurgery, Research Article
Abstract

In this study, Mendelian randomization was used to study genes known to modify iron levels, and the effect of iron on Parkinson's disease (PD) risk was estimated. Based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date, the findings suggest that increased iron levels in the blood are associated with a 3% reduction in the risk of Parkinson's disease for every 10 µg/dL increase in iron. The results of this analysis have potentially important implications for future research into the prevention of Parkinson's disease. Please see later in the article for the Editors' Summary, Background Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date. Methods and Findings We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%–6%; p = 0.001) per 10 µg/dl increase in serum iron. Conclusions Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made. Please see later in the article for the Editors' Summary, Editors' Summary Background Parkinson disease is a degenerative disorder of the central nervous system caused by the death of dopamine-generating cells in the substania nigra, a region of the midbrain. The earliest symptoms are usually movement-related and include tremor, slow movements, and difficulty walking, and later cognitive and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease. Parkinson disease affects around ten million people world-wide and incidence increases with age, with men more affected than women. To date, the causes of Parkinson disease remain unknown although a combination of genetic and environmental factors is thought to play a role. Identifying possible modifiable risks is an important step in the possible prevention of Parkinson disease. Why Was This Study Done? Previous studies have shown a possible association between lower blood levels of iron in people with Parkinson disease compared with controls, although the quality of these studies makes this finding difficult to interpret. So in this study, the researchers used a mendelian randomization approach to investigate whether there was any evidence of an effect of blood iron levels on the risk of Parkinson disease and if so to further explore the direction and scale of any link. Mendelian randomization is a method of using measured variation in genes of known function to examine the causal effect of a modifiable exposure on disease in situations where it is inappropriate to perform a randomized controlled trial. What Did the Researchers Do and Find? The researchers estimated the effect of blood iron levels on the risk of Parkinson disease using three polymorphisms in two genes, HFE and TMPRSS6. For each polymorphism, they performed a meta-analysis combining the results of studies investigating the genetic effect on iron levels, which included almost 22,000 people from Europe and Australia, and a meta-analysis of studies investigating the genetic effect on the risk of Parkinson disease, which included a total of 20,809 people with Parkinson disease and 88,892 controls from Europe and North America. They then performed three separate mendelian randomization analyses to estimate the effect of iron on Parkinson disease for the three polymorphisms. By combining the three estimates, they obtained a statistically significant odds ratio of 0.97 for Parkinson disease per 10 µg/dl increase in iron, corresponding to a 3% reduction in the risk of Parkinson disease for every 10 µg/dl increase in blood iron. Since genotype influences on blood iron levels represent differences that generally persist throughout adult life, the combined mendelian randomization estimate reflects an effect of iron over the course of a lifetime. What Do These Findings Mean? These findings suggest that increased iron levels in the blood are associated with a 3% reduction in the risk of Parkinson disease for every 10 µg/dl increase in iron. This finding is important as it suggests that increased blood iron levels may have a protective effect against Parkinson disease, although the underlying mechanism remains unclear. Furthermore, although mendelian randomization is an increasingly used approach to address the issue of classical confounding, there may be remaining confounding factors specific of mendelian randomization that may influence the interpretation of this study. Nevertheless, the results of this analysis have potentially important implications for future research into the prevention of Parkinson disease. Further studies on the underlying mechanisms are needed before any specific treatment recommendations can be proposed. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001462. The National Institutes of Neurological Disorder and Stroke, MedlinePlus, and NHS Choices have several pages with comprehensive information on Parkinson disease Wikipedia gives an explanation of mendelian randomization (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)

Published
2013

35. Molecular basis for chromatin assembly and modification by multiprotein complexes.

Author

Ricketts, M. Daniel, Han, Joseph, Szurgot, Mary R., and Marmorstein, Ronen

Abstract

Abstract: Epigenetic regulation of the chromatin landscape is often orchestrated through modulation of nucleosomes. Nucleosomes are composed of two copies each of the four core histones, H2A, H2B, H3, and H4, wrapped in ~150 bp of DNA. We focus this review on recent structural studies that further elucidate the mechanisms used by macromolecular complexes to mediate histone modification and nucleosome assembly. Nucleosome assembly, spacing, and variant histone incorporation are coordinated by chromatin remodeler and histone chaperone complexes. Several recent structural studies highlight how disparate families of histone chaperones and chromatin remodelers share similar features that underlie how they interact with their respective histone or nucleosome substrates. Post‐translational modification of histone residues is mediated by enzymatic subunits within large complexes. Until recently, relatively little was known about how association with auxiliary subunits serves to modulate the activity and specificity of the enzymatic subunit. Analysis of several recent structures highlights the different modes that auxiliary subunits use to influence enzymatic activity or direct specificity toward individual histone residues. [ABSTRACT FROM AUTHOR]

Published
2019
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36. Exome-wide study of ankylosing spondylitis demonstrates additional shared genetic background with inflammatory bowel disease

Author

Robinson, PC, Leo, PJ, Pointon, JJ, Harris, J, Cremin, K, Bradbury, LA, Stebbings, S, Harrison, AA, Duncan, EL, Evans, DM, Wordsworth, PB, Brown, MA, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CN, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Spencer, CC, 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, Spencer, CCA, McCloskey, E, Eisman, J, Jones, G, Nicholson, G, Eastell, R, Sambrook, P, Prince, R, Dennison, E, Reid, I, Wark, J, Robinson, PC, Leo, PJ, Pointon, JJ, Harris, J, Cremin, K, Bradbury, LA, Stebbings, S, Harrison, AA, Duncan, EL, Evans, DM, Wordsworth, PB, Brown, MA, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CN, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Spencer, CC, 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, Spencer, CCA, McCloskey, E, Eisman, J, Jones, G, Nicholson, G, Eastell, R, Sambrook, P, Prince, R, Dennison, E, Reid, I, and Wark, J

Abstract

Ankylosing spondylitis (AS) is a common chronic immune-mediated arthropathy affecting primarily the spine and pelvis. The condition is strongly associated with HLA-B*27 as well as other human leukocyte antigen variants and at least 47 individual non-MHC-associated variants. However, substantial additional heritability remains as yet unexplained. To identify further genetic variants associated with the disease, we undertook an association study of AS in 5,040 patients and 21,133 healthy controls using the Illumina Exomechip microarray. A novel association achieving genome-wide significance was noted at CDKAL1. Suggestive associations were demonstrated with common variants in FAM118A, C7orf72 and FAM114A1 and with a low-frequency variant in PNPLA1. Two of the variants have been previously associated with inflammatory bowel disease (IBD; CDKAL1 and C7orf72). These findings further increase the evidence for the marked similarity of genetic risk factors for IBD and AS, consistent with the two diseases having similar aetiopathogenesis.

Published
2016

41. A 'Candidate-Interactome' Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

Author

Mechelli, R, Umeton, R, Policano, C, Annibali, V, Coarelli, G, Ricigliano, VAG, Vittori, D, Fornasiero, A, Buscarinu, MC, Romano, S, Salvetti, M, Ristori, G, Sawcer, S, Hellenthal, G, Pirinen, M, Spencer, CCA, Patsopoulos, NA, Moutsianas, L, Dilthey, A, Su, Z, Freeman, C, Hunt, SE, Edkins, S, Gray, E, Booth, DR, Potter, SC, Goris, A, Band, G, Oturai, AB, Strange, A, Saarela, J, Bellenguez, C, Fontaine, B, Gillman, M, Hemmer, B, Gwilliam, R, Zipp, F, Jayakumar, A, Martin, R, Leslie, S, Hawkins, S, Giannoulatou, E, D'alfonso, S, Blackburn, H, Boneschi, FM, Liddle, J, Harbo, HF, Perez, ML, Spurkland, A, Waller, MJ, Mycko, MP, Ricketts, M, Comabella, M, Hammond, N, and Kockum, I

Abstract

Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms. © 2013 Mechelli et al.

Published
2013

43. Genome-wide association analysis identifies 13 new risk loci for schizophrenia

Author

Ripke, S, O'Dushlaine, C, Chambert, K, Moran, Jl, Kähler, Ak, Akterin, S, Bergen, Se, Collins, Al, Crowley, Jj, Fromer, M, Kim, Y, Lee, Sh, Magnusson, Pk, Sanchez, N, Stahl, Ea, Williams, S, Wray, Nr, Xia, K, Bettella, F, Borglum, Ad, Bulik Sullivan, Bk, Cormican, P, Craddock, N, Leeuw, De, C, Durmishi, N, Gill, M, Golimbet, V, Hamshere, Ml, Holmans, P, Hougaard, Dm, Kendler, Ks, Lin, K, Morris, Dw, Mors, O, Mortensen, Pb, Neale, Bm, O'Neill, Fa, Owen, Mj, Milovancevic, Mp, Posthuma, D, Powell, J, Richards, Al, Riley, Bp, Ruderfer, D, Rujescu, D, Sigurdsson, E, Silagadze, T, Smit, Ab, Stefansson, H, Steinberg, S, Suvisaari, J, Tosato, Sarah, Verhage, M, Walters, Jt, Multicenter Genetic Studies of Schizophrenia Consortium, Levinson, Df, Gejman, Pv, Laurent, C, Mowry, Bj, O'Donovan, Mc, Pulver, Ae, Schwab, Sg, Wildenauer, Db, Dudbridge, F, Shi, J, Albus, M, Alexander, M, Campion, D, Cohen, D, Dikeos, D, Duan, J, Eichhammer, P, Godard, S, Hansen, M, Lerer, Fb, Liang, Ky, Maier, W, Mallet, J, Nertney, Da, Nestadt, G, Norton, N, Papadimitriou, Gn, Ribble, R, Sanders, Ar, Silverman, Jm, Walsh, D, Williams, Nm, Wormley, B, Psychosis Endophenotypes International Consortium, Arranz, Mj, Bakker, S, Bender, S, Bramon, E, Collier, D, Crespo Facorro, B, Hall, J, Iyegbe, C, Jablensky, A, Kahn, Rs, Kalaydjieva, L, Lawrie, S, Lewis, Cm, Linszen, Dh, Mata, I, Mcintosh, A, Murray, Rm, Ophoff, Ra, Van, Os, J, Walshe, M, Weisbrod, M, Wiersma, D, Wellcome Trust Case Control Consortium 2, Donnelly, P, Barroso, I, Blackwell, Jm, Brown, Ma, Casas, Jp, Corvin, Ap, Deloukas, P, Duncanson, A, Jankowski, J, Markus, Hs, Mathew, Cg, Palmer, Cn, Plomin, R, Rautanen, A, Sawcer, Sj, Trembath, Rc, Viswanathan, Ac, Wood, Nw, Spencer, Cc, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, Rd, 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, Tashakkori Ghanbaria, A, Waller, Mj, Weston, P, Widaa, S, Whittaker, P, Mccarthy, Mi, Stefansson, K, Scolnick, E, Purcell, S, Mccarroll, Sa, Sklar, P, Hultman, Cm, Sullivan, P. F., Functional Genomics, Molecular and Cellular Neurobiology, AIMMS, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Adult Psychiatry, Ripke, Stephan, O'Dushlaine, Colm, Chambert, Kimberly, Moran, Jennifer L, Lee, Sang Hong, Sullivan, Patrick F, Multicenter Genetic Studies of Schizophrenia Consortium, Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium 2, Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY USA Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA deCODE Genet, Reykjavik, Iceland Aarhus Univ Hosp, Risskov, Denmark Aarhus Univ, Ctr Integrat Sequencing iSEQ, Aarhus, Denmark Lundbeck Fdn Initiat Integrat Psychiat Res iPSYCH, Aarhus, Denmark Lundbeck Fdn Initiat Integrat Psychiat Res iPSYCH, Copenhagen, Denmark Univ Dublin Trinity Coll, Dept Psychiat, Dublin 2, Ireland Cardiff Univ, Sch Med, Ctr Psychiat Genet & Genom, MRC, Cardiff CF10 3AX, S Glam, Wales Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Dept Funct Genom, Amsterdam, Netherlands Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands Radboud Univ Nijmegen, Inst Comp & Informat Sci, NL-6525 ED Nijmegen, Netherlands Univ Clin Psychiat, Dept Child & Adolescent Psychiat, Skopje, Macedonia Univ Dublin Trinity Coll, Neuropsychiat Genet Res Grp, Dublin 2, Ireland Russian Acad Med Sci, Mental Hlth Res Ctr, Moscow 109801, Russia Statens Serum Inst, DK-2300 Copenhagen, Denmark Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA Kings Coll London, Inst Psychiat, London, England Aarhus Univ Hosp, Ctr Psychiat Res, Risskov, Denmark Aarhus Univ, Natl Ctr Register Based Res, Aarhus, DenmarkQueens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland Univ Belgrade, Fac Med, Belgrade, Serbia Erasmus Univ, Med Ctr, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands Kings Coll London, Dept Neurosci, London, England Virginia Commonwealth Univ, Dept Human & Mol Genet, Richmond, VA USA Univ Halle, Dept Psychiat, Halle, Germany Univ Munich, Dept Psychiat, D-80539 Munich, Germany Univ Iceland, Dept Psychiat, Reykjavik, Iceland Landspitali University Hospital Reykjavik, Iceland Tbilisi State Univ, Dept Psychiat, GE-380086 Tbilisi, Rep of Georgia Vrije Univ Amsterdam, Ctr Neurogen & Cognit Res, Amsterdam, Netherlands Vrije Univ Amsterdam, Dept Mol & Cellular Neurosci, Amsterdam, Netherlands Natl Inst Hlth & Welf, Mental Hlth & Subst Abuse Serv, Helsinki, Finland Univ Verona, Sect Psychiat, I-37100 Verona, Italy UCL, Inst Cognit Neurosci, London, England UCL, Mental Hlth Sci Unit, London, England Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA Harvard Univ, Sch Med, Dept Genet, Boston, MA USA, Child and Adolescent Psychiatry / Psychology, Psychiatrie & Neuropsychologie, RS: MHeNs School for Mental Health and Neuroscience, Human genetics, NCA - Brain mechanisms in health and disease, and NCA - Neurobiology of mental health

Subjects
Male, Candidate gene, SNP, Single-nucleotide polymorphism, Genome-wide association study, Disease, Biology, heritability, neuronal calcium signaling, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Genetics, medicine, Humans, GWAS, Genetic Predisposition to Disease, Bipolar disorder, 030304 developmental biology, Genetic association, Sweden, Genetics & Heredity, 0303 health sciences, medicine.disease, 3. Good health, genome sequencing, schizophrenia, Schizophrenia, Meta-analysis, Case-Control Studies, genetic variation, Female, genome-wide scan, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field. Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder. NIMH R01 MH077139 R01 MH095034 Stanley Center for Psychiatric Research Sylvan Herman Foundation Friedman Brain Institute at the Mount Sinai School of Medicine Karolinska Institutet, Karolinska University Hospital Swedish Research Council Swedish County Council Soderstrom Konigska Foundation Netherlands Scientific Organization NWO 645-000-003 info:eu-repo/grantAgreement/EC/FP7/223423 Danish Strategic Research Council H. Lundbeck A/S Faculty of Health Sciences at Aarhus University Lundbeck Foundation Stanley Research Foundation Wellcome Trust 085475/B/08/Z 085475/Z/08/Z

Published
2013

45. Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study

Author

Zeggini, E., Panoutsopoulou, K., Southam, L., Rayner, N.W., Day-Williams, A.G., Lopes, M.C., Boraska, V., Esko, T., Evangelou, E., Hofman, A., Houwing-Duistermaat, J.J., Ingvarsson, T., Jonsdottir, I., Jonsson, H., Kerkhof, H.J.M., Kloppenburg, M., Bos, S.D., Mangino, M., Metrustry, S., Slagboom, P.E., Thorleifsson, G., Raine, E.V.A., Ratnayake, M., Ricketts, M., Beazley, C., Blackburn, H., Bumpstead, S., Elliott, K.S., Hunt, S.E., Potter, S.C., Shin, S.Y., Yadav, V.K., Zhai, G.J., Sherburn, K., Dixon, K., Arden, E., Aslam, N., Battley, P.K., Carluke, I., Doherty, S., Gordon, A., Joseph, J., Keen, R., Koller, N.C., Mitchell, S., O'Neill, F., Paling, E., Reed, M.R., Rivadeneira, F., Swift, D., Walker, K., Watkins, B., Wheeler, M., Birrell, F., Ioannidis, J.P.A., Meulenbelt, I., Metspalu, A., Rai, A., Salter, D., Stefansson, K., Styrkarsdottir, U., Uitterlinden, A.G., Meurs, J.B.J. van, Chapman, K., Deloukas, P., Ollier, W.E.R., Wallis, G.A., Arden, N., Carr, A., Doherty, M., McCaskie, A., Wilkinson, J.M., Ralston, S.H., Valdes, A.M., Spector, T.D., Loughlin, J., and arcOGEN Consortium & arcOGEN Colla

Published
2012

46. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Author

Jostins, Luke, Ripke, Stephan, Weersma, Rinse K., Duerr, Richard H., Mcgovern, Dermot P., Hui, Ken Y., Lee, James C., Philip Schumm, L., Sharma, Yashoda, Anderson, Carl A., Essers, Jonah, Mitrovic, Mitja, Ning, Kaida, Cleynen, Isabelle, Theatre, Emilie, Spain, Sarah L., Raychaudhuri, Soumya, Goyette, Philippe, Wei, Zhi, Abraham, Clara, Achkar, Jean Paul, Ahmad, Tariq, Amininejad, Leila, Ananthakrishnan, Ashwin N., Andersen, Vibeke, Andrews, Jane M., Baidoo, Leonard, Balschun, Tobias, Bampton, Peter A., Bitton, Alain, Boucher, Gabrielle, Brand, Stephan, Büning, Carsten, Cohain, Ariella, Cichon, Sven, D'Amato, Mauro, De Jong, Dirk, Devaney, Kathy L., Dubinsky, Marla, Edwards, Cathryn, Ellinghaus, David, Ferguson, Lynnette R., Franchimont, Denis, Fransen, Karin, Gearry, Richard, Georges, Michel, Gieger, Christian, Glas, Jürgen, Haritunians, Talin, Hart, Ailsa, Hawkey, Chris, Hedl, Matija, Xinli, Hu, Karlsen, Tom H., Kupcinskas, Limas, Kugathasan, Subra, Latiano, Anna, Laukens, Debby, Lawrance, Ian C., Lees, Charlie W., Louis, Edouard, Mahy, Gillian, Mansfield, John, Morgan, Angharad R., Mowat, Craig, Newman, William, Palmieri, Orazio, Ponsioen, Cyriel Y., Potocnik, Uros, Prescott, Natalie J., Regueiro, Miguel, Rotter, Jerome I., Russell, Richard K., Sanderson, Jeremy D., Sans, Miquel, Satsangi, Jack, Schreiber, Stefan, Simms, Lisa A., Sventoraityte, Jurgita, Targan, Stephan R., Taylor, Kent D., Tremelling, Mark, Verspaget, Hein W., De Vos, Martine, Wijmenga, Cisca, Wilson, David C., Winkelmann, Juliane, Xavier, Ramnik J., Zeissig, Sebastian, Zhang, Bin, Zhang, Clarence K., Zhao, Hongyu, Silverberg, Mark S., Annese, Vito, Hakonarson, Hakon, Brant, Steven R., Radford Smith, Graham, Mathew, Christopher G., Rioux, John D., Schadt, Eric E., Daly, Mark J., Franke, Andre, Parkes, Miles, Vermeire, Severine, Barrett, Jeffrey C., Cho, Judy H., Barclay, M, Peyrin Biroulet, L, Chamaillard, M, Colombel, Jf, Cottone, M, Croft, A, D'Incà, R, Halfvarson J, Hanigan K, Henderson, P, Hugot, Jp, Karban, A, Kennedy, Na, Khan, Ma, Lémann, M, Levine, A, Massey, D, Milla, M, Montgomery, Gw, Ng, Sm, Oikonomou, I, Peeters, H, Proctor, Dd, Rahier, Jf, Roberts, R, Rutgeerts, P, Seibold, F, Stronati, Laura, Taylor, Km, Törkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, Mh, Zhang, H, Zhang, W, Andrews, Jm, Bampton, Pa, Florin, Th, Gearry, R, Krishnaprasad, K, Lawrance, Ic, Mahy, G, Radford Smith, G, Roberts, Rl, Simms, La, Amininijad, L, Cleynen, I, Dewit, O, Franchimont, D, Georges, M, Laukens, D, Theatre, E, Vermeire, S, Aumais, G, Baidoo, L, Barrie AM 3rd, Beck, K, Bernard, Ej, Binion, Dg, Bitton, A, Brant, Sr, Cho, Jh, Cohen, A, Croitoru, K, Daly, Mj, Datta, Lw, Deslandres, C, Duerr, Rh, Dutridge, D, Ferguson, J, Fultz, J, Goyette, P, Greenberg, Gr, Haritunians, T, Jobin, G, Katz, S, Lahaie, Rg, Mcgovern, Dp, Nelson, L, Ning, K, Paré, P, Regueiro, Md, Rioux, Jd, Ruggiero, E, Schumm, L, Schwartz, M, Scott, R, Sharma, Y, Silverberg, Ms, Spears, D, Steinhart, A, Stempak, Jm, Swoger, Jm, Tsagarelis, C, Zhang, C, Zhao, H, Aerts, J, Ahmad, T, Arbury, H, Attwood, A, Auton, A, Ball, Sg, Balmforth, Aj, Barnes, C, Barrett, Jc, Barroso, I, Barton, A, Bennett, Aj, Bhaskar, S, Blaszczyk, K, Bowes, J, Brand, Oj, Braund, Ps, Bredin, F, Breen, G, Brown, Mj, Bruce, In, Bull, J, Burren, Os, Burton, J, Byrnes, J, Caesar, S, Cardin, N, Clee, Cm, Coffey, Aj, Connell, Jm, Conrad, Df, Cooper, Jd, Dominiczak, Af, Downes, K, Drummond, He, Dudakia, D, Dunham, A, Ebbs, B, Eccles, D, Edkins, S, Edwards, C, Elliot, A, Emery, P, Evans, Dm, Evans, G, Eyre, S, Farmer, A, Ferrier, In, Flynn, E, Forbes, A, Forty, L, Franklyn, Ja, Frayling, Tm, Freathy, Rm, Giannoulatou, E, Gibbs, P, Gilbert, P, Gordon Smith, K, Gray, E, Green, E, Groves, Cj, Grozeva, D, Gwilliam, R, Hall, A, Hammond, N, Hardy, M, Harrison, P, Hassanali, N, Hebaishi, H, Hines, S, Hinks, A, Hitman, Ga, Hocking, L, Holmes, C, Howard, E, Howard, P, Howson, Jm, Hughes, D, Hunt, S, Isaacs, Jd, Jain, M, Jewell, Dp, Johnson, T, Jolley, Jd, Jones, Ir, Jones, La, Kirov, G, Langford, Cf, Lango Allen, H, Lathrop, Gm, Lee, J, Lee, Kl, Lees, C, Lewis, K, Lindgren, Cm, Maisuria Armer, M, Maller, J, Mansfield, J, Marchini, Jl, Martin, P, Massey, Dc, Mcardle, Wl, Mcguffin, P, Mclay, Ke, Mcvean, G, Mentzer, A, Mimmack, Ml, Morgan, Ae, Morris, Ap, Mowat, C, Munroe, Pb, Myers, S, Newman, W, Nimmo, Er, O'Donovan, Mc, Onipinla, A, Ovington, Nr, Owen, Mj, Palin, K, Palotie, A, Parnell, K, Pearson, R, Pernet, D, Perry, Jr, Phillips, A, Plagnol, V, Prescott, Nj, Prokopenko, I, Quail, Ma, Rafelt, S, Rayner, Nw, Reid, Dm, Renwick, A, Ring, Sm, Robertson, N, Robson, S, Russell, E, St Clair, D, Sambrook, Jg, Sanderson, Jd, Sawcer, Sj, Schuilenburg, H, Scott, Ce, Seal, S, Shaw Hawkins, S, Shields, Bm, Simmonds, Mj, Smyth, Dj, Somaskantharajah, E, Spanova, K, Steer, S, Stephens, J, Stevens, He, Stirrups, K, Stone, Ma, Strachan, Dp, Su, Z, Symmons, Dp, Thompson, Jr, Thomson, W, Tobin, Md, Travers, Me, Turnbull, C, Vukcevic, D, Wain, Lv, Walker, M, Walker, Nm, Wallace, C, Warren Perry, M, Watkins, Na, Webster, J, Weedon, Mn, Wilson, Ag, Woodburn, M, Wordsworth, Bp, Yau, C, Young, Ah, Zeggini, E, Brown, Ma, Burton, Pr, Caulfield, Mj, Compston, A, Farrall, M, Gough, Sc, Hall, As, Hattersley, At, Hill, Av, Mathew, Cg, Pembrey, M, Satsangi, J, Stratton, Mr, Worthington, J, Hurles, Me, Duncanson, A, Ouwehand, Wh, Parkes, M, Rahman, N, Todd, Ja, Samani, Nj, Kwiatkowski, Dp, Mccarthy, Mi, Craddock, N, Deloukas, P, Donnelly, P, Blackwell, Jm, Bramon, E, Casas, Jp, Corvin, A, Jankowski, J, Markus, Hs, Palmer, Cn, Plomin, R, Rautanen, A, Trembath, Rc, Viswanathan, Ac, Wood, Nw, Spencer, Cc, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Pirinen, M, Strange, A, Blackburn, H, Bumpstead, Sj, Dronov, S, Gillman, M, Jayakumar, A, Mccann, Ot, Liddle, J, Potter, Sc, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P., AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
Genome-wide association study, Disease, SUSCEPTIBILITY, Inflammatory bowel disease, NUMBER, 0302 clinical medicine, Crohn Disease, NETWORK, Genetics, 0303 health sciences, Multidisciplinary, Genomics, Ulcerative colitis, 3. Good health, Colitis, Ulcerative, Genetic Predisposition to Disease, Genome, Human, Haplotypes, Humans, Inflammatory Bowel Diseases, Mycobacterium, Mycobacterium Infections, Mycobacterium tuberculosis, Phenotype, Polymorphism, Single Nucleotide, Reproducibility of Results, Genome-Wide Association Study, Host-Pathogen Interactions, IRGM, Medical genetics, 030211 gastroenterology & hepatology, EXPRESSION, medicine.medical_specialty, Immunology, Biology, Molecular gastro-enterology and hepatology Pathogenesis and modulation of inflammation [IGMD 2], TUBERCULOSIS, 03 medical and health sciences, Medical research, medicine, Allele, METAANALYSIS, 030304 developmental biology, HYPER-IGE SYNDROME, MUTATIONS, medicine.disease, RISK LOCI, Genetic architecture, digestive system diseases
Abstract

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations(1). Genome-wide association studies and subsequent meta-analyses of these two diseases(2,3) as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy(4), in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases(5). Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

Published
2012

47. A CA-repeat polymorphism in the first intron of the HSD11B2 (11β-hydroxysteroid dehydrogenase) gene is associated with blood pressure sensitivity to both chronic and acute salt loading

Author

AGARWAL AK, GIACCHETTI G, LAVERY G, NIKKILA H, PALERMO M, RICKETTS M, MCTERNAN C, BIANCHI G, MANUNTA P, MANTERO F, WHITE PC, STRAZZULLO, PASQUALE, Agarwal, Ak, Giacchetti, G, Lavery, G, Nikkila, H, Palermo, M, Ricketts, M, Mcternan, C, Bianchi, G, Manunta, P, Strazzullo, Pasquale, Mantero, F, and White, Pc

Published
2000

48. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Author

Evans, Dm, Spencer, Cc, Pointon, Jj, Su, Z, Harvey, D, Kochan, G, Oppermann, U, Dilthey, A, Pirinen, M, Stone, Ma, Appleton, L, Moutsianas, L, Leslie, S, Wordsworth, T, Kenna, Tj, Karaderi, T, Thomas, Gp, Ward, Mm, Weisman, Mh, Farrar, C, Bradbury, La, Danoy, P, Inman, Rd, Maksymowych, W, Gladman, D, Rahman, P, Spondyloarthritis Research Consortium of Canada, Morgan, A, Marzo Ortega, H, Bowness, P, Gaffney, K, Gaston, Js, Smith, M, Bruges Armas, J, Couto, Ar, Sorrentino, Rosa, Paladini, Fabiana, Ferreira, Ma, Xu, H, Liu, Y, Jiang, L, Lopez Larrea, C, Díaz Peña, R, López Vázquez, A, Zayats, T, Band, G, Bellenguez, C, Blackburn, H, Blackwell, Jm, Bramon, E, Bumpstead, Sj, Casas, Jp, Corvin, A, Craddock, N, Deloukas, P, Dronov, S, Duncanson, A, Edkins, S, Freeman, C, Gillman, M, Gray, E, Gwilliam, R, Hammond, N, Hunt, Se, Jankowski, J, Jayakumar, A, Langford, C, Liddle, J, Markus, Hs, Mathew, Cg, Mccann, Ot, Mccarthy, Mi, Palmer, Cn, Peltonen, L, Plomin, R, Potter, Sc, Rautanen, A, Ravindrarajah, R, Ricketts, M, Samani, N, Sawcer, Sj, Strange, A, Trembath, Rc, Viswanathan, Ac, Waller, M, Weston, P, Whittaker, P, Widaa, S, Wood, Nw, Mcvean, G, Reveille, Jd, Wordsworth, Bp, Brown, Ma, Donnelly, P, Australo Anglo American Spondyloarthritis Consortium, and Wellcome Trust Case Control Consortium, 2

Subjects
Receptors, Peptide, HLA-B27, ERAP1, ANKYLOSING SPONDYLITIS, Inflammatory arthritis, Population, Genome-wide association study, Human leukocyte antigen, Biology, CD8-Positive T-Lymphocytes, Bioinformatics, Aminopeptidases, White People, Minor Histocompatibility Antigens, Meta-Analysis as Topic, Genetics, medicine, Humans, Spondylitis, Ankylosing, education, Spondylitis, HLA-B27 Antigen, education.field_of_study, Ankylosing spondylitis, HLA-B27, Polymorphism, Genetic, Interleukin-12 Subunit p40, Membrane Proteins, medicine.disease, Endoplasmic reticulum aminopeptidase 2, Peptide Fragments, CARD Signaling Adaptor Proteins, Core Binding Factor Alpha 3 Subunit, Latent TGF-beta Binding Proteins, Receptors, Tumor Necrosis Factor, Type I, Case-Control Studies, Immunology, Disease Susceptibility, Receptors, Prostaglandin E, EP4 Subtype, Genome-Wide Association Study
Abstract

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

Published
2011

49. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Author

Sawcer, S, Hellenthal, G, Pirinen, M, Spencer, CCA, Patsopoulos, NA, Moutsianas, L, Dilthey, A, Su, Z, Freeman, C, Hunt, SE, Edkins, S, Gray, E, Booth, DR, Potter, SC, Goris, A, Band, G, Oturai, AB, Strange, A, Saarela, J, Bellenguez, C, Fontaine, B, Gillman, M, Hemmer, B, Gwilliam, R, Zipp, F, Jayakumar, A, Martin, R, Leslie, S, Hawkins, S, Giannoulatou, E, D'Alfonso, S, Blackburn, H, Boneschi, FM, Liddle, J, Harbo, HF, Perez, ML, Spurkland, A, Waller, MJ, Mycko, MP, Ricketts, M, Comabella, M, Hammond, N, Kockum, I, McCann, OT, Ban, M, Whittaker, P, Kemppinen, A, Weston, P, Hawkins, C, Widaa, S, Zajicek, J, Dronov, S, Robertson, N, Bumpstead, SJ, Barcellos, LF, Ravindrarajah, R, Abraham, R, Alfredsson, L, Ardlie, K, Aubin, C, Baker, A, Baker, K, Baranzini, SE, Bergamaschi, L, Bergamaschi, R, Bernstein, A, Berthele, A, Boggild, M, Bradfield, JP, Brassat, D, Broadley, SA, Buck, D, Butzkueven, H, Capra, R, Carroll, WM, Cavalla, P, Celius, EG, Cepok, S, Chiavacci, R, Clerget-Darpoux, F, Clysters, K, Comi, G, Cossburn, M, Cournu-Rebeix, I, Cox, MB, Cozen, W, Cree, BAC, Cross, AH, Cusi, D, and Daly, MJ

Abstract

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis. © 2011 Macmillan Publishers Limited. All rights reserved.

Published
2011

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