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1. Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study

Author

Panoutsopoulou, K, Southam, L, Elliott, KS, Wrayner, N, Zhai, G, Beazley, C, Thorleifsson, G, Arden, NK, Carr, A, Chapman, K, Deloukas, P, Doherty, M, McCaskie, A, Ollier, WER, Ralston, SH, Spector, TD, Valdes, AM, Wallis, GA, Wilkinson, JM, Arden, E, Battley, K, Blackburn, H, Blanco, FJ, Bumpstead, S, Cupples, LA, Day-Williams, AG, Dixon, K, Doherty, SA, Esko, T, Evangelou, E, Felson, D, Gomez-Reino, JJ, Gonzalez, A, Gordon, A, Gwilliam, R, Halldorsson, BV, Hauksson, VB, Hofman, A, Hunt, SE, Ioannidis, JPA, Ingvarsson, T, Jonsdottir, I, Jonsson, H, Keen, R, Kerkhof, HJM, Kloppenburg, MG, Koller, N, Lakenberg, N, Lane, NE, Lee, AT, Metspalu, A, Meulenbelt, I, Nevitt, MC, O'Neill, F, Parimi, N, Potter, SC, Rego-Perez, I, Riancho, JA, Sherburn, K, Slagboom, PE, Stefansson, K, Styrkarsdottir, U, Sumillera, M, Swift, D, Thorsteinsdottir, U, Tsezou, A, Uitterlinden, AG, van Meurs, JBJ, Watkins, B, Wheeler, M, Mitchell, S, Zhu, Y, Zmuda, JM, Consortium, arcOGEN, Zeggini, E, and Loughlin, J

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Immunology, Arthritis, Genetics, Prevention, Aging, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Musculoskeletal, Case-Control Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Osteoarthritis, Hip, Osteoarthritis, Knee, Polymorphism, Single Nucleotide, arcOGEN Consortium, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract

ObjectivesThe genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis.MethodsThe authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44,449 individuals), and de novo in 14 534 independent samples, all of European descent.ResultsNone of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects.ConclusionsIdentifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.

Published
2011

2. Most common principal diagnoses assigned to Australian emergency department presentations involving alcohol use: a multi-centre study

Author

Miller, P, Vakidis, T, Taylor, N, Baker, T, Stella, J, Egerton-Warburton, D, Hyder, S, Staiger, P, Bowe, SJ, Shepherd, J, Zordan, R, Walby, A, Jones, ML, Caldicott, D, Barker, D, Hall, M, Doran, CM, Ezard, N, Preisz, P, Havard, A, Shakeshaft, A, Akhlaghi, H, Kloot, K, Lowry, N, Bumpstead, S, Miller, P, Vakidis, T, Taylor, N, Baker, T, Stella, J, Egerton-Warburton, D, Hyder, S, Staiger, P, Bowe, SJ, Shepherd, J, Zordan, R, Walby, A, Jones, ML, Caldicott, D, Barker, D, Hall, M, Doran, CM, Ezard, N, Preisz, P, Havard, A, Shakeshaft, A, Akhlaghi, H, Kloot, K, Lowry, N, and Bumpstead, S

Abstract

OBJECTIVES: Alcohol is the most widely consumed psychoactive substance in Australia and the consequences of alcohol consumption have enormous personal and social impacts. This study aimed to describe the principal diagnoses of emergency department (ED) presentations involving alcohol use in the previous 12 hours at eight hospitals in Victoria and the Australian Capital Territory, Australia. METHODS: Twelve months' data (1 July 2018 - 30 June 2019) were collected from eight EDs, including demographics, ICD-10 codes, hospital location and self-reported drinking in the preceding 12 hours. The ten most common ICD-10 discharge codes were analysed based on age, sex and hospital geographic area. RESULTS: ICD codes pertaining to mental and behavioural disorders due to alcohol use accounted for the highest proportion in most EDs. Suicide ideation/attempt was in the five highest ICD codes for all but one hospital. It was the second most common alcohol-related presentation for both males and females. CONCLUSIONS: Alcohol plays a major role in a range of presentations, especially in relation to mental health and suicide. IMPLICATIONS FOR PUBLIC HEALTH: The collection of alcohol involvement in ED presentations represents a major step forward in informing the community about the burden of alcohol on their health resources.

Published
2022

3. From little things, big things grow: An exploratory analysis of the national cost of peripheral intravenous catheter insertion in Australian adult emergency care.

Author

Morgan, R, Callander, E, Cullen, L, Walker, K, Bumpstead, S, Hawkins, T, Kuhn, L, Egerton-Warburton, D, Morgan, R, Callander, E, Cullen, L, Walker, K, Bumpstead, S, Hawkins, T, Kuhn, L, and Egerton-Warburton, D

Abstract

OBJECTIVE: To estimate the total economic impact of peripheral intravenous catheter (PIVC) or cannula insertion and use in adult Australian EDs, including those cannulas that remain unused for therapeutic purposes. METHODS: Searches on Australian government websites were conducted to find rates of insertion, complications and cost of cannula; following this, gaps in national data sets were filled with MEDLINE and PubMed searches to estimate the total cost of cannula use in Australian EDs. Once the data were collected, totals were combined to establish an estimated cost for the listed categories. RESULTS: The estimated cost of cannulation in Australia may be up to A$594 million per year, including the cost of insertion (equipment and staff), cost of complications such as Staphylococcus aureus bacteraemia and phlebitis, and patient-centred costs (lost patient productivity, infiltration, occlusion and dislodgement). Approximately A$305.9 million is attributed to unused cannulas and approximately 11 790 days of clinician time is spent annually inserting cannula that remains idle. CONCLUSION: The figures developed in the present study represent an important educational opportunity to encourage thoughtful consideration of all interventions, no matter how small. ED cannula insertion represents a large economic and health cost to Australia's health system, many of which remain unused. There are no national data sets that record complications associated with PIVCs and we highlight the urgent need for improved data.

Published
2022

4. Large-scale discovery of novel genetic causes of developmental disorders

Author

Fitzgerald, T. W., Gerety, S. S., Jones, W. D., van Kogelenberg, M., King, D. A., McRae, J., Morley, K. I., Parthiban, V., Al-Turki, S., Ambridge, K., Barrett, D. M., Bayzetinova, T., Clayton, S., Coomber, E. L., Gribble, S., Jones, P., Krishnappa, N., Mason, L. E., Middleton, A., Miller, R., Prigmore, E., Rajan, D., Sifrim, A., Tivey, A. R., Ahmed, M., Akawi, N., Andrews, R., Anjum, U., Archer, H., Armstrong, R., Balasubramanian, M., Banerjee, R., Baralle, D., Batstone, P., Baty, D., Bennett, C., Berg, J., Bernhard, B., Bevan, A. P., Blair, E., Blyth, M., Bohanna, D., Bourdon, L., Bourn, D., Brady, A., Bragin, E., Brewer, C., Brueton, L., Brunstrom, K., Bumpstead, S. J., Bunyan, D. J., Burn, J., Burton, J., Canham, N., Castle, B., Chandler, K., Clasper, S., Clayton-Smith, J., Cole, T., Collins, A., Collinson, M. N., Connell, F., Cooper, N., Cox, H., Cresswell, L., Cross, G., Crow, Y., DʼAlessandro, M., Dabir, T., Davidson, R., Davies, S., Dean, J., Deshpande, C., Devlin, G., Dixit, A., Dominiczak, A., Donnelly, C., Donnelly, D., Douglas, A., Duncan, A., Eason, J., Edkins, S., Ellard, S., Ellis, P., Elmslie, F., Evans, K., Everest, S., Fendick, T., Fisher, R., Flinter, F., Foulds, N., Fryer, A., Fu, B., Gardiner, C., Gaunt, L., Ghali, N., Gibbons, R., Pereira, Gomes S. L., Goodship, J., Goudie, D., Gray, E., Greene, P., Greenhalgh, L., Harrison, L., Hawkins, R., Hellens, S., Henderson, A., Hobson, E., Holden, S., Holder, S., Hollingsworth, G., Homfray, T., Humphreys, M., Hurst, J., Ingram, S., Irving, M., Jarvis, J., Jenkins, L., Johnson, D., Jones, D., Jones, E., Josifova, D., Joss, S., Kaemba, B., Kazembe, S., Kerr, B., Kini, U., Kinning, E., Kirby, G., Kirk, C., Kivuva, E., Kraus, A., Kumar, D., Lachlan, K., Lam, W., Lampe, A., Langman, C., Lees, M., Lim, D., Lowther, G., Lynch, S. A., Magee, A., Maher, E., Mansour, S., Marks, K., Martin, K., Maye, U., McCann, E., McConnell, V., McEntagart, M., McGowan, R., McKay, K., McKee, S., McMullan, D. J., McNerlan, S., Mehta, S., Metcalfe, K., Miles, E., Mohammed, S., Montgomery, T., Moore, D., Morgan, S., Morris, A., Morton, J., Mugalaasi, H., Murday, V., Nevitt, L., Newbury-Ecob, R., Norman, A., OʼShea, R., Ogilvie, C., Park, S., Parker, M. J., Patel, C., Paterson, J., Payne, S., Phipps, J., Pilz, D. T., Porteous, D., Pratt, N., Prescott, K., Price, S., Pridham, A., Procter, A., Purnell, H., Ragge, N., Rankin, J., Raymond, L., Rice, D., Robert, L., Roberts, E., Roberts, G., Roberts, J., Roberts, P., Ross, A., Rosser, E., Saggar, A., Samant, S., Sandford, R., Sarkar, A., Schweiger, S., Scott, C., Scott, R., Selby, A., Seller, A., Sequeira, C., Shannon, N., Sharif, S., Shaw-Smith, C., Shearing, E., Shears, D., Simonic, I., Simpkin, D., Singzon, R., Skitt, Z., Smith, A., Smith, B., Smith, K., Smithson, S., Sneddon, L., Splitt, M., Squires, M., Stewart, F., Stewart, H., Suri, M., Sutton, V., Swaminathan, G. J., Sweeney, E., Tatton-Brown, K., Taylor, C., Taylor, R., Tein, M., Temple, I. K., Thomson, J., Tolmie, J., Torokwa, A., Treacy, B., Turner, C., Turnpenny, P., Tysoe, C., Vandersteen, A., Vasudevan, P., Vogt, J., Wakeling, E., Walker, D., Waters, J., Weber, A., Wellesley, D., Whiteford, M., Widaa, S., Wilcox, S., Williams, D., Williams, N., Woods, G., Wragg, C., Wright, M., Yang, F., Yau, M., Carter, N. P., Parker, M., Firth, H. V., FitzPatrick, D. R., Wright, C. F., Barrett, J. C., and Hurles, M. E.

Published
2015
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6. The sourcing and use of high physical resemblance personal protective equipment to train healthcare workers, improve confidence and conserve medical-grade equipment.

Author

Bumpstead S., Lim Z.J., Kuhn L., Flynn D., Bakos C.-L., Potter E., Egerton-Warburton D., Bumpstead S., Lim Z.J., Kuhn L., Flynn D., Bakos C.-L., Potter E., and Egerton-Warburton D.

Abstract

Personal protective equipment (PPE) is essential for healthcare worker (HCW) safety. Conservation of PPE for clinical use during the COVID-19 pandemic reduced its availability for training, necessitating an innovative approach to sourcing high physical resemblance PPE (HPR-PPE). We present a case study of crowd-sourcing of HPR-PPE to train HCWs. Survey results indicated that HPR-PPE enabled high-fidelity practise of PPE application and removal, aided procedure recall, improved user confidence and was sufficiently similar to medical-grade PPE. HPR-PPE provided a novel and cost-effective alternative. We also demonstrated that medical-grade PPE can be sourced from non-medical institutions and businesses during a pandemic.Copyright © 2021 The Healthcare Infection Society

Published
2021

7. The sourcing and use of high physical resemblance personal protective equipment to train health care workers, improve confidence and conserve medical grade equipment.

Author

Flynn D., Kuhn L., Bakos C.-L., Egerton-Warburton D., Potter E., Bumpstead S., Lim Z.J., Flynn D., Kuhn L., Bakos C.-L., Egerton-Warburton D., Potter E., Bumpstead S., and Lim Z.J.

Abstract

Personal protective equipment (PPE) is essential for health care worker (HCW) safety. Conservation of PPE for clinical use during the COVID-19 pandemic reduced its availability for training, necessitating an innovative approach to sourcing high physical resemblance PPE (HPR-PPE). We present a case study of crowd-sourcing HPR-PPE to train HCW. Survey results indicated that HPR-PPE enabled high-fidelity practice of PPE application and removal, aided procedure recall, improved user confidence and was sufficiently similar to medical-grade PPE. HPR-PPE provided a novel and cost-effective alternative. We also demonstrated that medical-grade PPE can be sourced from non-medical institutions and businesses during a pandemic.Copyright © 2021 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

Published
2021

9. 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

10. Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women

Author

Steinthorsdottir, V. (Valgerdur), McGinnis, R. (Ralph), Williams, N. O. (Nicholas O.), Stefansdottir, L. (Lilja), Thorleifsson, G. (Gudmar), Shooter, S. (Scott), Fadista, J. (Joao), Sigurdsson, J. K. (Jon K.), Auro, K. M. (Kirsi M.), Berezina, G. (Galina), Borges, M.-C. (Maria-Carolina), Bumpstead, S. (Suzannah), Bybjerg-Grauholm, J. (Jonas), Colgiu, I. (Irina), Dolby, V. A. (Vivien A.), Dudbridge, F. (Frank), Engel, S. M. (Stephanie M.), Franklin, C. S. (Christopher S.), Frigge, M. L. (Michael L.), Frisbaek, Y. (Yr), Geirsson, R. T. (Reynir T.), Geller, F. (Frank), Gretarsdottir, S. (Solveig), Gudbjartsson, D. F. (Daniel F.), Harmon, Q. (Quaker), Hougaard, D. M. (David Michael), Hegay, T. (Tatyana), Helgadottir, A. (Anna), Hjartardottir, S. (Sigrun), Jaeaeskelaeinen, T. (Tiina), Johannsdottir, H. (Hrefna), Jonsdottir, I. (Ingileif), Juliusdottir, T. (Thorhildur), Kalsheker, N. (Noor), Kasimov, A. (Abdumadjit), Kemp, J. P. (John P.), Kivinen, K. (Katja), Klungsoyr, K. (Kari), Lee, W. K. (Wai K.), Melbye, M. (Mads), Miedzybrodska, Z. (Zosia), Moffett, A. (Ashley), Najmutdinova, D. (Dilbar), Nishanova, F. (Firuza), Olafsdottir, T. (Thorunn), Perola, M. (Markus), Pipkin, F. B. (Fiona Broughton), Poston, L. (Lucilla), Prescott, G. (Gordon), Saevarsdottir, S. (Saedis), Salimbayeva, D. (Damilya), Scaife, P. J. (Paula Juliet), Skotte, L. (Line), Staines-Urias, E. (Eleonora), Stefansson, O. A. (Olafur A.), Sorensen, K. M. (Karina Meden), Thomsen, L. C. (Liv Cecilie Vestrheim), Tragante, V. (Vinicius), Trogstad, L. (Lill), Simpson, N. A. (Nigel A. B.), Laivuori, H. (Hannele), Morgan, L. (Linda), Aripova, T. (Tamara), Casas, J. P. (Juan P.), Dominiczak, A. F. (Anna F.), Walker, J. J. (James J.), Thorsteinsdottir, U. (Unnur), Iversen, A.-C. (Ann-Charlotte), Feenstra, B. (Bjarke), Lawlor, D. A. (Deborah A.), Boyd, H. A. (Heather Allison), Magnus, P. (Per), Zakhidova, N. (Nodira), Svyatova, G. (Gulnara), Stefansson, K. (Kari), Heinonen, S. (Seppo), Kajantie, E. (Eero), Kere, J. (Juha), Pouta, A. (Anneli), Macphail, S. (Sheila), Kilby, M. (Mark), Habiba, M. (Marwan), Williamson, C. (Catherine), O'Shaughnessy, K. (Kevin), O'Brien, S. (Shaughn), Cameron, A. (Alan), Redman, C. W. (Christopher W. G.), Farrall, M. (Martin), and Caulfield, M. (Mark)

Subjects
embryonic structures, reproductive and urinary physiology, female genital diseases and pregnancy complications
Abstract

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia. Studies to identify maternal variants associated with preeclampsia have been limited by sample size. Here, the authors meta-analyze eight GWAS of 9,515 preeclamptic women, identifying five variants associated with preeclampsia and showing that genetic predisposition to hypertension is a major risk factor for preeclampsia.

Published
2020

13. 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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14. Variants in the fetal genome near FLT1 are associated with risk of preeclampsia

Author

McGinnis, R, Steinthorsdottir, V, Williams, NO, Thorleifsson, G, Shooter, S, Hjartardottir, S, Bumpstead, S, Stefansdottir, L, Hildyard, L, Sigurdsson, JK, Kemp, JP, Silva, GB, Thomsen, LCV, Jääskeläinen, T, Kajantie, E, Chappell, S, Kalsheker, N, Moffett, A, Hiby, S, Lee, WK, Padmanabhan, S, Simpson, NAB, Dolby, VA, Staines-Urias, E, Engel, SM, Haugan, A, Trogstad, L, Svyatova, G, Zakhidova, N, Najmutdinova, D, FINNPEC Consortium, GOPEC Consortium, Dominiczak, AF, Gjessing, HK, Casas, JP, Dudbridge, F, Walker, JJ, Pipkin, FB, Thorsteinsdottir, U, Geirsson, RT, Lawlor, DA, Iversen, AC, Magnus, P, Laivuori, H, Stefansson, K, Morgan, L, COLLABORATORS, Heinonen, S, Kere, J, Kivinen, K, Pouta, A, Macphail, S, Kilby, M, Habiba, M, Williamson, C, O'Shaughnessy, K, O'Brien, S, Cameron, A, Poston, L, Miedzybrodzka, Z, Redman, CWG, Farrall, M, and Caulfield, M

Subjects
embryonic structures, female genital diseases and pregnancy complications, reproductive and urinary physiology
Abstract

Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10(-11)) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes.

Published
2017

15. Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

Author

Jones, G.T., Tromp, G., Kuivaniemi, H., Gretarsdottir, S., Baas, A.F., Giusti, B., Strauss, E., Hof, F.N. van 't, Webb, T.R., Erdman, R., Ritchie, M.D., Elmore, J.R., Verma, A., Pendergrass, S., Kullo, I.J., Ye, Z., Peissig, P.L., Gottesman, O., Verma, S.S., Malinowski, J., Rasmussen-Torvik, L.J., Borthwick, K.M., Smelser, D.T., Crosslin, D.R., Andrade, M. de, Ryer, E.J., McCarty, C.A., Bottinger, E.P., Pacheco, J.A., Crawford, D.C., Carrell, D.S., Gerhard, G.S., Franklin, D.P., Carey, D.J., Phillips, V.L., Williams, M.J., Wei, W., Blair, R., Hill, A.A., Vasudevan, T.M., Lewis, D.R., Thomson, I.A., Krysa, J., Hill, G.B., Roake, J., Merriman, T.R., Oszkinis, G., Galora, S., Saracini, C., Abbate, R., Pulli, R., Pratesi, C., Saratzis, A., Verissimo, A.R., Bumpstead, S., Badger, S.A., Clough, R.E., Cockerill, G., Hafez, H., Scott, D.J., Futers, T.S., Romaine, S.P., Bridge, K., Griffin, K.J., Bailey, M.A., Smith, A., Thompson, M.M., Bockxmeer, F.M. van, Matthiasson, S.E., Thorleifsson, G., Thorsteinsdottir, U., Blankensteijn, J.D., Teijink, J.A., Wijmenga, C., Graaf, J. de, Kiemeney, L.A.L.M., Lindholt, J.S., Hughes, A., Bradley, D.T., Stirrups, K., Golledge, J., Norman, P.E., Powell, J.T., Humphries, S.E., Hamby, S.E., Goodall, A.H., Nelson, C.P., Sakalihasan, N., Courtois, A., Ferrell, R.E., Eriksson, P., Folkersen, L., Franco-Cereceda, A., Eicher, J.D., Johnson, A.D., Betsholtz, C., Ruusalepp, A., Franzen, O., Schadt, E.E., and Bjorkegren, J.L.

Subjects
Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], cardiovascular system, cardiovascular diseases
Abstract

Contains fulltext : 169744.pdf (Publisher’s version ) (Open Access) RATIONALE: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. OBJECTIVE: To identify additional AAA risk loci using data from all available genome-wide association studies. METHODS AND RESULTS: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. CONCLUSIONS: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.

Published
2017

17. Parental origin of sequence variants associated with complex diseases

Author

Voight, B.F., Raychaudhuri, S., Purcell, S., McCarroll, S.A., Segrè, A.V., Ardlie, K., Burtt, N.P., Crawford, G., Elliott, A.L., Green, T., Guiducci, C., Saxena, R., Daly, M.J., Florez, J.C., Altshuler, D., Meigs, J.B., Scott, L.J., Welch, R.P., Willer, C.J., Ganser, M., Jackson, A.U., Stringham, H.M., Abecasis, G.R., Boehnke, M., Steinthorsdottir, V., Thorleifsson, G., Kong, A., Walters, G.B., Thorsteinsdottir, U., Stefansson, K., Dina, C., Proença, C., Cauchi, S., Froguel, P., Zeggini, E., Bumpstead, S., Payne, F., Smith, N., Barroso, I., Ferreira, T., Elliott, K.S., Lindgren, C.M., Prokopenko, I., Rayner, N.W., Robertson, N.R., Morris, A.P., McCarthy, M.I., Huth, C., Grallert, H., Gieger, C., Klopp, N., Meitinger, T., Petersen, A.-K., Thorand, B., Wichmann, H.-E., Illig, T., Aulchenko, Y.S., Amin, N., Witteman, J., Hofman, A., Van Duijn, C.M., McCulloch, L.J., Bennett, A.J., Groves, C.J., Hassanali, N., Owen, K.R., Gloyn, A.L., Wu, G., Stein, L.D., Langenberg, C., Griffin, S., Wareham, N.J., Hoffmann, O.M., Hide, W.A., Dupuis, J., Qi, L., Kraft, P., Sun, Q., Hunter, D., Hu, F.B., Cornelis, M., VanDam, R., Van Hoek, M., Van Herpt, T., Sijbrands, E., Uitterlinden, A., Navarro, P., Balkau, B., Benediktsson, R., Sigurdsson, G., Blagieva, R., Boehm, B.O., Boerwinkle, E., Bonnycastle, L.L., Chines, P.S., Erdos, M.R., Morken, M.A., Narisu, N., Swift, A.J., Boström, K.B., Bravenboer, B., Charpentier, G., Couper, D.J., Doney, A.S.F., Morris, A.D., Palmer, C.N.A., Fox, C.S., Franklin, C.S., Rudan, I., Grarup, N., Hadjadj, S., Thomas Sparsø, [No Value], Campbell, H., Wilson, J.F., Hansen, T., Pedersen, O., Herder, C., Roden, M., Isomaa, B., Tuomi, T., Johnson, P.R.V., Jørgensen, T., Kao, W.H.L., Kuusisto, J., Laakso, M., Lauritzen, T., Li, M., Lieverse, A., Lyssenko, V., Nilsson, P., Groop, L., Marre, M., Midthjell, K., Platou, C., Hveem, K., Perry, J.R.B., Shields, B.M., Weedon, M.N., Frayling, T.M., Hattersley, A.T., Rathmann, W., Strassburger, K., Rocheleau, G., Sladek, R., Sampson, M.J., Shrader, P., Tichet, J., Bergman, R.N., Collins, F.S., Gyllensten, U., Hitman, G.A., Mohlke, K.L., Pramstaller, P.P., Tuomilehto, J., Walker, M., Watanabe, R.M., Pankow, J.S., and deCODE genetics, Sturlugata 8, 101 Reykjavík, Iceland. kong@decode.is

Subjects
Male, CCCTC-Binding Factor, Iceland, Mothers, Breast Neoplasms, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Fathers, Genomic Imprinting, 03 medical and health sciences, 0302 clinical medicine, Polymorphism (computer science), Humans, SNP, Genetic Predisposition to Disease, Allele, Alleles, 030304 developmental biology, Genetics, 0303 health sciences, Binding Sites, Multidisciplinary, Genome, Human, Chromosomes, Human, Pair 11, Haplotype, DNA Methylation, Pedigree, Repressor Proteins, Diabetes Mellitus, Type 2, Haplotypes, Carcinoma, Basal Cell, DNA methylation, Female, Human genome, Genomic imprinting, Chromosomes, Human, Pair 7, 030217 neurology & neurosurgery
Abstract

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field Effects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five-one with breast cancer, one with basal-cell carcinoma and three with type 2 diabetes-have parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site. info:eu-repo/grantAgreement/EC/FP7/218071

Published
2009
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18. Genome-wide and fine-resolution association analysis of malaria in West Africa

Author

Muminatou, Jallow, Yik Ying Teo, Small, Kerrin S., Rockett, Kirk A., Panos, Deloukas, Clark, Taane G., Katja, Kivinen, Bojang, Kalifa A., Conway, David J., Margaret, Pinder, Giorgio, Sirugo, Fatou Sisay Joof, Stanley, Usen, Sarah, Auburn, Bumpstead, Suzannah J., Susana, Campino, Alison, Coffey, Andrew, Dunham, Fry, Andrew E., Angela, Green, Rhian, Gwilliam, Hunt, Sarah E., Michael, Inouye, Jeffreys, Anna E., Alieu, Mendy, Aarno, Palotie, Simon, Potter, Jiannis, Ragoussis, Jane, Rogers, Kate, Rowlands, Elilan, Somaskantharajah, Pamela, Whittaker, Claire, Widden, Peter, Donnelly, Bryan, Howie, Jonathan, Marchini, Andrew, Morris, Miguel, Sanjoaquin, Eric Akum Achidi, Tsiri, Agbenyega, Angela, Allen, Olukemi, Amodu, Patrick, Corran, Abdoulaye, Djimde, Amagana, Dolo, Doumbo, Ogobara K., Chris, Drakeley, Sarah, Dunstan, Jennifer, Evans, Jeremy, Farrar, Hien Tt, Fernando D., Horstmann, R. D., Ibrahim, M., Karunaweera, N., Kokwaro, G., Koram, K. A., Lemnge, M., Makani, J., Marsh, K., Michon, P., David, Modiano, Molyneux, M. E., Mueller, I., Parker, M., Peshu, N., Plowe, C. V., Puijalon, O., Reeder, J., Reyburn, H., Riley, E. M., Sakuntabhai, A., Singhasivanon, P., Sirima, S., Tall, A., Taylor, T. E., Thera, M., Troye Blomberg, M., Williams, T. N., Wilson, M., Wellcome Trust Case Control Consortium Kwiatkowski, D. P., Epidemiology Network: Achidi, Malaria Genomic E. A., Agbenyega, T., Ahmad, T., Alcock, D., Allen, S., Amenga Etego, L., Amodu, O., Apinjoh, T. O., Attwood, A. P., Auburn, S., Ball, S. G., Balmforth, A. J., Ban, M., Barbour, J., Barnwell, D., Barrett, J. C., Barrett, J. H., Barton, A., Bentley, D., Bishop, D. T., Bojang, K., Boorman, J. P., Bougouma, E., Bradbury, L. A., Braga Marcano, C. A., Braund, P. S., Bredin, F., Breen, G., Brown, M. A., Brown, M. J., Bruce, I. N., Bryan, C., Bull, S., Bumpstead, S. J., Burke, B., Burton, P. R., Caesar, S., Campino, S., Cant, B., Cardin, N. J., Cardon, L. R., Carucci, D., Caulfield, M., Chaney, A., Clark, T., Clayton, D. G., Collier, D. A., Compston, A., Compston, D. A., Connell, J., Conway, D., Cook, K., Corran, P., Craddock, N., Cummings, F. R., Davison, D., Deloukas, P., Devries, J., Dewasurendra, R., Diakite, M., Dixon, R. J., Djimde, A., Dobson, R., Dolo, A., Dominiczak, A., Donnelly, P., Donovan, H., Doumbo, O., Downes, K., Doyle, A., Drakeley, C., Drummond, H., Duffy, P., Duncanson, A., Dunger, D. B., Dunstan, S., Duombo, O., Easton, D., Elkin, A., Elliott, K. S., Elzein, A., Enimil, A., Evans, D., Evans, J., Everson, U., Eyre, S., Farmer, A., Farrall, M., Farrar, C., Farrar, J., Fernando, D., Ferreira, T., Ferrier, I. N., Fisher, S. A., Fitzpatrick, K., Forbes, A., Franklyn, J. A., Fraser, C., Frayling, T. M., Freathy, R. M., Ghansah, A., Ghori, J., Gilbert, P. D., Gordon Smith, K., Goris, A., Gottlieb, M., Gough, S. C., Green, A., Green, E. K., Groves, C. J., Grozeva, D., Gungadoo, J., Gwilliam, R., Hall, A. S., Hallgrimsdóttir, I. B., Hamshere, M. L., Hart, L., Hattersley, A. T., Heward, J. M., Hider, S. L., Tran Tinh Hien, Hill, A. V., Hilton, E., Hinks, A. M., Hitman, G. A., Holmans, P. A., Horstmann, Rolf D., Howie, B. N., Hubbart, C., Hughes, C., Hunt, S. E., Hussein, A., Hussey, J. M., Muntaser, Ibrahim, Iles, M. M., Inouye, M., Ishengoma, D., Jallow, M., Jeffreys, A. E., Jewell, D. P., John, Sl, Jolley, J. D., Jones, I. R., Jones, L., Jones, R. W., Nadira, Karunaweera, Keniry, A., King, E., Kirov, G., Kivinen, K., Knight, A. S., Koch, K., Gilbert, Kokwaro, Koram, Kwadwo A., Lango, H., Lathrop, G. M., Lee, K. L., Lees, C. W., Martha, Lemnge, Leung, H. T., Lewis, C. M., Lin, E., Lindgren, C. M., Ly, A., Macinnis, B., Julie, Makani, Mangano, Valentina, Mangino, M., Manjurano, A., Manning, L., Mansfield, J. C., Manske, M., Maqbool, A., Marchini, J. L., Kevin, Marsh, Maslen, G., Mathew, C. G., Mcardle, W. L., Mccarthy, M. I., Mccreight, M., Mcginnis, R., Mcguffin, P., Meech, E., Mendy, A., Pascal, Michon, Mohiuddin, M. K., Molyneux, Malcolm E., Morris, A. P., Moskvina, V., Moyes, C., Ivo, Mueller, Munroe, P. B., Mutabingwa, T., Ndila, C. M., Newhouse, S. J., Newport, M., Nikolov, I., Nimmo, E. R., Nutland, S., Nyirongo, V., O'Donovan, M. C., Oluoch, T., Onipinla, A., Onnie, C. M., Ouwehand, W. H., Owen, M. J., Michael, Parker, Parkes, M., Pembrey, M., Pereira Gale, J., Perry, J. R., Norbert, Peshu, Plowe, Christopher V., Pointon, J. J., Potter, C., Potter, S., Prescott, N. J., Prowse, C. V., Odile, Puijalon, Quyen, N. T., Ragoussis, J., Rahman, N., Ravindrarajah, R., Rayner, N. W., John, Reeder, Hugh, Reyburn, Riley, Eleanor M., Ring, S. M., Risley, P., Rockett, K. A., Rogers, J., Rowlands, K., Anavaj, Sakuntabhai, Samani, N. J., Sanderson, J., Sanjoaquin, M., Satsangi, J., Sawcer, S. J., Seal, S., Shields, B. M., Silman, A. J., Simmonds, M. J., Pratap, Singhasivanon, Sodiomon, Sirima, Sirugo, G., Small, K. S., Somaskantharajah, E., Spencer, C. C., St Clair, D., Stevens, H. E., Stevens, M., Stevens, S., Strachan, D. P., Stratton, M. R., Su, Z., Suriyaphol, P., Symmons, D. P., Adama, Tall, Taylor, N. C., Taylor, Terrie E., Teo, Y., Teo, Y. Y., Mahamadou, Thera, Thompson, J. R., Thomson, W., Timpson, N. J., Tobin, M. D., Todd, J. A., Todhunter, C. E., Toure, O., Tremelling, M., Marita Troye Blomberg, Vanderwal, A., Vukcevic, D., Walker, M., Walker, N. M., Wallace, C., Walters, G. R., Walton, R., Watkins, N. A., Watson, R., Webster, J., Weedon, M. N., Whittaker, P., Widmer, B., Williams, Thomas N., Williamson, R., Michael, Wilson, Winzer, T., Withers, D., Wordsworth, P., Worthington, J., Wrigley, R., Xue, M., Young, A. H., Yuldasheva, N., and Zeggini, E.

Subjects
Linkage disequilibrium, Hemoglobin, Sickle, Population, Genome-wide association study, Locus (genetics), Biology, Population stratification, Polymorphism, Single Nucleotide, Severity of Illness Index, Linkage Disequilibrium, Article, Gene mapping, Reference Values, Ethnicity, Genetics, Humans, education, Genetic association, education.field_of_study, Polymorphism, Genetic, Chromosome Mapping, Genetic Variation, Malaria, Gambia, Imputation (genetics), Genome-Wide Association Study
Abstract

We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10(-7) to P = 4 × 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.

Published
2009
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19. Large scale association analysis of novel genetic loci for coronary artery disease

Author

Amouyel, P., Arveiler, D., Boekholdt, S. M., Braund, P., Bruse, P., Bumpstead, S. J., Bugert, P., Cambien, F., Danesh, J., Deloukas, P., Doering, A., Ducimetiere, P., Dunn, R. M., El Mokhtari, N. E., Erdmann, J., Evans, A., Ewels, P., Ferrieres, J., Fischer, Matthias, Frossard, P., Garner, S., Gieger, C., Gohri, M. J. R., Goodall, A. H., Grosshennig, A., Hall, A., Hardwick, R., Haukijarvi, A., Hengstenberg, C., Illig, T., Karvanen, J., Kastelein, J., Kee, F., Khaw, K. T., Kluter, H., Konig, I. R., Kuulasmaa, K., Laiho, P., Luc, G., Marz, W., McGinnis, R., McLaren, W., Meisinger, C., Morrison, C., Ou, X., Ouwehand, W. H., Preuss, M., Proust, C., Ravindrarajah, R., Renner, W., Rice, K., Ruidavets, J. B., Saleheen, D., Salomaa, V., Samani, N. J., Sandhu, M. S., Schafer, A. S., Scholz, M., Schreiber, Stefan, Schunkert, H., Silander, K., Singh, R., Soranzo, N., Stark, K., Stegmayr, B., Stephens, J., Thompson, J., Tiret, L., Trip, M. D., van der Schoot, E., Virtamo, J., Wareham, N. J., Wichmann, H. E., Wiklund, P. G., Wright, B., Ziegler, A., Zwaginga, J. J., Amsterdam Cardiovascular Sciences, and Cardiology

Subjects
Male, Risk, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, White People, Article, Coronary artery disease, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Odds Ratio, medicine, Humans, Genetic Predisposition to Disease, Family history, Aged, 030304 developmental biology, Genetic association, Genetics, 0303 health sciences, business.industry, Case-control study, Odds ratio, Middle Aged, medicine.disease, Case-Control Studies, Female, business, Cardiology and Cardiovascular Medicine, Genome-Wide Association Study
Abstract

Background— Combined analysis of 2 genome-wide association studies in cases enriched for family history recently identified 7 loci (on 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21, 10q11.21, and 15q22.33) that may affect risk of coronary artery disease (CAD). Apart from the 9p21 locus, the other loci await substantive replication. Furthermore, the effect of these loci on CAD risk in a broader range of individuals remains to be determined. Methods and Results— We undertook association analysis of single nucleotide polymorphisms at each locus with CAD risk in 11 550 cases and 11 205 controls from 9 European studies. The 9p21.3 locus showed unequivocal association (rs1333049, combined odds ratio [OR]=1.20, 95% CI [1.16 to 1.25], probability value=2.81×10 −21 ). We also confirmed association signals at 1p13.3 (rs599839, OR=1.13 [1.08 to 1.19], P =1.44×10 −7 ), 1q41 (rs3008621, OR=1.10 [1.04 to 1.17], P =1.02×10 −3 ), and 10q11.21 (rs501120, OR=1.11 [1.05 to 1.18], P =4.34×10 −4 ). The associations with 6q25.1 (rs6922269, P =0.020) and 2q36.3 (rs2943634, P =0.032) were borderline and not statistically significant after correction for multiple testing. The 15q22.33 locus did not replicate. The 10q11.21 locus showed a possible sex interaction ( P =0.015), with a significant effect in women (OR=1.29 [1.15 to 1.45], P =1.86×10 −5 ) but not men (OR=1.03 [0.96 to 1.11], P =0.387). There were no other strong interactions of any of the loci with other traditional risk factors. The loci at 9p21, 1p13.3, 2q36.3, and 10q11.21 acted independently and cumulatively increased CAD risk by 15% (12% to 18%), per additional risk allele. Conclusions The findings provide strong evidence for association between at least 4 genetic loci and CAD risk. Cumulatively, these novel loci have a significant impact on risk of CAD at least in European populations.

Published
2009
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20. A linkage disequilibrium map of chromosome 22

Author

Cardon, L.R., Abecasis, G.R., Dawson, E., Bumpstead, S., Chen, Y., Hunt, S., Pabiol, J., Dibling, T., Tinsley, E., Curby, S., Carter, D., Papaspyridonos, M., Livingstone, S., Ganske, R., Rice, K., Deloukas, P., Dunham, I., and Bentley, D.

Subjects
Human genetics -- Research, Chromosome mapping -- Research, Biological sciences
Published
2001

21. The Lin28/let-7 axis regulates glucose metabolism

Author

Zhu H, Shyh Chang N, Segrè AV, Shinoda G, Shah SP, Einhorn WS, Takeuchi A, Engreitz JM, Hagan JP, Kharas MG, Urbach A, Thornton JE, Triboulet R, Gregory RI, DIAGRAM Consortium, MAGIC Investigators, Altshuler D, Daley G.Q. Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, McCulloch LJ, Ferreira T, Grallert H, Amin N, Wu G, Willer CJ, Raychaudhuri S, McCarroll SA, Langenberg C, Hofmann OM, Dupuis J, Qi L, van Hoek M, Navarro P, Ardlie K, Balkau B, Benediktsson R, Bennett AJ, Blagieva R, Boerwinkle E, Bonnycastle LL, Boström KB, Bravenboer B, Bumpstead S, Burtt NP, Charpentier G, Chines PS, Cornelis M, Couper DJ, Crawford G, Doney AS, Elliott KS, Elliott AL, Erdos MR, Fox CS, Franklin CS, Ganser M, Gieger C, Grarup N, Green T, Griffin S, Groves CJ, Guiducci C, Hadjadj S, Hassanali N, Herder C, Isomaa B, Jackson AU, Johnson PR, Jørgensen T, Kao WH, Klopp N, Kong A, Kraft P, Kuusisto J, Lauritzen T, Li M, Lieverse A, Lindgren CM, Lyssenko V, Marre M, Meitinger T, Midthjell K, Morken MA, Narisu N, Nilsson P, Owen KR, Payne F, Perry JR, Petersen AK, Platou C, Proença C, Prokopenko I, Rathmann W, Rayner NW, Robertson NR, Rocheleau G, Roden M, Sampson MJ, Saxena R, Shields BM, Shrader P, Sigurdsson G, Sparsø T, Strassburger K, Stringham HM, Sun Q, Swift AJ, Thorand B, Tichet J, Tuomi T, van Dam RM, van Haeften TW, van Herpt T, van Vliet Ostaptchouk JV, Walters GB, Weedon MN, Wijmenga C, Witteman J, Bergman RN, Cauchi S, Collins FS, Gloyn AL, Gyllensten U, Hansen T, Hide WA, Hitman GA, Hofman A, Hunter DJ, Hveem K, Laakso M, Mohlke KL, Morris AD, Palmer CN, Pramstaller PP, Rudan I, Sijbrands E, Stein LD, Tuomilehto J, Uitterlinden A, Walker M, Wareham NJ, Watanabe RM, Abecasis GR, Boehm BO, Campbell H, Daly MJ, Hattersley AT, Hu FB, Meigs JB, Pankow JS, Pedersen O, Wichmann HE, Barroso I, Florez JC, Frayling TM, Groop L, Sladek R, Thorsteinsdottir U, Wilson JF, Illig T, Froguel P, van Duijn CM, Stefansson K, Boehnke M, McCarthy MI, Soranzo N, Wheeler E, Glazer NL, Bouatia Naji N, Mägi R, Randall J, Johnson T, Elliott P, Rybin D, Henneman P, Dehghan A, Hottenga JJ, Song K, Goel A, Egan JM, Lajunen T, Doney A, Voight BF, Kanoni S, Cavalcanti Proença C, Kumari M, Timpson NJ, Zabena C, Ingelsson E, An P, O'Connell J, Luan J, Elliott A, Roccasecca RM, Pattou F, Sethupathy P, Ariyurek Y, Barter P, Beilby JP, Ben Shlomo Y, Bergmann S, Bochud M, Bonnefond A, Borch Johnsen K, Böttcher Y, Brunner E, Bumpstead SJ, Chen YD, Chines P, Clarke R, Coin LJ, Cooper MN, Crisponi L, Day IN, de Geus EJ, Delplanque J, Fedson AC, Fischer Rosinsky A, Forouhi NG, Frants R, Franzosi MG, Galan P, Goodarzi MO, Graessler J, Grundy S, Gwilliam R, Hallmans G, Hammond N, Han X, Hartikainen AL, Hayward C, Heath SC, Hercberg S, Hicks AA, Hillman DR, Hingorani AD, Hui J, Hung J, Jula A, Kaakinen M, Kaprio J, Kesaniemi YA, Kivimaki M, Knight B, Koskinen S, Kovacs P, Kyvik KO, Lathrop GM, Lawlor DA, Le Bacquer O, Lecoeur C, Li Y, Mahley R, Mangino M, Manning AK, Martínez Larrad MT, McAteer JB, McPherson R, Meisinger C, Melzer D, Meyre D, Mitchell BD, Mukherjee S, Naitza S, Neville MJ, Oostra BA, Orrù M, Pakyz R, Pattaro C, Pearson D, Peden JF, Pedersen NL, Perola M, Pfeiffer AF, Pichler I, Polasek O, Posthuma D, Potter SC, Pouta A, Province MA, Psaty BM, Rice K, Ripatti S, Rivadeneira F, Rolandsson O, Sandbaek A, Sandhu M, Sanna S, Sayer AA, Scheet P, Seedorf U, Sharp SJ, Shields B, Sigurðsson G, Sijbrands EJ, Silveira A, Simpson L, Singleton A, Smith NL, Sovio U, Swift A, Syddall H, Syvänen AC, Tanaka T, Tönjes A, Uitterlinden AG, van Dijk KW, Varma D, Visvikis Siest S, Vitart V, Vogelzangs N, Waeber G, Wagner PJ, Walley A, Ward KL, Watkins H, Wild SH, Willemsen G, Witteman JC, Yarnell JW, Zelenika D, Zethelius B, Zhai G, Zhao JH, Zillikens MC, Borecki IB, Loos RJ, Meneton P, Magnusson PK, Nathan DM, Williams GH, Silander K, Salomaa V, Smith GD, Bornstein SR, Schwarz P, Spranger J, Karpe F, Shuldiner AR, Cooper C, Dedoussis GV, Serrano Ríos M, Lind L, Palmer LJ, Franks PW, Ebrahim S, Marmot M, Wright AF, Stumvoll M, Hamsten A, Buchanan TA, Valle TT, Rotter JI, Siscovick DS, Penninx BW, Boomsma DI, Deloukas P, Spector TD, Ferrucci L, Cao A, Scuteri A, Schlessinger D, Uda M, Ruokonen A, Jarvelin MR, Waterworth DM, Vollenweider P, Peltonen L, Mooser V, Barroso I., PAOLISSO, Giuseppe, Zhu, H, Shyh Chang, N, Segrè, Av, Shinoda, G, Shah, Sp, Einhorn, W, Takeuchi, A, Engreitz, Jm, Hagan, Jp, Kharas, Mg, Urbach, A, Thornton, Je, Triboulet, R, Gregory, Ri, Diagram, Consortium, Magic, Investigator, Altshuler, D, Voight BF, Daley G. Q., Scott, Lj, Steinthorsdottir, V, Morris, Ap, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Y, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Langenberg, C, Hofmann, Om, Dupuis, J, Qi, L, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Boström, Kb, Bravenboer, B, Bumpstead, S, Burtt, Np, Charpentier, G, Chines, P, Cornelis, M, Couper, Dj, Crawford, G, Doney, A, Elliott, K, Elliott, Al, Erdos, Mr, Fox, C, Franklin, C, Ganser, M, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Isomaa, B, Jackson, Au, Johnson, Pr, Jørgensen, T, Kao, Wh, Klopp, N, Kong, A, Kraft, P, Kuusisto, J, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Lyssenko, V, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Narisu, N, Nilsson, P, Owen, Kr, Payne, F, Perry, Jr, Petersen, Ak, Platou, C, Proença, C, Prokopenko, I, Rathmann, W, Rayner, Nw, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Swift, Aj, Thorand, B, Tichet, J, Tuomi, T, van Dam, Rm, van Haeften, Tw, van Herpt, T, van Vliet Ostaptchouk, Jv, Walters, Gb, Weedon, Mn, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Collins, F, Gloyn, Al, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Laakso, M, Mohlke, Kl, Morris, Ad, Palmer, Cn, Pramstaller, Pp, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Walker, M, Wareham, Nj, Watanabe, Rm, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Hu, Fb, Meigs, Jb, Pankow, J, Pedersen, O, Wichmann, He, Barroso, I, Florez, Jc, Frayling, Tm, Groop, L, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Froguel, P, van Duijn, Cm, Stefansson, K, Boehnke, M, Mccarthy, Mi, Soranzo, N, Wheeler, E, Glazer, Nl, Bouatia Naji, N, Mägi, R, Randall, J, Johnson, T, Elliott, P, Rybin, D, Henneman, P, Dehghan, A, Hottenga, Jj, Song, K, Goel, A, Egan, Jm, Lajunen, T, Voight, Bf, Kanoni, S, Cavalcanti Proença, C, Kumari, M, Timpson, Nj, Zabena, C, Ingelsson, E, An, P, O'Connell, J, Luan, J, Elliott, A, Roccasecca, Rm, Pattou, F, Sethupathy, P, Ariyurek, Y, Barter, P, Beilby, Jp, Ben Shlomo, Y, Bergmann, S, Bochud, M, Bonnefond, A, Borch Johnsen, K, Böttcher, Y, Brunner, E, Bumpstead, Sj, Chen, Yd, Clarke, R, Coin, Lj, Cooper, Mn, Crisponi, L, Day, In, de Geus, Ej, Delplanque, J, Fedson, Ac, Fischer Rosinsky, A, Forouhi, Ng, Frants, R, Franzosi, Mg, Galan, P, Goodarzi, Mo, Graessler, J, Grundy, S, Gwilliam, R, Hallmans, G, Hammond, N, Han, X, Hartikainen, Al, Hayward, C, Heath, Sc, Hercberg, S, Hicks, Aa, Hillman, Dr, Hingorani, Ad, Hui, J, Hung, J, Jula, A, Kaakinen, M, Kaprio, J, Kesaniemi, Ya, Kivimaki, M, Knight, B, Koskinen, S, Kovacs, P, Kyvik, Ko, Lathrop, Gm, Lawlor, Da, Le Bacquer, O, Lecoeur, C, Li, Y, Mahley, R, Mangino, M, Manning, Ak, Martínez Larrad, Mt, Mcateer, Jb, Mcpherson, R, Meisinger, C, Melzer, D, Meyre, D, Mitchell, Bd, Mukherjee, S, Naitza, S, Neville, Mj, Oostra, Ba, Orrù, M, Pakyz, R, Paolisso, Giuseppe, Pattaro, C, Pearson, D, Peden, Jf, Pedersen, Nl, Perola, M, Pfeiffer, Af, Pichler, I, Polasek, O, Posthuma, D, Potter, Sc, Pouta, A, Province, Ma, Psaty, Bm, Rice, K, Ripatti, S, Rivadeneira, F, Rolandsson, O, Sandbaek, A, Sandhu, M, Sanna, S, Sayer, Aa, Scheet, P, Seedorf, U, Sharp, Sj, Shields, B, Sigurðsson, G, Sijbrands, Ej, Silveira, A, Simpson, L, Singleton, A, Smith, Nl, Sovio, U, Swift, A, Syddall, H, Syvänen, Ac, Tanaka, T, Tönjes, A, Uitterlinden, Ag, van Dijk, Kw, Varma, D, Visvikis Siest, S, Vitart, V, Vogelzangs, N, Waeber, G, Wagner, Pj, Walley, A, Ward, Kl, Watkins, H, Wild, Sh, Willemsen, G, Witteman, Jc, Yarnell, Jw, Zelenika, D, Zethelius, B, Zhai, G, Zhao, Jh, Zillikens, Mc, Borecki, Ib, Loos, Rj, Meneton, P, Magnusson, Pk, Nathan, Dm, Williams, Gh, Silander, K, Salomaa, V, Smith, Gd, Bornstein, Sr, Schwarz, P, Spranger, J, Karpe, F, Shuldiner, Ar, Cooper, C, Dedoussis, Gv, Serrano Ríos, M, Lind, L, Palmer, Lj, Franks, Pw, Ebrahim, S, Marmot, M, Wright, Af, Stumvoll, M, Hamsten, A, Buchanan, Ta, Valle, Tt, Rotter, Ji, Siscovick, D, Penninx, Bw, Boomsma, Di, Deloukas, P, Spector, Td, Ferrucci, L, Cao, A, Scuteri, A, Schlessinger, D, Uda, M, Ruokonen, A, Jarvelin, Mr, Waterworth, Dm, Vollenweider, P, Peltonen, L, Mooser, V, and Barroso, I.

Published
2011

22. The correlation between reading and mathematics ability at age twelve has a substantial genetic component

Author

Davis, O, Band, G, Pirinen, M, Haworth, C, Meaburn, E, Kovas, Y, Harlaar, N, Docherty, S, Hanscombe, K, Trzaskowski, M, Curtis, C, Strange, A, Freeman, C, Bellenguez, C, Su, Z, Pearson, R, Vukcevic, D, Langford, C, Deloukas, P, Hunt, S, Gray, E, Dronov, S, Potter, S, Tashakkori-Ghanbaria, A, Edkins, S, Bumpstead, S, Blackwell, J, Bramon, E, Brown, M, Casas, J, Corvin, A, Duncanson, A, Jankowski, J, Markus, H, Mathew, C, Palmer, C, Rautanen, A, Sawcer, S, Trembath, R, Viswanathan, A, Wood, N, Barroso, I, Peltonen, L, Dale, P, Petrill, SA, Schalkwyk, L, Craig, I, Lewis, C, Price, T, Donnelly, P, Plomin, R, Spencer, C, and Consortium, The Wellcome Trust Case Control

Abstract

Dissecting how genetic and environmental influences impact on learning is helpful for maximizing numeracy and literacy. Here we show, using twin and genome-wide analysis, that there is a substantial genetic component to children's ability in reading and mathematics, and estimate that around one half of the observed correlation in these traits is due to shared genetic effects (so-called Generalist Genes). Thus, our results highlight the potential role of the learning environment in contributing to differences in a child's cognitive abilities at age twelve., Dissecting how genetic and environmental influences impact on learning is helpful for maximizing numeracy and literacy. Here we show, using twin and genome-wide analysis, that there is a substantial genetic component to children’s ability in reading and mathematics, and estimate that around one half of the observed correlation in these traits is due to shared genetic effects (so-called Generalist Genes). Thus, our results highlight the potential role of the learning environment in contributing to differences in a child’s cognitive abilities at age twelve.

Published
2014

23. Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis

Author

Beaudoin, Melissa, Goyette, Philippe, Goel, Gautam, Louis, E., Mansfield, J. C., Mathew, C. G., McGovern, D. P., Mitrovic, M., Montgomery, G. W., Mowat, C., Newman, W., Palmieri, O., Panés, J., Lagace, Caroline, Parkes, M., Phillips, A., Ponsioen, C. Y., Potocnik, U., Prescott, N. J., Proctor, D. D., Radford-Smith, G. L., Regueiro, M., Rioux, J. D., Roberts, R., Annese, Vito, Rotter, J. I., Rutgeerts, P., Sanderson, J., Sans, M., Satsangi, J., Schreiber, S., Schumm, P., Seibold, F., Sharma, Y., Silverberg, M. S., Bitton, Alain, Simms, L. A., Steinhart, A., Targan, S. R., Taylor, K. D., Torkvist, L., Vermeire, S., Halfvarson, J., Verspaget, H. W., De Vos, M., Walters, T., Begun, Jakob, Wang, K., Weersma, R. K., Whiteman, D., Wijmenga, C., Brant, Steven R., Bresso, Francesca, Cho, Judy H., Duerr, Richard H., Halfvarson, Jonas, Boucher, Gabrielle, McGovern, Dermot P. B., Radford-Smith, Graham, Schreiber, Stefan, Schumm, Philip L., Sharma, Yashoda, Silverberg, Mark S., Weersma, Rinse K., Quebec IBD Genetics Consortium, NIDDK IBD Genetics Consortium, International IBD Genetics Consortium (IIBDGC), Lo, Ken Sin, D'Amato, Mauro, Vermeire, Severine, Franke, Andre, Lettre, Guillaume, Xavier, Ramnik J., Daly, Mark J., Rioux, John D., Aumais, G., Bernard, E. J., Bitton, A., Rivas, Manuel A., Cohen, A., Deslandres, C., Lahaie, R., Paré, P., Brant, S. R., Cho, J. H., Duerr, R. H., Stevens, Christine, Ahmad, T., Anderson, C. A., Annese, V., Baldassano, R. N., Balschun, T., Barclay, M., Barrett, J. C., Bayless, T. M., Bis, J. C., Alikashani, Azadeh, Brand, S., Bumpstead, S., Buning, C., Colombel, J. F., Cottone, M., D'Amato, M., D'Inca, R., Ladouceur, Martin, Daly, M. J., Denson, T., Dubinsky, M., Edwards, C., Ellinghaus, D., Florin, T., Franchimont, D., Franke, A., Gearry, R., Ellinghaus, David, Georges, M., Glas, J., Van Gossum, A., Griffiths, A. M., Guthery, S. L., Hakonarson, H., Haritunians, T., Hugot, J. P., de Jong, D. J., Jostins, L., Torkvist, Leif, Kugathasan, S., Kullak-Ublick, G., Latiano, A., Laukens, D., Lawrance, I., Lee, J., Lees, C. W., Lemann, M., Levine, A., Libioulle, C., and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
Cancer Research, Génétique clinique, LIVER, Genome-wide association study, Inflammatory bowel disease, 0302 clinical medicine, Crohn Disease, GENETIC-VARIANTS, Medicine and Health Sciences, Ethnicity, UBIQUITIN LIGASES, Genetics(clinical), Genetics (clinical), Genetics, 0303 health sciences, Ecology, High-Throughput Nucleotide Sequencing, CROHN-DISEASE, CROHNS-DISEASE, 3. Good health, 030220 oncology & carcinogenesis, Medical genetics, Biologie, Research Article, EXPRESSION, medicine.medical_specialty, Canada, lcsh:QH426-470, SUSCEPTIBILITY LOCI, Evolution, Ubiquitin-Protein Ligases, Ethnic Groups, Evolution des espèces, Biology, Molecular gastro-enterology and hepatology Pathogenesis and modulation of inflammation [IGMD 2], Polymorphism, Single Nucleotide, 03 medical and health sciences, Behavior and Systematics, medicine, Humans, Genetic Predisposition to Disease, Ligase activity, MODULATION, Allele, GENOME-WIDE ASSOCIATION, Molecular Biology, Genotyping, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Genetic association, Ecologie, Biologie moléculaire, Receptors, Interleukin, medicine.disease, NUCLEAR FACTOR 4-ALPHA, Genetic architecture, Cancérologie, CARD Signaling Adaptor Proteins, lcsh:Genetics, CELLS, Colitis, Ulcerative, INTESTINAL EPITHELIAL-CELLS, Genome-Wide Association Study, INFLAMMATORY-BOWEL-DISEASE
Abstract

Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci. © 2013 Beaudoin et al., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2013
Full Text
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24. 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

25. Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis

Author

Stahl, E. A., Wegmann, D., Trynka, G., Gutierrez Achury, J., Do, R., Voight, B. F., Kraft, P., Chen, R., Kallberg, H. J., F. A. S., Replication, D. G., Consortium, M. a., Genetics, M. I., Kathiresan, S., Wijmenga, C., Gregersen, P. K., Alfredsson, L., Siminovitch, K. A., Worthington, J., P. I. W., Raychaudhuri, S., Plenge, R. M., Voight, Bf, Scott, Lj, Steinthorsdottir, V, Morris, Ap, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Ys, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Langenberg, C, Hofmann, Om, Dupuis, J, Qi, L, Segrè, Av, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Boström, Kb, Bravenboer, B, Bumpstead, S, Burtt, Np, Charpentier, G, Chines, Ps, Cornelis, M, Couper, Dj, Crawford, G, Doney, As, Elliott, Ks, Elliott, Al, Erdos, Mr, Fox, Cs, Franklin, Cs, Ganser, M, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Isomaa, B, Jackson, Au, Johnson, Pr, Jørgensen, T, Kao, Wh, Klopp, N, Kong, A, Kraft, P, Kuusisto, J, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Lyssenko, V, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Narisu, N, Nilsson, P, Owen, Kr, Payne, F, Perry, Jr, Petersen, Ak, Platou, C, Proença, C, Prokopenko, I, Rathmann, W, Rayner, Nw, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Swift, Aj, Thorand, B, Tichet, J, Tuomi, T, van Dam RM, van Haeften TW, van Herpt, T, van Vliet Ostaptchouk JV, Walters, Gb, Weedon, Mn, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Collins, Fs, Gloyn, Al, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Laakso, M, Mohlke, Kl, Morris, Ad, Palmer, Cn, Pramstaller, Pp, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Walker, M, Wareham, Nj, Watanabe, Rm, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Hu, Fb, Meigs, Jb, Pankow, Js, Pedersen, O, Wichmann, He, Barroso, I, Florez, Jc, Frayling, Tm, Groop, L, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Froguel, P, van Duijn CM, Stefansson, K, Altshuler, D, Boehnke, M, Mccarthy, Mi, Kathiresan, S, Williams, G, Nathan, Dm, Macrae, Ca, O'Donnell, Cj, Ardissino, D, Merlini, Pa, Berzuini, C, Bernardinelli, L, Peyvandi, F, Tubaro, M, Celli, P, Ferrario, M, Fetiveau, R, Marziliano, N, Casari, G, Galli, M, Ribichini, Flavio Luciano, Rossi, M, Bernardi, F, Zonzin, P, Piazza, A, Mannucci, Pm, Schwartz, Sm, Siscovick, Ds, Yee, J, Friedlander, Y, Elosua, R, Marrugat, J, Lucas, G, Subirana, I, Sala, J, Ramos, R, Salomaa, V, Havulinna, As, Peltonen, L, Melander, O, Berglund, G, Hirschhorn, Jn, Asselta, R, Duga, S, Spreafico, M, Musunuru, K, Purcell, S, Surti, A, Gianniny, L, Mirel, D, Parkin, M, Burtt, N, Gabriel, Sb, Stahl, Ea, Wegmann, D, Trynka, G, Gutierrez achury, J, Do, R, Voight, Bf, Kraft, P, Che, R, Kallberg, H, Kurreeman, F, Diabetes Genetics Replication And Meta analysis Consortium: Myocardial Infarction Genetics, Consortium, Casari, GIORGIO NEVIO, Kathiresan, S, Wijmenga, C, Gregersen, Pk, Alfredsson, L, Siminovitch, Ka, Worthington, J, De Bakker, Pi, Raychaudhuri, S, Plenge, Rm, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
Multifactorial Inheritance, SUSCEPTIBILITY LOCI, GENETIC SUSCEPTIBILITY, Genome-wide association study, Single-nucleotide polymorphism, Disease, HEART-DISEASE, Biology, VARIANTS, Polymorphism, Single Nucleotide, Article, Arthritis, Rheumatoid, COMMON SNPS, Missing heritability problem, MISSING HERITABILITY, Rheumatoid, Genetic model, Genetic predisposition, Diabetes Mellitus, Humans, genetics, Genetic Predisposition to Disease, Human height, Polymorphism, GENOME-WIDE ASSOCIATION, Arthritis, genetics, Bayes Theorem, Cardiovascular Diseases, genetics, Case-Control Studies, Celiac Disease, genetics, Diabetes Mellitus, Type 2, genetics, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Genetics, CELIAC-DISEASE, Bayes Theorem, RISK LOCI, Genetic architecture, Celiac Disease, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Genetic Loci, Case-Control Studies, HUMAN HEIGHT, Genome-Wide Association Study
Abstract

The genetic architectures of common, complex diseases are largely uncharacterized. We modeled the genetic architecture underlying genome-wide association study (GWAS) data for rheumatoid arthritis and developed a new method using polygenic risk-score analyses to infer the total liability-scale variance explained by associated GWAS SNPs. Using this method, we estimated that, together, thousands of SNPs from rheumatoid arthritis GWAS explain an additional 20% of disease risk (excluding known associated loci). We further tested this method on datasets for three additional diseases and obtained comparable estimates for celiac disease (43% excluding the major histocompatibility complex), myocardial infarction and coronary artery disease (48%) and type 2 diabetes (49%). Our results are consistent with simulated genetic models in which hundreds of associated loci harbor common causal variants and a smaller number of loci harbor multiple rare causal variants. These analyses suggest that GWAS will continue to be highly productive for the discovery of additional susceptibility loci for common diseases.

Published
2012

26. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Author

Strawbridge, Rj, Dupuis, J, Prokopenko, I, Barker, A, Ahlqvist, E, Rybin, D, Petrie, Jr, Travers, Me, Bouatia Naji, N, Dimas, As, Nica, A, Wheeler, E, Chen, H, Voight, Bf, Taneera, J, Kanoni, S, Peden, Jf, Turrini, F, Gustafsson, S, Zabena, C, Almgren, P, Barker, Dj, Barnes, D, Dennison, Em, Eriksson, Jg, Eriksson, P, Eury, E, Folkersen, L, Fox, Cs, Frayling, Tm, Goel, A, Gu, Hf, Horikoshi, M, Isomaa, B, Jackson, Au, Jameson, Ka, Kajantie, E, Kerr Conte, J, Kuulasmaa, T, Kuusisto, J, Loos, Rj, Luan, J, Makrilakis, K, Manning, Ak, Martínez Larrad MT, Narisu, N, Nastase Mannila, M, Ohrvik, J, Osmond, C, Pascoe, L, Payne, F, Sayer, Aa, Sennblad, B, Silveira, A, Stancáková, A, Stirrups, K, Swift, Aj, Syvänen, Ac, Tuomi, T, van 't Hooft FM, Walker, M, Weedon, Mn, Xie, W, Zethelius, B, Diagram, Consortium, Giant, Consortium, Muther, Consortium, Cardiogram, Consortium, C4d, Consortium, Ongen, H, Mälarstig, A, Hopewell, Jc, Saleheen, D, Chambers, J, Parish, S, Danesh, J, Kooner, J, Ostenson, Cg, Lind, L, Cooper, Cc, Serrano Ríos, M, Ferrannini, E, Forsen, Tj, Clarke, R, Franzosi, Mg, Seedorf, U, Watkins, H, Froguel, P, Johnson, P, Deloukas, P, Collins, Fs, Laakso, M, Dermitzakis, Et, Boehnke, M, Mccarthy, Mi, Wareham, Nj, Groop, L, Pattou, F, Gloyn, Al, Dedoussis, Gv, Lyssenko, V, Meigs, Jb, Barroso, I, Watanabe, Rm, Ingelsson, E, Langenberg, C, Hamsten, A, Voight BF, Florez J. C., Scott, Lj, Steinthorsdottir, V, Morris, Ap, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Ys, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Hofmann, Om, Qi, L, Segrè, Av, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Bengtsson Boström, K, Bravenboer, B, Bumpstead, S, Burtt, P, Charpentier, G, Chines, Ps, Cornelis, M, Couper, Dj, Crawford, G, Doney, As, Elliott, Ks, Elliott, Al, Erdos, Mr, Franklin, Cs, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Johnson, Pr, Jørgensen, T, Kao, Wh, Klopp, N, Kong, A, Kraft, P, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Nilsson, P, Owen, Kr, Perry, Jr, Petersen, K, Platou, C, Proença, C, Rathmann, W, William Rayner, N, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Thorand, B, Tichet, J, van Dam RM, van Haeften TW, van Herpt, T, van Vliet JV, Bragi Walters, G, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Mohlke, Kl, Morris, Ad, Palmer, Cn, Pramstaller, Pp, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Hu, Fb, Pankow, Js, Pedersen, O, Wichmann, E, Florez, Jc, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Stefansson, K, Altshuler, D, Speliotes, Ek, Berndt, Si, Monda, Kl, Allen, Hl, Mägi, R, Randall, Jc, Vedantam, S, Winkler, Tw, Workalemahu, T, Heid, Im, Wood, Ar, Weyant, Rj, Estrada, K, Liang, L, Nemesh, J, Park, Jh, Kilpeläinen, To, Yang, J, Esko, T, Feitosa, Mf, Kutalik, Z, Mangino, M, Scherag, A, Smith, Av, Welch, R, Zhao, Jh, Aben, Kk, Absher, Dm, Dixon, Al, Fisher, E, Glazer, Nl, Goddard, Me, Heard Costa NL, Hoesel, V, Hottenga, Jj, Johansson, Å, Johnson, T, Ketkar, S, Lamina, C, Li, S, Moffatt, Mf, Myers, Rh, Peters, Mj, Preuss, M, Ripatti, S, Rivadeneira, F, Sandholt, C, Timpson, Nj, Tyrer, Jp, van Wingerden, S, White, Cc, Wiklund, F, Barlassina, C, Chasman, Di, Cooper, Mn, Jansson, Jo, Lawrence, Rw, Pellikka, N, Shi, J, Thiering, E, Alavere, H, Alibrandi, Mt, Arnold, Am, Aspelund, T, Atwood, Ld, Balmforth, Aj, Ben Shlomo, Y, Bergmann, S, Biebermann, H, Blakemore, Ai, Boes, T, Bornstein, Sr, Brown, Mj, Buchanan, Ta, Busonero, F, Cappuccio, Fp, Cavalcanti Proença, C, Ida Chen YD, Chen, Cm, Coin, L, Connell, J, Day, In, den Heijer, M, Duan, J, Ebrahim, S, Elliott, P, Elosua, R, Eiriksdottir, G, Facheris, Mf, Felix, Sb, Fischer Posovszky, P, Folsom, Ar, Friedrich, N, Freimer, Nb, Fu, M, Gaget, S, Gejman, Pv, Geus, Ej, Gjesing, Ap, Goyette, P, Grässler, J, Greenawalt, Dm, Gudnason, V, Hartikainen, Al, Hall, As, Havulinna, As, Hayward, C, Heath, Ac, Hengstenberg, C, Hicks, Aa, Hinney, A, Homuth, G, Hui, J, Igl, W, Iribarren, C, Jacobs, Kb, Jarick, I, Jewell, E, John, U, Jousilahti, P, Jula, A, Kaakinen, M, Kaplan, Lm, Kathiresan, S, Kettunen, J, Kinnunen, L, Knowles, Jw, Kolcic, I, König, Ir, Koskinen, S, Kovacs, P, Kvaløy, K, Laitinen, J, Lantieri, O, Lanzani, C, Launer, Lj, Lecoeur, C, Terho, L, Lettre, G, Liu, J, Lokki, Ml, Lorentzon, M, Luben, Rn, Ludwig, B, Magic, Manunta, P, Marek, D, Martin, Ng, Mcardle, Wl, Mccarthy, A, Mcknight, B, Melander, O, Meyre, D, Montgomery, Gw, Mulic, R, Ngwa, Js, Nelis, M, Neville, Mj, Nyholt, Dr, O'Donnell, Cj, O'Rahilly, S, Ong, Kk, Oostra, B, Paré, G, Parker, An, Perola, M, Pichler, I, Pietiläinen, Kh, Platou, Cg, Polasek, O, Pouta, A, Rafelt, S, Raitakari, O, Rayner, Nw, Ridderstråle, M, Rief, W, Ruokonen, A, Rzehak, P, Salomaa, V, Sanders, Ar, Sandhu, Ms, Sanna, S, Saramies, J, Savolainen, Mj, Scherag, S, Schipf, S, Schreiber, S, Schunkert, H, Silander, K, Sinisalo, J, Siscovick, Ds, Smit, Jh, Soranzo, N, Sovio, U, Stephens, J, Surakka, I, Tammesoo, Ml, Tardif, Jc, Teder Laving, M, Teslovich, Tm, Thompson, Jr, Thomson, B, Tönjes, A, van Meurs JB, van Ommen GJ, Vatin, V, Viikari, J, Visvikis Siest, S, Vitart, V, Vogel, Ci, Waite, Ll, Wallaschofski, H, Walters, Gb, Widen, E, Wiegand, S, Wild, Sh, Willemsen, G, Witte, Dr, Witteman, Jc, Xu, J, Zhang, Q, Zgaga, L, Ziegler, A, Zitting, P, Beilby, Jp, Farooqi, Is, Hebebrand, J, Huikuri, Hv, James, Al, Kähönen, M, Levinson, Df, Macciardi, F, Nieminen, Ms, Ohlsson, C, Palmer, Lj, Ridker, Pm, Stumvoll, M, Beckmann, Js, Boeing, H, Dorret, I. B., Caulfield, Mj, Chanock, Sj, Cupples, La, Smith, Gd, Erdmann, J, Grönberg, H, Hall, P, Harris, Tb, Hayes, Rb, Heinrich, J, Jarvelin, Mr, Kaprio, J, Karpe, F, Khaw, Kt, Kiemeney, La, Krude, H, Lawlor, Da, Metspalu, A, Munroe, Pb, Ouwehand, Wh, Penninx, Bw, Peters, A, Quertermous, T, Reinehr, T, Rissanen, A, Samani, Nj, Schwarz, Pe, Shuldiner, Ar, Spector, Td, Uda, M, Valle, Tt, Wabitsch, M, Waeber, G, Shaun, P, Eric, E. S., Peter, M. V., Assimes, Tl, Borecki, Ib, Groop, Lc, Haritunians, T, Kaplan, Rc, O'Connell, Jr, Peltonen, L, Schlessinger, D, Strachan, Dp, van Duijn CM, Barroso, H, North, Ke, Hirschhorn, Jn, Nica, Ac, Parts, L, Glass, D, Nisbet, J, Barrett, A, Sekowska, M, Travers, M, Potter, S, Grundberg, E, Small, K, Hedman, Åk, Bataille, V, Bell, Jt, Surdulescu, G, Ingle, C, Nestle, Fo, di Meglio, P, Min, Jl, Wilk, A, Hammond, Cj, Yang, Tp, Montgomery, Sb, Zondervan, Kt, Durbin, R, Ahmadi, K, Reilly, Mp, Holm, H, Stewart, Af, Barbalic, M, Absher, D, Aherrahrou, Z, Allayee, H, Anand, Ss, Andersen, K, Anderson, Jl, Ardissino, D, Ball, Sg, Barnes, Ta, Becker, Dm, Becker, Lc, Berger, K, Bis, Jc, Boekholdt, Sm, Braund, Ps, Burnett, Ms, Buysschaert, I, Cardiogenics, Carlquist, Jf, Chen, L, Cichon, S, Codd, V, Davies, Rw, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, Jm, Diemert, P, Do, R, Doering, A, Eifert, S, El Mokhtari NE, Ellis, Sg, Engert, Jc, Epstein, Se, de Faire, U, Fischer, M, Freyer, J, Gigante, B, Girelli, Domenico, Gretarsdottir, S, Gulcher, Jr, Halperin, E, Hammond, N, Hazen, Sl, Horne, Bd, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kastelein, Jj, Kolovou, G, Laaksonen, R, Lambrechts, D, Leander, K, Lieb, W, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meisinger, C, Merlini, Pa, Mooser, V, Morgan, T, Mühleisen, Tw, Muhlestein, Jb, Münzel, T, Musunuru, K, Nahrstaedt, J, Nelson, Cp, Nöthen, Mm, Olivieri, Oliviero, Patel, Rs, Patterson, Cc, Peyvandi, F, Qu, L, Quyyumi, Aa, Rader, Dj, Rallidis, Ls, Rice, C, Rosendaal, Fr, Rubin, D, Sampietro, Ml, Schadt, E, Schäfer, A, Schillert, A, Schrezenmeir, J, Schwartz, Sm, Sivananthan, M, Sivapalaratnam, S, Smith, A, Smith, Tb, Snoep, Jd, Spertus, Ja, Stark, K, Stoll, M, Tang, Wh, Tennstedt, S, Thorgeirsson, G, Tomaszewski, M, Uitterlinden, Ag, van Rij AM, Wells, Ga, Wichmann, He, Wild, Ps, Willenborg, C, Wright, Bj, Ye, S, Zeller, T, Cambien, F, Goodall, Ah, März, W, Blankenberg, S, Roberts, R, Mcpherson, R, Nilesh, J. S., Medical Research Council (MRC), Nica, Alexandra, Ongen, Halit, Dermitzakis, Emmanouil, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Vascular Medicine, Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Scherag, Andre (Beitragende*r), Hinney, Anke (Beitragende*r), Scherag, S. (Beitragende*r), Vogel, C (Beitragende*r), Hebebrand, Johannes (Beitragende*r), University of Groningen, Wheeler, Eleanor [0000-0002-8616-6444], Barnes, Daniel [0000-0002-3781-7570], Luan, Jian'an [0000-0003-3137-6337], Johnson, Kathleen [0000-0002-6823-3252], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], Barroso, Ines [0000-0001-5800-4520], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository

Subjects
Male, Netherlands Twin Register (NTR), endocrine system diseases, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Medizin, Genome-wide association study, Type 2 diabetes, CORONARY HEART-DISEASE, Fasting/blood, 0302 clinical medicine, Insulin, Glucose homeostasis, ddc:576.5, Genome-wide, Diabetes Mellitus, Type 2/blood/genetics/metabolism, CARDIoGRAM Consortium, POPULATION, Proinsulin, RISK, Genetics, 0303 health sciences, INSULIN SENSITIVITY, 11 Medical And Health Sciences, Fasting, Polymorphism, Single Nucleotide/genetics, OBESITY, Female, type 2 diabetes, Life Sciences & Biomedicine, hormones, hormone substitutes, and hormone antagonists, Insulin processing, Adult, medicine.medical_specialty, endocrine system, ENDOCRINOLOGY & METABOLISM, SUSCEPTIBILITY LOCI, Genotype, 030209 endocrinology & metabolism, DIAGRAM Consortium, Biology, C4D Consortium, Polymorphism, Single Nucleotide, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Insulin resistance, BETA-CELL FUNCTION, SDG 3 - Good Health and Well-being, Internal medicine, GIANT Consortium, Internal Medicine, medicine, Humans, METAANALYSIS, 030304 developmental biology, Science & Technology, Genome, Human, Hormonal regulation [IGMD 6], Genetic Variation, nutritional and metabolic diseases, proinsulin, medicine.disease, Proinsulin/blood, TCF7L2, Endocrinology, Diabetes Mellitus, Type 2, MuTHER Consortium, GLUCOSE-HOMEOSTASIS, Insulin/blood
Abstract

OBJECTIVE Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Published
2011
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27. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

Author

Anderson, C.A. Boucher, G. Lees, C.W. Franke, A. D'Amato, M. Taylor, K.D. Lee, J.C. Goyette, P. Imielinski, M. Latiano, A. Lagacé, C. Scott, R. Amininejad, L. Bumpstead, S. Baidoo, L. Baldassano, R.N. Barclay, M. Bayless, T.M. Brand, S. Büning, C. Colombel, J.-F. Denson, L.A. De Vos, M. Dubinsky, M. Edwards, C. Ellinghaus, D. Fehrmann, R.S.N. Floyd, J.A.B. Florin, T. Franchimont, D. Franke, L. Georges, M. Glas, J. Glazer, N.L. Guthery, S.L. Haritunians, T. Hayward, N.K. Hugot, J.-P. Jobin, G. Laukens, D. Lawrance, I. Lémann, M. Levine, A. Libioulle, C. Louis, E. McGovern, D.P. Milla, M. Montgomery, G.W. Morley, K.I. Mowat, C. Ng, A. Newman, W. Ophoff, R.A. Papi, L. Palmieri, O. Peyrin-Biroulet, L. Panés, J. Phillips, A. Prescott, N.J. Proctor, D.D. Roberts, R. Russell, R. Rutgeerts, P. Sanderson, J. Sans, M. Schumm, P. Seibold, F. Sharma, Y. Simms, L.A. Seielstad, M. Steinhart, A.H. Targan, S.R. Van Den Berg, L.H. Vatn, M. Verspaget, H. Walters, T. Wijmenga, C. Wilson, D.C. Westra, H.-J. Xavier, R.J. Zhao, Z.Z. Ponsioen, C.Y. Andersen, V. Torkvist, L. Gazouli, M. Anagnou, N.P. Karlsen, T.H. Kupcinskas, L. Sventoraityte, J. Mansfield, J.C. Kugathasan, S. Silverberg, M.S. Halfvarson, J. Rotter, J.I. Mathew, C.G. Griffiths, A.M. Gearry, R. Ahmad, T. Brant, S.R. Chamaillard, M. Satsangi, J. Cho, J.H. Schreiber, S. Daly, M.J. Barrett, J.C. Parkes, M. Annese, V. Hakonarson, H. Radford-Smith, G. Duerr, R.H. Vermeire, S. Weersma, R.K. Rioux, J.D.

Abstract

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10-8), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. © 2011 Nature America, Inc. All rights reserved.

Published
2011

28. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Author

Strawbridge, R.J. Dupuis, J. Prokopenko, I. Barker, A. Ahlqvist, E. Rybin, D. Petrie, J.R. Travers, M.E. Bouatia-Naji, N. Dimas, A.S. Nica, A.C. Wheeler, E. Chen, H. Voight, B.F. Taneera, J. Kanoni, S. Peden, J.F. Turrini, F. Gustafsson, S. Zabena, C. Almgren, P. Barker, D.J.P. Barnes, D. Dennison, E.M. Eriksson, J.G. Eriksson, P. Eury, E. Folkersen, L. Fox, C.S. Frayling, T.M. Goel, A. Gu, H.F. Horikoshi, M. Isomaa, B. Jackson, A.U. Jameson, K.A. Kajantie, E. Kerr-Conte, J. Kuulasmaa, T. Kuusisto, J. Loos, R.J.F. Luan, J. Makrilakis, K. Manning, A.K. Martínez-Larrad, M.T. Narisu, N. Mannila, M.N. Öhrvik, J. Osmond, C. Pascoe, L. Payne, F. Sayer, A.A. Sennblad, B. Silveira, A. Stančcáková, A. Stirrups, K. Swift, A.J. Syvänen, A.-C. Tuomi, T. Van't Hooft, F.M. Walker, M. Weedon, M.N. Xie, W. Zethelius, B. Scott, L.J. Steinthorsdottir, V. Morris, A.P. Dina, C. Welch, R.P. Zeggini, E. Huth, C. Aulchenko, Y.S. Thorleifsson, G. Mcculloch, L.J. Ferreira, T. Grallert, H. Amin, N. Wu, G. Willer, C.J. Raychaudhuri, S. McCarroll, S.A. Hofmann, O.M. Qi, L. Segre, A.V. Van Hoek, M. Navarro, P. Ardlie, K. Balkau, B. Benediktsson, R. Bennett, A.J. Blagieva, R. Boerwinkle, E. Bonnycastle, L.L. Bostrom, K.B. Bravenboer, B. Bumpstead, S. Burtt, N.P. Charpentier, G. Chines, P.S. Cornelis, M. Couper, D.J. Crawford, G. Doney, A.S.F. Elliott, K.S. Elliott, A.L. Erdos, M.R. Franklin, C.S. Ganser, M. Gieger, C. Grarup, N. Green, T. Griffin, S. Groves, C.J. Guiducci, C. Hadjadj, S. Hassanali, N. Herder, C. Johnson, P.R.V. Jorgensen, T. Kao, W.H.L. Klopp, N. Kong, A. Kraft, P. Lauritzen, T. Li, M. Lieverse, A. Lindgren, C.M. Lyssenko, V. Marre, M. Meitinger, T. Midthjell, K. Morken, M.A. Nilsson, P. Owen, K.R. Perry, J.R.B. Petersen, A.-K. Platou, C. Proenca, C. Rathmann, W. Rayner, N.W. Robertson, N.R. Rocheleau, G. Roden, M. Sampson, M.J. Saxena, R. Shields, B.M. Shrader, P. Sigurdsson, G. Sparso, T. Strassburger, K. Stringham, H.M. Sun, Q. Thorand, B. Tichet, J. Van Dam, R.M. Van Haeften, T.W. Van Herpt, T. Van Vliet-Ostaptchouk, J.V. Walters, G.B. Wijmenga, C. Witteman, J.C.M. Bergman, R.N. Cauchi, S. Collins, F.S. Gloyn, A.L. Gyllensten, U. Hansen, T. Hide, W.A. Hitman, G.A. Hofman, A. Hunter, D.J. Hveem, K. Laakso, M. Mohlke, K.L. Morris, A.D. Palmer, C.N.A. Pramstaller, P.P. Rudan, I. Sijbrands, E. Stein, L.D. Tuomilehto, J. Uitterlinden, A.G. Wareham, N.J. Watanabe, R.M. Abecasis, G.R. Boehm, B.O. Campbell, H. Daly, M.J. Hattersley, A.T. Hu, F.B. Meigs, J.B. Pankow, J.S. Pedersen, O. Wichmann, H.-E. Barroso, I. Groop, L. Sladek, R. Thorsteinsdottir, U. Wilson, J.F. Illig, T. Froguel, P. Van Duijn, C.M. Stefansson, K. Altshuler, D. Boehnke, M. McCarthy, M.I. Speliotes, E.K. Berndt, S.I. Monda, K.L. Allen, H.L. Magi, R. Randall, J.C. Vedantam, S. Winkler, T.W. Workalemahu, T. Heid, I.M. Wood, A.R. Weyant, R.J. Estrada, K. Liang, L. Nemesh, J. Park, J.-H. Kilpelainen, T.O. Yang, J. Esko, T. Feitosa, M.F. Kutalik, Z. Mangino, M. Scherag, A. Smith, A.V. Zhao, J.H. Aben, K.K. Absher, D.M. Dixon, A.L. Fisher, E. Glazer, N.L. Goddard, M.E. Heard-Costa, N.L. Hoesel, V. Hottenga, J.-J. Johansson, A. Johnson, T. Ketkar, S. Lamina, C. Li, S. Moffatt, M.F. Myers, R.H. Peters, M.J. Preuss, M. Ripatti, S. Rivadeneira, F. Sandholt, C. Timpson, N.J. Tyrer, J.P. Van Wingerden, S. White, C.C. Wiklund, F. Barlassina, C. Chasman, D.I. Cooper, M.N. Jansson, J.-O. Lawrence, R.W. Pellikka, N. Shi, J. Thiering, E. Alavere, H. Alibrandi, M.T.S. Arnold, A.M. Aspelund, T. Atwood, L.D. Balmforth, A.J. Ben-Shlomo, Y. Bergmann, S. Biebermann, H. Blakemore, A.I.F. Boes, T. Bornstein, S.R. Brown, M.J. Buchanan, T.A. Busonero, F. Cappuccio, F.P. Cavalcanti-Proenca, C. Chen, Y.-D.I. Chen, C.-M. Clarke, R. Coin, L. Connell, J. Day, I.N.M. Den Heijer, M. Duan, J. Ebrahim, S. Elliott, P. Elosua, R. Eiriksdottir, G. Facheris, M.F. Felix, S.B. Fischer-Posovszky, P. Folsom, A.R. Friedrich, N. Freimer, N.B. Fu, M. Gaget, S. Gejman, P.V. Geus, E.J.C. Gjesing, A.P. Goyette, P. Grasler, J. Greenawalt, D.M. Gudnason, V. Hartikainen, A.-L. Hall, A.S. Havulinna, A.S. Hayward, C. Heath, A.C. Hengstenberg, C. Hicks, A.A. Hinney, A. Homuth, G. Hui, J. Igl, W. Iribarren, C. Jacobs, K.B. Jarick, I. Jewell, E. John, U. Jousilahti, P. Jula, A. Kaakinen, M. Kaplan, L.M. Kathiresan, S. Kettunen, J. Kinnunen, L. Knowles, J.W. Kolcic, I. König, I.R. Koskinen, S. Kovacs, P. Kvaloy, K. Laitinen, J. Lantieri, O. Lanzani, C. Launer, L.J. Lecoeur, C. Lehtimaki, T. Lettre, G. Liu, J. Lokki, M.-L. Lorentzon, M. Luben, R.N. Ludwig, B. Manunta, P. Marek, D. Martin, N.G. McArdle, W.L. McCarthy, A. McKnight, B. Melander, O. Meyre, D. Montgomery, G.W. Mulic, R. Ngwa, J.S. Nelis, M. Neville, M.J. Nyholt, D.R. O'Donnell, C.J. O'Rahilly, S. Ong, K.K. Oostra, B. Pare, G. Parker, A.N. Perola, M. Pichler, I. Pietilainen, K.H. Platou, C.G.P. Polasek, O. Pouta, A. Rafelt, S. Raitakari, O. Rayner, N.W. Ridderstrale, M. Rief, W. Ruokonen, A. Rzehak, P. Salomaa, V. Sanders, A.R. Sandhu, M.S. Sanna, S. Saramies, J. Savolainen, M.J. Scherag, S. Schipf, S. Schreiber, S. Schunkert, H. Silander, K. Sinisalo, J. Siscovick, D.S. Smit, J.H. Soranzo, N. Sovio, U. Stephens, J. Surakka, I. Tammesoo, M.-L. Tardif, J.-C. Teder-Laving, M. Teslovich, T.M. Thompson, J.R. Thomson, B. Tonjes, A. Van Meurs, J.B.J. Van Ommen, G.-J. Vatin, V. Viikari, J. Visvikis-Siest, S. Vitart, V. Vogel, C.I.G. Waite, L.L. Wallaschofski, H. Widen, E. Wiegand, S. Wild, S.H. Willemsen, G. Witte, D.R. Xu, J. Zhang, Q. Zgaga, L. Ziegler, A. Zitting, P. Beilby, J.P. Farooqi, I.S. Hebebrand, J. Huikuri, H.V. James, A.L. Kahonen, M. Levinson, D.F. Macciardi, F. Nieminen, M.S. Ohlsson, C. Palmer, L.J. Ridker, P.M. Stumvoll, M. Beckmann, J.S. Boeing, H. Boomsma, D.I. Caulfield, M.J. Chanock, S.J. Cupples, L.A. Smith, G.D. Erdmann, J. Gronberg, H. Hall, P. Harris, T.B. Hayes, R.B. Heinrich, J. Jarvelin, M.-R. Kaprio, J. Karpe, F. Khaw, K.-T. Kiemeney, L.A. Krude, H. Lawlor, D.A. Metspalu, A. Munroe, P.B. Ouwehand, W.H. Penninx, B.W. Peters, A. Quertermous, T. Reinehr, T. Rissanen, A. Samani, N.J. Schwarz, P.E.H. Shuldiner, A.R. Spector, T.D. Uda, M. Valle, T.T. Wabitsch, M. Waeber, G. Watkins, H. Wright, A.F. Zillikens, M.C. Chatterjee, N. Purcell, S. Schadt, E.E. Visscher, P.M. Assimes, T.L. Borecki, I.B. Deloukas, P. Haritunians, T. Kaplan, R.C. O'Connell, J.R. Peltonen, L. Schlessinger, D. Strachan, D.P. North, K.E. Hirschhorn, J.N. Ingelsson, E. Parts, L. Glass, D. Nisbet, J. Barrett, A. Sekowska, M. Potter, S. Grundberg, E. Small, K. Hedman, A.K. Bataille, V. Bell, J.T. Surdulescu, G. Ingle, C. Nestle, F.O. Di Meglio, P. Min, J.L. Wilk, A. Hammond, C.J. Yang, T.-P. Montgomery, S.B. Zondervan, K.T. Durbin, R. Ahmadi, K. Dermitzakis, E.T. Reilly, M.P. Holm, H. Stewart, A.F.R. Barbalic, M. Aherrahrou, Z. Allayee, H. Anand, S.S. Andersen, K. Anderson, J.L. Ardissino, D. Ball, S.G. Barnes, T.A. Becker, D.M. Becker, L.C. Berger, K. Bis, J.C. Boekholdt, S.M. Braund, P.S. Burnett, M.S. Buysschaert, I. Carlquist, J.F. Chen, L. Codd, V. Davies, R.W. Cichon, S. Dedoussis, G.V. Demissie, S. Dehghan, A. Devaney, J.M. Diemert, P. Do, R. Doering, A. Eifert, S. El Mokhtari, N.E. Ellis, S.G. Engert, J.C. Epstein, S.E. De Faire, U. Fischer, M. Freyer, J. Gigante, B. Girelli, D. Gretarsdottir, S. Gulcher, J.R. Halperin, E. Hammond, N. Hazen, S.L. Horne, B.D. Jones, G.T. Jukema, J.W. Kaiser, M.A. Kastelein, J.J.P. Kolovou, G. Laaksonen, R. Lambrechts, D. Leander, K. Li, M. Lieb, W. Loley, C. Lotery, A.J. Mannucci, P.M. Maouche, S. Martinelli, N. McKeown, P.P. Meisinger, C. Merlini, P.A. Mooser, V. Morgan, T. Mühleisen, T.W. Muhlestein, J.B. Münzel, T. Musunuru, K. Nahrstaedt, J. Nelson, C.P. Nöthen, M.M. Olivieri, O. Patel, R.S. Patterson, C.C. Peyvandi, F. Qu, L. Quyyumi, A.A. Rader, D.J. Rallidis, L.S. Rice, C. Rosendaal, F.R. Rubin, D. Sampietro, M.L. Sandhu, M.S. Schadt, E. Schäfer, A. Schillert, A. Schrezenmeir, J. Schwartz, S.M. Sivananthan, M. Sivapalaratnam, S. Smith, T.B. Snoep, J.D. Spertus, J.A. Stark, K. Stoll, M. Wilson Tang, W.H. Tennstedt, S. Thorgeirsson, G. Tomaszewski, M. Van Rij, A.M. Wells, G.A. Wild, P.S. Willenborg, C. Wright, B.J. Ye, S. Zeller, T. Cambien, F. Goodall, A.H. Marz, W. Blankenberg, S. Roberts, R. McPherson, R. Hopewell, J.C. Parish, S. Offer, A. Bowman, L. Sleight, P. Armitage, J. Peto, R. Collins, R. Chambers, J.C. Ahmed, N. Donnelly, P. Kooner, A.S. Scott, J. Sehmi, J. Zhang, W. Kooner, J. Sabater-Lleal, M. Mälarstig, A. Hellénius, M.-L. Olsson, G. Rust, S. Assmann, G. Seedorf, U. Barlera, S. Tognoni, G. Franzosi, M.G. Linksted, P. Ongen, H. Kyriakou, T. Green, F. Farrall, M. Saleheen, D. Rasheed, A. Zaidi, M. Shah, N. Samuel, M. Mallick, N. Azhar, M. Zaman, K. Samad, A. Ishaq, M. Gardezi, A. Memon, F.-U.-R. Frossard, P. Danesh, J. Östenson, C.-G. Lind, L. Cooper, C.C. Serrano-Ríos, M. Ferrannini, E. Forsen, T.J. Pattou, F. Langenberg, C. Hamsten, A. Florez, J.C.

Subjects
endocrine system, endocrine system diseases, nutritional and metabolic diseases
Abstract

OBJECTIVE - Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired b-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS - We have conducted a meta-analysis of genome-wide association tests of ;2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS - Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10-8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/ C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 3 10-4), improved b-cell function (P = 1.1 × 10-5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10-6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS - We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis. © 2011 by the American Diabetes Association.

Published
2011

29. Common Variants at 10 Genomic Loci Influence Hemoglobin A(1C) Levels via Glycemic and Nonglycemic Pathways

Author

Soranzo, N, Sanna, S, Wheeler, E, Gieger, C, Radke, D, Dupuis, J, Bouatia-Naji, N, Langenberg, C, Prokopenko, I, Stolerman, E, Sandhu, MS, Heeney, MM, Devaney, JM, Reilly, MP, Ricketts, SL, Stewart, AF, Voight, BF, Willenborg, C, Wright, B, Altshuler, D, Arking, D, Balkau, B, Barnes, D, Boerwinkle, E, Böhm, B, Bonnefond, A, Bonnycastle, LL, Boomsma, DI, Bornstein, SR, Böttcher, Y, Bumpstead, S, Burnett-Miller, MS, Campbell, H, Cao, A, Chambers, J, Clark, R, Collins, FS, Coresh, J, de Geus, EJ, Dei, M, Deloukas, P, Döring, A, Egan, JM, Elosua, R, Ferrucci, L, Forouhi, N, Fox, CS, Franklin, C, Franzosi, MG, Gallina, S, Goel, A, Graessler, J, Grallert, H, Greinacher, A, Hadley, D, Hall, A, Hamsten, A, Hayward, C, Heath, S, Herder, C, Homuth, G, Hottenga, JJ, Hunter-Merrill, R, Illig, T, Jackson, AU, Jula, A, Kleber, M, Knouff, CW, Kong, A, Kooner, J, Köttgen, A, Kovacs, P, Krohn, K, Kühnel, B, Kuusisto, J, Laakso, M, Lathrop, M, Lecoeur, C, Li, M, Loos, RJ, Luan, J, Lyssenko, V, Mägi, R, Magnusson, PK, Mälarstig, A, Mangino, M, Martínez-Larrad, MT, März, W, McArdle, WL, McPherson, R, Meisinger, C, Meitinger, T, Melander, O, Mohlke, KL, Mooser, VE, Morken, MA, Narisu, N, Nathan, DM, Nauck, M, O'Donnell, C, Oexle, K, Olla, N, Pankow, JS, Payne, F, Peden, JF, Pedersen, NL, Peltonen, L, Perola, M, Polasek, O, Porcu, E, Rader, DJ, Rathmann, W, Ripatti, S, Rocheleau, G, Roden, M, Rudan, I, Salomaa, V, Saxena, R, Schlessinger, D, Schunkert, H, Schwarz, P, Seedorf, U, Selvin, E, Serrano-Ríos, M, Shrader, P, Silveira, A, Siscovick, D, Song, K, Spector, TD, Stefansson, K, Steinthorsdottir, V, Strachan, DP, Strawbridge, R, Stumvoll, M, Surakka, I, Swift, AJ, Tanaka, T, Teumer, A, Thorleifsson, G, Thorsteinsdottir, U, Tönjes, A, Usala, G, Vitart, V, Völzke, H, Wallaschofski, H, Waterworth, DM, Watkins, H, Wichmann, HE, Wild, SH, Willemsen, G, Williams, GH, Wilson, JF, Winkelmann, J, Wright, AF, WTCCC, Zabena, C, Zhao, JH, Epstein, SE, Erdmann, J, Hakonarson, HH, Kathiresan, S, Khaw, KT, Roberts, R, Samani, NJ, Fleming, MD, Sladek, R, Abecasis, G, Boehnke, M, Froguel, P, Groop, L, McCarthy, MI, Kao, WH, Florez, JC, Uda, M, Wareham, NJ, Barroso, I, and Meigs, JB

Subjects
endocrine system diseases, nutritional and metabolic diseases
Published
2010

30. THE arcOGEN CONSORTIUM: STAGE 1 OF A GENOME-WIDE ASSOCIATION SCAN FOR OSTEOARTHRITIS

Author

Panoutsopoulou, K., Southam, L., Rayner, W., Zhai, G., Beazley, C., Arden, N., Carr, A., Chapman, K., Deloukas, P., Doherty, M., McCaskie, A., Olher, W., Ralston, S., Spector, T., Valdes, A., Wallis, G., Wilkinson, M., Arden, E., Battley, K., Blackburn, H., Blanco, F., Bumpstead, S., Cupples, A., Day-Williams, A., Dixon, K., Dohertys, S., Elliott, K., Evangelou, E., Felson, D., Gomez-Reino, J., Gonzalez, A., Gordon, A., Gwilliam, R., Hofman, A., Hunt, S., Ioannidis, J., Jonsdottir, I., Keen, R., Kerkhof, H., Kloppenburg, M., Koller, N., Lakenberg, N., Lane, N., Lee, A., Meulenbelt, I., Nevitt, M., O'Neill, F., Parimi, N., Potter, S., Rego-Perez, I., Riancho, J., Sherburn, K., Slagboom, E., Styrkarsdottir, U., Sumillera, M., Swift, D., Tsezou, A., Uitterlinden, A., Meurs, J. van, Watkins, B., Wheeler, M., Mitchelle, S., Zhu, Y., Zmuda, J., Zeggini, E., Loughlin, J., and ArcOGEN Consortium

Abstract

Osteoarthritis and Cartilage

Published
2010

31. Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans

Author

Ingelsson, E., Graessler, J., Knowles, J. W., Zethelius, B., Chines, P., Buchanan, T. A., Assimes, T. L., Bergman, R. N., Collins, F. S., Hao, K., Lyssenko, V., Sharp, S., Langenberg, C., Dennison, E. M., Fox, C. S., Boehnke, M., Berne, C., Erdos, M. R., Ferrannini, E., Bumpstead, S. J., Jackson, A. U., Magi, R., Cooper, C. C., Hivert, M. F., Bergmann, A., Bornstein, S. R., Dupuis, J., Bonnycastle, L. L., Bottcher, Y., Prokopenko, I., Shrader, P., and Abbasi, F. A.

Abstract

OBJECTIVERecent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action.RESEARCH DESIGN AND METHODSWe investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084).RESULTSThe glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 × 10−71). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction.CONCLUSIONSGenetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.

Published
2010
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32. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Author

Postmus, D. (Douwe), Trompet, S. (Stella), Deshmukh, H. (Harshal), Barnes, M.J. (Michael), Li, X. (Xiaohui), Warren, H. (Helen), Chasman, D.I. (Daniel), Zhou, K. (Kaixin), Arsenault, B.J. (Benoit J.), Donnelly, L.A. (Louise), Wiggins, K.L. (Kerri), Avery, C.L., Griffin, P. (Paula), Feng, Q. (Qiping), Taylor, K.D. (Kent), Li, G. (Guo), Evans, D.S. (Daniel), Smith, A.V. (Davey), Keyser, C.E. (Catherina Elisabeth) de, Johnson, A.D. (Andrew), Craen, A.J. (Anton) de, Stott, D.J. (David. J.), Buckley, B.M. (Brendan M.), Ford, I., Westendorp, R.G.J. (Rudi), Slagboom, P.E. (Eline), Sattar, N. (Naveed), Munroe, P. (Patricia), Sever, P. (Peter), Poulter, N.R. (Neil), Stanton, A. (Alice), Shields, D.C. (Denis C.), O'Brien, E. (Eoin), Shaw-Hawkins, S. (Sue), Chen, Y.-D.I. (Ida), Nickerson, D.A. (Deborah), Smith, J.D. (Joshua D.), Dubé, G.P. (Gregory), Boekholdt, S.M. (Matthijs), Hovingh, G.K. (Kees), Kastelein, J.J.P. (John), Mckeigue, P.M. (Paul), Betteridge, J. (John), Neil, A. (Andrew), Durrington, P.N. (Paul), Doney, A.S.F. (Alex), Carr, F. (Fiona), Morris, A.D. (Andrew), McCarthy, M.I. (Mark), Groop, L. (Leif), Ahlqvist, E. (Emma), Barroso, I.E. (Inês), Blackwell, K.L. (Kimberly), Bramon, E. (Elvira), Brown, M.A. (Matthew), Casas, J.P. (Juan), Corvin, A. (Aiden), Deloukas, P. (Panagiotis), Duncanson, A. (Audrey), Jankowski, J.A. (Janusz Antoni), Markus, H.S. (Hugh), Mathew, C.G. (Christopher G.), Palmer, C.N.A. (Colin), Plomin, R. (Robert), Rautanen, A. (Anna), Sawcer, S.J. (Stephen), Trembath, R.C. (Richard), Viswanathan, A.C. (Ananth), Wood, N.W. (Nicholas), 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), Donnelly, P. (Peter), Langford, C. (Cordelia), Hunt, S.E. (Sarah), 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, M. (Matthew), Weston, P. (Paul), Widaa, S. (Sara), Whittaker, P. (Pamela), Bis, J.C. (Joshua), Rice, K.M. (Kenneth), Smith, N.L. (Nicholas), Lumley, T. (Thomas), Whitsel, E.A. (Eric), Stürmer, T., Boerwinkle, E.A. (Eric), Ngwa, J.S., O'Donnell, C.J. (Christopher J.), Vasan, R.S. (Ramachandran Srini), Wei, W.-Q. (Wei-Qi), Wilke, R.A. (Russell A.), Liu, C.-T. (Ching-Ti), Sun, F. (Fangui), Guo, X. (Xiuqing), Heckbert, S.R. (Susan), Post, W. (Wendy), Sotoodehnia, N. (Nona), Arnold, A.M. (Alice), Stafford, J.M. (Jeanette M.), Ding, J. (Jingzhong), Herrington, D.M. (David), Kritchevsky, S.B. (Stephen), Eiriksdottir, G. (Gudny), Launer, L.J. (Lenore), Harris, T.B. (Tamara), Chu, A.Y. (Audrey), Giulianini, F. (Franco), MacFadyen, J.G. (Jean G.), Barratt, B.J. (Bryan J.), Nyberg, F. (Fredrik), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Hofman, A. (Albert), Rivadeneira Ramirez, F. (Fernando), Emilsson, V. (Valur), Franco, O.H. (Oscar), Ridker, P.M. (Paul), Gudnason, V. (Vilmundur), Liu, Y. (YongMei), Denny, J.C. (Joshua C.), Ballantyne, C. (Christie), Rotter, J.I. (Jerome I.), Cupples, L.A. (Adrienne), Psaty, B.M. (Bruce), Tardif, J.-C. (Jean-Claude), Colhoun, H.M. (H.), Hitman, G.A. (Graham), Krauss, R.M. (Ronald), Jukema, J.W. (Jan Wouter), Caulfield, M. (Mark), Postmus, D. (Douwe), Trompet, S. (Stella), Deshmukh, H. (Harshal), Barnes, M.J. (Michael), Li, X. (Xiaohui), Warren, H. (Helen), Chasman, D.I. (Daniel), Zhou, K. (Kaixin), Arsenault, B.J. (Benoit J.), Donnelly, L.A. (Louise), Wiggins, K.L. (Kerri), Avery, C.L., Griffin, P. (Paula), Feng, Q. (Qiping), Taylor, K.D. (Kent), Li, G. (Guo), Evans, D.S. (Daniel), Smith, A.V. (Davey), Keyser, C.E. (Catherina Elisabeth) de, Johnson, A.D. (Andrew), Craen, A.J. (Anton) de, Stott, D.J. (David. J.), Buckley, B.M. (Brendan M.), Ford, I., Westendorp, R.G.J. (Rudi), Slagboom, P.E. (Eline), Sattar, N. (Naveed), Munroe, P. (Patricia), Sever, P. (Peter), Poulter, N.R. (Neil), Stanton, A. (Alice), Shields, D.C. (Denis C.), O'Brien, E. (Eoin), Shaw-Hawkins, S. (Sue), Chen, Y.-D.I. (Ida), Nickerson, D.A. (Deborah), Smith, J.D. (Joshua D.), Dubé, G.P. (Gregory), Boekholdt, S.M. (Matthijs), Hovingh, G.K. (Kees), Kastelein, J.J.P. (John), Mckeigue, P.M. (Paul), Betteridge, J. (John), Neil, A. (Andrew), Durrington, P.N. (Paul), Doney, A.S.F. (Alex), Carr, F. (Fiona), Morris, A.D. (Andrew), McCarthy, M.I. (Mark), Groop, L. (Leif), Ahlqvist, E. (Emma), Barroso, I.E. (Inês), Blackwell, K.L. (Kimberly), Bramon, E. (Elvira), Brown, M.A. (Matthew), Casas, J.P. (Juan), Corvin, A. (Aiden), Deloukas, P. (Panagiotis), Duncanson, A. (Audrey), Jankowski, J.A. (Janusz Antoni), Markus, H.S. (Hugh), Mathew, C.G. (Christopher G.), Palmer, C.N.A. (Colin), Plomin, R. (Robert), Rautanen, A. (Anna), Sawcer, S.J. (Stephen), Trembath, R.C. (Richard), Viswanathan, A.C. (Ananth), Wood, N.W. (Nicholas), 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), Donnelly, P. (Peter), Langford, C. (Cordelia), Hunt, S.E. (Sarah), 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, M. (Matthew), Weston, P. (Paul), Widaa, S. (Sara), Whittaker, P. (Pamela), Bis, J.C. (Joshua), Rice, K.M. (Kenneth), Smith, N.L. (Nicholas), Lumley, T. (Thomas), Whitsel, E.A. (Eric), Stürmer, T., Boerwinkle, E.A. (Eric), Ngwa, J.S., O'Donnell, C.J. (Christopher J.), Vasan, R.S. (Ramachandran Srini), Wei, W.-Q. (Wei-Qi), Wilke, R.A. (Russell A.), Liu, C.-T. (Ching-Ti), Sun, F. (Fangui), Guo, X. (Xiuqing), Heckbert, S.R. (Susan), Post, W. (Wendy), Sotoodehnia, N. (Nona), Arnold, A.M. (Alice), Stafford, J.M. (Jeanette M.), Ding, J. (Jingzhong), Herrington, D.M. (David), Kritchevsky, S.B. (Stephen), Eiriksdottir, G. (Gudny), Launer, L.J. (Lenore), Harris, T.B. (Tamara), Chu, A.Y. (Audrey), Giulianini, F. (Franco), MacFadyen, J.G. (Jean G.), Barratt, B.J. (Bryan J.), Nyberg, F. (Fredrik), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Hofman, A. (Albert), Rivadeneira Ramirez, F. (Fernando), Emilsson, V. (Valur), Franco, O.H. (Oscar), Ridker, P.M. (Paul), Gudnason, V. (Vilmundur), Liu, Y. (YongMei), Denny, J.C. (Joshua C.), Ballantyne, C. (Christie), Rotter, J.I. (Jerome I.), Cupples, L.A. (Adrienne), Psaty, B.M. (Bruce), Tardif, J.-C. (Jean-Claude), Colhoun, H.M. (H.), Hitman, G.A. (Graham), Krauss, R.M. (Ronald), Jukema, J.W. (Jan Wouter), and Caulfield, M. (Mark)

Published
2014
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33. Distribution and Medical Impact of Loss-of-Function Variants in the Finnish Founder Population

Author

Cutler, D, Lim, ET, Wuertz, P, Havulinna, AS, Palta, P, Tukiainen, T, Rehnstrom, K, Esko, T, Magi, R, Inouye, M, Lappalainen, T, Chan, Y, Salem, RM, Lek, M, Flannick, J, Sim, X, Manning, A, Ladenvall, C, Bumpstead, S, Hamalainen, E, Aalto, K, Maksimow, M, Salmi, M, Blankenberg, S, Ardissino, D, Shah, S, Horne, B, McPherson, R, Hovingh, GK, Reilly, MP, Watkins, H, Goel, A, Farrall, M, Girelli, D, Reiner, AP, Stitziel, NO, Kathiresan, S, Gabriel, S, Barrett, JC, Lehtimaki, T, Laakso, M, Groop, L, Kaprio, J, Perola, M, McCarthy, MI, Boehnke, M, Altshuler, DM, Lindgren, CM, Hirschhorn, JN, Metspalu, A, Freimer, NB, Zeller, T, Jalkanen, S, Koskinen, S, Raitakari, O, Durbin, R, MacArthur, DG, Salomaa, V, Ripatti, S, Daly, MJ, Palotie, A, Cutler, D, Lim, ET, Wuertz, P, Havulinna, AS, Palta, P, Tukiainen, T, Rehnstrom, K, Esko, T, Magi, R, Inouye, M, Lappalainen, T, Chan, Y, Salem, RM, Lek, M, Flannick, J, Sim, X, Manning, A, Ladenvall, C, Bumpstead, S, Hamalainen, E, Aalto, K, Maksimow, M, Salmi, M, Blankenberg, S, Ardissino, D, Shah, S, Horne, B, McPherson, R, Hovingh, GK, Reilly, MP, Watkins, H, Goel, A, Farrall, M, Girelli, D, Reiner, AP, Stitziel, NO, Kathiresan, S, Gabriel, S, Barrett, JC, Lehtimaki, T, Laakso, M, Groop, L, Kaprio, J, Perola, M, McCarthy, MI, Boehnke, M, Altshuler, DM, Lindgren, CM, Hirschhorn, JN, Metspalu, A, Freimer, NB, Zeller, T, Jalkanen, S, Koskinen, S, Raitakari, O, Durbin, R, MacArthur, DG, Salomaa, V, Ripatti, S, Daly, MJ, and Palotie, A

Abstract

Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10⁻⁸) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5×10⁻¹¹⁷). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10⁻⁴), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers.

Published
2014

34. A variant in LDLR is associated with abdominal aortic aneurysm

Author

Bradley, D.T., Hughes, A.E., Badger, S.A., Jones, G.T., Harrison, S.C., Wright, B.J., Bumpstead, S., Baas, A.F., Gretarsdottir, S., Burnand, K., Child, A.H., Clough, R.E., Cockerill, G., Hafez, H., Scott, D.J., Ariens, R.A., Johnson, A., Sohrabi, S., Smith, A., Thompson, M.M., Bockxmeer, F.M. van, Waltham, M., Matthiasson, S.E., Thorleifsson, G., Thorsteinsdottir, U., Blankensteijn, J.D., Teijink, J.A., Wijmenga, C., Graaf, J. de, Kiemeney, L.A.L.M., Wild, J.B., Edkins, S., Gwilliam, R., Hunt, S.E., Potter, S., Lindholt, J.S., Golledge, J., Norman, P.E., Rij, A. van, Powell, J.T., Eriksson, P., Stefansson, K., Thompson, J.R., Humphries, S.E., Sayers, R.D., Deloukas, P., Samani, N.J., Bown, M.J., Bradley, D.T., Hughes, A.E., Badger, S.A., Jones, G.T., Harrison, S.C., Wright, B.J., Bumpstead, S., Baas, A.F., Gretarsdottir, S., Burnand, K., Child, A.H., Clough, R.E., Cockerill, G., Hafez, H., Scott, D.J., Ariens, R.A., Johnson, A., Sohrabi, S., Smith, A., Thompson, M.M., Bockxmeer, F.M. van, Waltham, M., Matthiasson, S.E., Thorleifsson, G., Thorsteinsdottir, U., Blankensteijn, J.D., Teijink, J.A., Wijmenga, C., Graaf, J. de, Kiemeney, L.A.L.M., Wild, J.B., Edkins, S., Gwilliam, R., Hunt, S.E., Potter, S., Lindholt, J.S., Golledge, J., Norman, P.E., Rij, A. van, Powell, J.T., Eriksson, P., Stefansson, K., Thompson, J.R., Humphries, S.E., Sayers, R.D., Deloukas, P., Samani, N.J., and Bown, M.J.

Abstract

Item does not contain fulltext, BACKGROUND: Abdominal aortic aneurysm (AAA) is a common cardiovascular disease among older people and demonstrates significant heritability. In contrast to similar complex diseases, relatively few genetic associations with AAA have been confirmed. We reanalyzed our genome-wide study and carried through to replication suggestive discovery associations at a lower level of significance. METHODS AND RESULTS: A genome-wide association study was conducted using 1830 cases from the United Kingdom, New Zealand, and Australia with infrarenal aorta diameter>/=30 mm or ruptured AAA and 5435 unscreened controls from the 1958 Birth Cohort and National Blood Service cohort from the Wellcome Trust Case Control Consortium. Eight suggestive associations with P<1x10(-4) were carried through to in silico replication in 1292 AAA cases and 30,503 controls. One single-nucleotide polymorphism associated with P<0.05 after Bonferroni correction in the in silico study underwent further replication (706 AAA cases and 1063 controls from the United Kingdom, 507 AAA cases and 199 controls from Denmark, and 885 AAA cases and 1000 controls from New Zealand). Low-density lipoprotein receptor (LDLR) rs6511720 A was significantly associated overall and in 3 of 5 individual replication studies. The full study showed an association that reached genome-wide significance (odds ratio, 0.76; 95% confidence interval, 0.70-0.83; P=2.08x10(-10)). CONCLUSIONS: LDLR rs6511720 is associated with AAA. This finding is consistent with established effects of this variant on coronary artery disease. Shared causal pathways with other cardiovascular diseases may present novel opportunities for preventative and therapeutic strategies for AAA.

Published
2013

35. Genome-wide association study of intraocular pressure identifies the GLCCI1/ICA1 region as a glaucoma susceptibility locus

Author

Strange, A., Bellenguez, C., Sim, X., Luben, R., Hysi, P. G., Ramdas, W. D., van Koolwijk, L. M. E., Freeman, C., Pirinen, M., Su, Z., Band, G., Pearson, R., Vukcevic, D., Langford, C., Deloukas, P., Hunt, S., Gray, E., Dronov, S., Potter, S. C., Tashakkori-Ghanbaria, A., Edkins, S., Bumpstead, S. J., Blackwell, J. M., Bramon, E., Brown, M. A., Casas, J. P., Corvin, A., Duncanson, A., Jankowski, Janusz, Markus, H. S., Mathew, C. G., Palmer, C. N. A., Plomin, R., Rautanen, A., Sawcer, S. J., Trembath, R. C., Wood, N. W., Barroso, I., Peltonen, L., Healey, P., McGuffin, P., Topouzis, F., Klaver, C. C. W., van Duijn, C. M., Mackey, D. A., Young, T. L., Hammond, C. J., Khaw, K.-T., Wareham, N., Wang, J. J., Wong, T. Y., Foster, P. J., Mitchell, P., Spencer, C. C. A., Donnelly, P., Viswanathan, A. C., Strange, A., Bellenguez, C., Sim, X., Luben, R., Hysi, P. G., Ramdas, W. D., van Koolwijk, L. M. E., Freeman, C., Pirinen, M., Su, Z., Band, G., Pearson, R., Vukcevic, D., Langford, C., Deloukas, P., Hunt, S., Gray, E., Dronov, S., Potter, S. C., Tashakkori-Ghanbaria, A., Edkins, S., Bumpstead, S. J., Blackwell, J. M., Bramon, E., Brown, M. A., Casas, J. P., Corvin, A., Duncanson, A., Jankowski, Janusz, Markus, H. S., Mathew, C. G., Palmer, C. N. A., Plomin, R., Rautanen, A., Sawcer, S. J., Trembath, R. C., Wood, N. W., Barroso, I., Peltonen, L., Healey, P., McGuffin, P., Topouzis, F., Klaver, C. C. W., van Duijn, C. M., Mackey, D. A., Young, T. L., Hammond, C. J., Khaw, K.-T., Wareham, N., Wang, J. J., Wong, T. Y., Foster, P. J., Mitchell, P., Spencer, C. C. A., Donnelly, P., and Viswanathan, A. C.

Abstract

To discover quantitative trait loci for intraocular pressure, a major risk factor for glaucoma and the only modifiable one, we performed a genome-wide association study on a discovery cohort of 2175 individuals from Sydney, Australia. We found a novel association between intraocular pressure and a common variant at 7p21 near to GLCCI1 and ICA1. The findings in this region were confirmed through two UK replication cohorts totalling 4866 individuals (rs59072263, Pcombined = 1.10 × 10−8). A copy of the G allele at this SNP is associated with an increase in mean IOP of 0.45 mmHg (95%CI = 0.30–0.61 mmHg). These results lend support to the implication of vesicle trafficking and glucocorticoid inducibility pathways in the determination of intraocular pressure and in the pathogenesis of primary open-angle glaucoma.

Published
2013

36. Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis

Author

Beaudoin, M, Goyette, P, Boucher, G, Lo, KS, Rivas, MA, Stevens, C, Alikashani, A, Ladouceur, M, Ellinghaus, D, Törkvist, L, Goel, G, Lagacé, C, Annese, V, Bitton, A, Begun, J, Brant, SR, Bresso, F, Cho, JH, Duerr, RH, Halfvarson, J, McGovern, DPB, Radford-Smith, GL, Schreiber, S, Schumm, PL, Sharma, Y, Silverberg, MS, Weersma, RK, D'Amato, M, Vermeire, S, Franke, A, Lettre, G, Xavier, RJ, Daly, MJ, Rioux, JD, Aumais, G, Bernard, EJ, Cohen, A, Deslandres, C, Lahaie, R, Paré, P, Targan, SR, Rutgeerts, P, Steinhart, AH, Ahmad, T, Anderson, CA, Baldassano, RN, Balschun, T, Barclay, M, Barrett, JC, Bayless, TM, Bis, JC, Brand, S, Bumpstead, S, Buning, C, Colombel, JF, Cottone, M, D'Inca, R, Denson, T, Dubinsky, M, Edwards, C, Florin, T, Franchimont, D, Gearry, R, Georges, M, Glas, J, van Gossum, A, Griffiths, AM, Guthery, SL, Hakonarson, H, Haritunians, T, Hugot, JP, de Jong, DJ, Jostins, L, Kugathasan, S, Kullak-Ublick, G, Latiano, A, Laukens, D, Lawrance, I, Lee, J, Lees, CW, Lemann, M, Levine, A, Libioulle, C, Louis, E, Mansfield, JC, Mathew, CG, Mitrovic, M, Montgomery, GW, Mowat, C, Newman, W, Palmieri, O, Panés, J, Parkes, M, Phillips, A, Ponsioen, CY, Potocnik, U, Prescott, NJ, Proctor, DD, Regueiro, M, Beaudoin, M, Goyette, P, Boucher, G, Lo, KS, Rivas, MA, Stevens, C, Alikashani, A, Ladouceur, M, Ellinghaus, D, Törkvist, L, Goel, G, Lagacé, C, Annese, V, Bitton, A, Begun, J, Brant, SR, Bresso, F, Cho, JH, Duerr, RH, Halfvarson, J, McGovern, DPB, Radford-Smith, GL, Schreiber, S, Schumm, PL, Sharma, Y, Silverberg, MS, Weersma, RK, D'Amato, M, Vermeire, S, Franke, A, Lettre, G, Xavier, RJ, Daly, MJ, Rioux, JD, Aumais, G, Bernard, EJ, Cohen, A, Deslandres, C, Lahaie, R, Paré, P, Targan, SR, Rutgeerts, P, Steinhart, AH, Ahmad, T, Anderson, CA, Baldassano, RN, Balschun, T, Barclay, M, Barrett, JC, Bayless, TM, Bis, JC, Brand, S, Bumpstead, S, Buning, C, Colombel, JF, Cottone, M, D'Inca, R, Denson, T, Dubinsky, M, Edwards, C, Florin, T, Franchimont, D, Gearry, R, Georges, M, Glas, J, van Gossum, A, Griffiths, AM, Guthery, SL, Hakonarson, H, Haritunians, T, Hugot, JP, de Jong, DJ, Jostins, L, Kugathasan, S, Kullak-Ublick, G, Latiano, A, Laukens, D, Lawrance, I, Lee, J, Lees, CW, Lemann, M, Levine, A, Libioulle, C, Louis, E, Mansfield, JC, Mathew, CG, Mitrovic, M, Montgomery, GW, Mowat, C, Newman, W, Palmieri, O, Panés, J, Parkes, M, Phillips, A, Ponsioen, CY, Potocnik, U, Prescott, NJ, Proctor, DD, and Regueiro, M

Abstract

Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci. © 2013 Beaudoin et al.

Published
2013

37. A systematic survey of loss-of-function variants in human protein-coding genes

Author

MacArthur, D.G., Balasubramanian, S., Frankish, A., Huang, N., Morris, J., Walter, K., Jostins, L., Habegger, L., Pickrell, J.K., Montgomery, S.B., Albers, C.A., Zhang, Z.D., Conrad, D.F., Lunter, G., Zheng, H., Ayub, Q., DePristo, M.A., Banks, E., Hu, M., Handsaker, R.E., Rosenfeld, J.A., Fromer, M., Jin, M., Mu, X.J., Khurana, E., Ye, K., Kay, M., Saunders, G.I., Suner, M.M., Hunt, T., Barnes, I.H., Amid, C., Carvalho-Silva, D.R., Bignell, A.H., Snow, C., Yngvadottir, B., Bumpstead, S., Cooper, D.N., Xue, Y., Romero, I.G., Genomes Project, C., Wang, J, Li, Y., Gibbs, R.A., McCarroll, S.A., Dermitzakis, E.T., Pritchard, J.K., Barrett, J.C., Harrow, J., Hurles, M.E., Gerstein, M.B., Tyler-Smith, C., MacArthur, D.G., Balasubramanian, S., Frankish, A., Huang, N., Morris, J., Walter, K., Jostins, L., Habegger, L., Pickrell, J.K., Montgomery, S.B., Albers, C.A., Zhang, Z.D., Conrad, D.F., Lunter, G., Zheng, H., Ayub, Q., DePristo, M.A., Banks, E., Hu, M., Handsaker, R.E., Rosenfeld, J.A., Fromer, M., Jin, M., Mu, X.J., Khurana, E., Ye, K., Kay, M., Saunders, G.I., Suner, M.M., Hunt, T., Barnes, I.H., Amid, C., Carvalho-Silva, D.R., Bignell, A.H., Snow, C., Yngvadottir, B., Bumpstead, S., Cooper, D.N., Xue, Y., Romero, I.G., Genomes Project, C., Wang, J, Li, Y., Gibbs, R.A., McCarroll, S.A., Dermitzakis, E.T., Pritchard, J.K., Barrett, J.C., Harrow, J., Hurles, M.E., Gerstein, M.B., and Tyler-Smith, C.

Abstract

Item does not contain fulltext, Genome-sequencing studies indicate that all humans carry many genetic variants predicted to cause loss of function (LoF) of protein-coding genes, suggesting unexpected redundancy in the human genome. Here we apply stringent filters to 2951 putative LoF variants obtained from 185 human genomes to determine their true prevalence and properties. We estimate that human genomes typically contain ~100 genuine LoF variants with ~20 genes completely inactivated. We identify rare and likely deleterious LoF alleles, including 26 known and 21 predicted severe disease-causing variants, as well as common LoF variants in nonessential genes. We describe functional and evolutionary differences between LoF-tolerant and recessive disease genes and a method for using these differences to prioritize candidate genes found in clinical sequencing studies.

Published
2012

38. A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance.

Author

DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Multiple Tissue Human Expression Resource (MUTHER) Consortium, Ahmadi, K.R., Ainali, C., Barrett, A., Bataille, V., Bell, J.T., Buil, A., Deloukas, P., Dermitzakis, E.T., Dimas, A.S., Durbin, R., Glass, D., Grundberg, E., Hassanali, N., Hedman, Å.K., Ingle, C., Knowles, D., Krestyaninova, M., Lindgren, C.M., Lowe, C.E., McCarthy, M.I., Meduri, E., di Meglio, P., Min, J.L., Montgomery, S.B., Nestle, F.O., Nica, A.C., Nisbet, J., O'Rahilly, S., Parts, L., Potter, S., Sekowska, M., Shin, S.Y., Small, K.S., Soranzo, N., Spector, T.D., Surdulescu, G., Travers, M.E., Tsaprouni, L., Tsoka, S., Wilk, A., Yang, T.P., Zondervan, K.T., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Morris, A.P., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Langenberg, C., Hofmann, O.M., Dupuis, J., Qi, L., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Couper, D.J., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Klopp, N., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Perry, J.R., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Mohlke, K.L., Morris, A.D., Palmer, C.N., Pramstaller, P.P., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Wareham, N.J., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Hu, F.B., Meigs, J.B., Pankow, J.S., Pedersen, O., Wichmann, H.E., Barroso, I., Florez, J.C., Frayling, T.M., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., Manning, A.K., Hivert, M.F., Scott, R.A., Grimsby, J.L., Bouatia-Naji, N., Chen, H., Rybin, D., Liu, C.T., Bielak, L.F., Barnes, D., Cadby, G., Hottenga, J.J., Ingelsson, E., Johnson, T., Kanoni, S., Ladenvall, C., Lagou, V., Lahti, J., Lecoeur, C., Liu, Y., Martinez-Larrad, M.T., Montasser, M.E., Rasmussen-Torvik, L.J., Salo, P., Sattar, N., Shungin, D., Strawbridge, R.J., Tanaka, T., An, P., de Andrade, M., Andrews, J.S., Aspelund, T., Atalay, M., Aulchenko, Y., Bandinelli, S., Beckmann, J.S., Beilby, J.P., Bellis, C., Blangero, J., Boban, M., Boomsma, D.I., Borecki, I.B., Böttcher, Y., Bouchard, C., Brunner, E., Budimir, D., Carlson, O., Clarke, R., Corbatón-Anchuelo, A., Couper, D., de Faire, U., Dedoussis, G.V., Dimitriou, M., Egan, J.M., Eiriksdottir, G., Eriksson, J.G., Eury, E., Ferrucci, L., Ford, I., Forouhi, N.G., Franzosi, M.G., Franks, P.W., Galan, P., de Geus, E., Gigante, B., Glazer, N.L., Goel, A., Gudnason, V., Hallmans, G., Hamsten, A., Hansson, O., Harris, T.B., Hayward, C., Heath, S., Hercberg, S., Hicks, A.A., Hingorani, A., Hui, J., Hung, J., Jarvelin, M.R., Jhun, M.A., Johnson, P.C., Jukema, J.W., Jula, A., Kaprio, J., Kardia, S.L., Keinanen-Kiukaanniemi, S., Kivimaki, M., Kolcic, I., Kovacs, P., Kumari, M., Kyvik, K.O., Lakka, T., Lannfelt, L., Lathrop, G.M., Launer, L.J., Leander, K., Li, G., Lind, L., Lindstrom, J., Lobbens, S., Loos, R.J., Luan, J., Mägi, R., Magnusson, P.K., Marmot, M., Meneton, P., Mooser, V., Miljkovic, I., O'Connell, J., Ong, K.K., Oostra, B.A., Palmer, L.J., Palotie, A., Peden, J.F., Pedersen, N.L., Pehlic, M., Peltonen, L., Penninx, B., Pericic, M., Perola, M., Perusse, L., Peyser, P.A., Polasek, O., Province, M.A., Räikkönen, K., Rauramaa, R., Rehnberg, E., Rice, K., Rotter, J.I., Ruokonen, A., Saaristo, T., Sabater-Lleal, M., Salomaa, V., Savage, D.B., Schwarz, P., Seedorf, U., Sennblad, B., Serrano-Rios, M., Shuldiner, A.R., Sijbrands, E.J., Siscovick, D.S., Smit, J.H., Smith, N.L., Smith, A.V., Stančáková, A., Stirrups, K., Stumvoll, M., Sun, Y.V., Tönjes, A., Trompet, S., Uitterlinden, A.G., Uusitupa, M., Vikström, M., Vitart, V., Vohl, M.C., Vollenweider, P., Waeber, G., Waterworth, D.M., Watkins, H., Wheeler, E., Widen, E., Wild, S.H., Willems, S.M., Willemsen, G., Witteman, J.C., Wright, A.F., Yaghootkar, H., Zelenika, D., Zemunik, T., Zgaga, L., DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Multiple Tissue Human Expression Resource (MUTHER) Consortium, Ahmadi, K.R., Ainali, C., Barrett, A., Bataille, V., Bell, J.T., Buil, A., Deloukas, P., Dermitzakis, E.T., Dimas, A.S., Durbin, R., Glass, D., Grundberg, E., Hassanali, N., Hedman, Å.K., Ingle, C., Knowles, D., Krestyaninova, M., Lindgren, C.M., Lowe, C.E., McCarthy, M.I., Meduri, E., di Meglio, P., Min, J.L., Montgomery, S.B., Nestle, F.O., Nica, A.C., Nisbet, J., O'Rahilly, S., Parts, L., Potter, S., Sekowska, M., Shin, S.Y., Small, K.S., Soranzo, N., Spector, T.D., Surdulescu, G., Travers, M.E., Tsaprouni, L., Tsoka, S., Wilk, A., Yang, T.P., Zondervan, K.T., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Morris, A.P., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Langenberg, C., Hofmann, O.M., Dupuis, J., Qi, L., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Couper, D.J., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Klopp, N., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Perry, J.R., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Mohlke, K.L., Morris, A.D., Palmer, C.N., Pramstaller, P.P., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Wareham, N.J., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Hu, F.B., Meigs, J.B., Pankow, J.S., Pedersen, O., Wichmann, H.E., Barroso, I., Florez, J.C., Frayling, T.M., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., Manning, A.K., Hivert, M.F., Scott, R.A., Grimsby, J.L., Bouatia-Naji, N., Chen, H., Rybin, D., Liu, C.T., Bielak, L.F., Barnes, D., Cadby, G., Hottenga, J.J., Ingelsson, E., Johnson, T., Kanoni, S., Ladenvall, C., Lagou, V., Lahti, J., Lecoeur, C., Liu, Y., Martinez-Larrad, M.T., Montasser, M.E., Rasmussen-Torvik, L.J., Salo, P., Sattar, N., Shungin, D., Strawbridge, R.J., Tanaka, T., An, P., de Andrade, M., Andrews, J.S., Aspelund, T., Atalay, M., Aulchenko, Y., Bandinelli, S., Beckmann, J.S., Beilby, J.P., Bellis, C., Blangero, J., Boban, M., Boomsma, D.I., Borecki, I.B., Böttcher, Y., Bouchard, C., Brunner, E., Budimir, D., Carlson, O., Clarke, R., Corbatón-Anchuelo, A., Couper, D., de Faire, U., Dedoussis, G.V., Dimitriou, M., Egan, J.M., Eiriksdottir, G., Eriksson, J.G., Eury, E., Ferrucci, L., Ford, I., Forouhi, N.G., Franzosi, M.G., Franks, P.W., Galan, P., de Geus, E., Gigante, B., Glazer, N.L., Goel, A., Gudnason, V., Hallmans, G., Hamsten, A., Hansson, O., Harris, T.B., Hayward, C., Heath, S., Hercberg, S., Hicks, A.A., Hingorani, A., Hui, J., Hung, J., Jarvelin, M.R., Jhun, M.A., Johnson, P.C., Jukema, J.W., Jula, A., Kaprio, J., Kardia, S.L., Keinanen-Kiukaanniemi, S., Kivimaki, M., Kolcic, I., Kovacs, P., Kumari, M., Kyvik, K.O., Lakka, T., Lannfelt, L., Lathrop, G.M., Launer, L.J., Leander, K., Li, G., Lind, L., Lindstrom, J., Lobbens, S., Loos, R.J., Luan, J., Mägi, R., Magnusson, P.K., Marmot, M., Meneton, P., Mooser, V., Miljkovic, I., O'Connell, J., Ong, K.K., Oostra, B.A., Palmer, L.J., Palotie, A., Peden, J.F., Pedersen, N.L., Pehlic, M., Peltonen, L., Penninx, B., Pericic, M., Perola, M., Perusse, L., Peyser, P.A., Polasek, O., Province, M.A., Räikkönen, K., Rauramaa, R., Rehnberg, E., Rice, K., Rotter, J.I., Ruokonen, A., Saaristo, T., Sabater-Lleal, M., Salomaa, V., Savage, D.B., Schwarz, P., Seedorf, U., Sennblad, B., Serrano-Rios, M., Shuldiner, A.R., Sijbrands, E.J., Siscovick, D.S., Smit, J.H., Smith, N.L., Smith, A.V., Stančáková, A., Stirrups, K., Stumvoll, M., Sun, Y.V., Tönjes, A., Trompet, S., Uitterlinden, A.G., Uusitupa, M., Vikström, M., Vitart, V., Vohl, M.C., Vollenweider, P., Waeber, G., Waterworth, D.M., Watkins, H., Wheeler, E., Widen, E., Wild, S.H., Willems, S.M., Willemsen, G., Witteman, J.C., Wright, A.F., Yaghootkar, H., Zelenika, D., Zemunik, T., and Zgaga, L.

Abstract

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

Published
2012

39. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Author

DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Procardis Consortium, MAGIC investigators, GLGC Consortium, Olson, J., Kronmal, R., Robbins, J., Chaves, PH., Burke, G., Kuller, LH., Tracy, R., Gottdiener, J., Prineas, R., Becker, JT., Enright, P., Klein, R., O'Leary, DH., Dastani, Z., Hivert, M.F., Timpson, N., Perry, J.R., Yuan, X., Scott, R.A., Henneman, P., Heid, I.M., Kizer, J.R., Lyytikäinen, L.P., Fuchsberger, C., Tanaka, T., Morris, A.P., Small, K., Isaacs, A., Beekman, M., Coassin, S., Lohman, K., Qi, L., Kanoni, S., Pankow, J.S., Uh, H.W., Wu, Y., Bidulescu, A., Rasmussen-Torvik, L.J., Greenwood, C.M., Ladouceur, M., Grimsby, J., Manning, A.K., Liu, C.T., Kooner, J., Mooser, V.E., Vollenweider, P., Kapur, K.A., Chambers, J., Wareham, N.J., Langenberg, C., Frants, R., Willems-Vandijk, K., Oostra, B.A., Willems, S.M., Lamina, C., Winkler, T.W., Psaty, B.M., Tracy, R.P., Brody, J., Chen, I., Viikari, J., Kähönen, M., Pramstaller, P.P., Evans, D.M., St Pourcain, B., Sattar, N., Wood, A.R., Bandinelli, S., Carlson, O.D., Egan, J.M., Böhringer, S., van Heemst, D., Kedenko, L., Kristiansson, K., Nuotio, M.L., Loo, B.M., Harris, T., Garcia, M., Kanaya, A., Haun, M., Klopp, N., Wichmann, H.E., Deloukas, P., Katsareli, E., Couper, D.J., Duncan, B.B., Kloppenburg, M., Adair, L.S., Borja, J.B., Wilson, J.G., Musani, S., Guo, X., Johnson, T., Semple, R., Teslovich, T.M., Allison, M.A., Redline, S., Buxbaum, S.G., Mohlke, K.L., Meulenbelt, I., Ballantyne, C.M., Dedoussis, G.V., Hu, F.B., Liu, Y., Paulweber, B., Spector, T.D., Slagboom, P.E., Ferrucci, L., Jula, A., Perola, M., Raitakari, O., Florez, J.C., Salomaa, V., Eriksson, J.G., Frayling, T.M., Hicks, A.A., Lehtimäki, T., Smith, G.D., Siscovick, D.S., Kronenberg, F., van Duijn, C., Loos, R.J., Waterworth, D.M., Meigs, J.B., Dupuis, J., Richards, J.B., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Hofmann, O.M., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Hassanali, N., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lindgren, C.M., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Morris, A.D., Palmer, C.N., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Pedersen, O., Barroso, I., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., McCarthy, M.I., Soranzo, N., Wheeler, E., Glazer, N.L., Bouatia-Naji, N., Mägi, R., Randall, J., Elliott, P., Rybin, D., Dehghan, A., Hottenga, J.J., Song, K., Goel, A., Lajunen, T., Doney, A., Cavalcanti-Proença, C., Kumari, M., Timpson, N.J., Zabena, C., Ingelsson, E., An, P., O'Connell, J., Luan, J., Elliott, A., Roccasecca, R.M., Pattou, F., Sethupathy, P., Ariyurek, Y., Barter, P., Beilby, J.P., Ben-Shlomo, Y., Bergmann, S., Bochud, M., Bonnefond, A., Borch-Johnsen, K., Böttcher, Y., Brunner, E., Bumpstead, S.J., Chen, Y.D., Chines, P., Clarke, R., Coin, L.J., Cooper, M.N., Crisponi, L., Day, I.N., de Geus, E.J., Delplanque, J., Fedson, A.C., Fischer-Rosinsky, A., Forouhi, N.G., Franzosi, M.G., Galan, P., Goodarzi, M.O., Graessler, J., Grundy, S., Gwilliam, R., Hallmans, G., Hammond, N., Han, X., Hartikainen, A.L., Hayward, C., Heath, S.C., Hercberg, S., Hillman, D.R., Hingorani, A.D., Hui, J., Hung, J., Kaakinen, M., Kaprio, J., Kesaniemi, Y.A., Kivimaki, M., Knight, B., Koskinen, S., Kovacs, P., Kyvik, K.O., Lathrop, G.M., Lawlor, D.A., Le Bacquer, O., Lecoeur, C., Li, Y., 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Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Morris, A.D., Palmer, C.N., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Pedersen, O., Barroso, I., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., McCarthy, M.I., Soranzo, N., Wheeler, E., Glazer, N.L., Bouatia-Naji, N., Mägi, R., Randall, J., Elliott, P., Rybin, D., Dehghan, A., Hottenga, J.J., Song, K., Goel, A., Lajunen, T., Doney, A., Cavalcanti-Proença, C., Kumari, M., Timpson, N.J., Zabena, C., Ingelsson, E., An, P., O'Connell, J., Luan, J., Elliott, A., Roccasecca, R.M., Pattou, F., Sethupathy, P., Ariyurek, Y., Barter, P., Beilby, J.P., Ben-Shlomo, Y., Bergmann, S., Bochud, M., Bonnefond, A., Borch-Johnsen, K., Böttcher, Y., Brunner, E., Bumpstead, S.J., Chen, Y.D., Chines, P., Clarke, R., Coin, L.J., Cooper, M.N., Crisponi, L., Day, I.N., de Geus, E.J., Delplanque, J., Fedson, A.C., Fischer-Rosinsky, A., Forouhi, N.G., Franzosi, M.G., Galan, P., Goodarzi, M.O., Graessler, J., Grundy, S., Gwilliam, R., Hallmans, G., Hammond, N., Han, X., Hartikainen, A.L., Hayward, C., Heath, S.C., Hercberg, S., Hillman, D.R., Hingorani, A.D., Hui, J., Hung, J., Kaakinen, M., Kaprio, J., Kesaniemi, Y.A., Kivimaki, M., Knight, B., Koskinen, S., Kovacs, P., Kyvik, K.O., Lathrop, G.M., Lawlor, D.A., Le Bacquer, O., Lecoeur, C., Li, Y., Mahley, R., Mangino, M., Martínez-Larrad, M.T., McAteer, J.B., McPherson, R., Meisinger, C., Melzer, D., Meyre, D., Mitchell, B.D., Mukherjee, S., Naitza, S., Neville, M.J., Orrù, M., Pakyz, R., Paolisso, G., Pattaro, C., Pearson, D., Peden, J.F., Pedersen, N.L., Pfeiffer, A.F., Pichler, I., Polasek, O., Posthuma, D., Potter, S.C., Pouta, A., Province, M.A., Rice, K., Ripatti, S., Rivadeneira, F., Rolandsson, O., Sandbaek, A., Sandhu, M., Sanna, S., Sayer, A.A., Scheet, P., Seedorf, U., Sharp, S.J., Shields, B., Sigurðsson, G., Sijbrands, E.J., Silveira, A., Simpson, L., Singleton, A., Smith, N.L., Sovio, U., Swift, A., Syddall, H., Syvänen, A.C., Tönjes, A., Uitterlinden, A.G., van Dijk, K.W., Varma, D., Visvikis-Siest, S., Vitart, V., Vogelzangs, N., Waeber, G., Wagner, P.J., Walley, A., Ward, K.L., Watkins, H., Wild, S.H., Willemsen, G., Witteman, J.C., Yarnell, J.W., Zelenika, D., Zethelius, B., Zhai, G., Zhao, J.H., Zillikens, M.C., Borecki, I.B., Meneton, P., Magnusson, P.K., Nathan, D.M., Williams, G.H., Silander, K., Bornstein, S.R., Schwarz, P., Spranger, J., Karpe, F., Shuldiner, A.R., Cooper, C., Serrano-Ríos, M., Lind, L., Palmer, L.J., Franks, P.W., Ebrahim, S., Marmot, M., Wright, A.F., Stumvoll, M., Hamsten, A., Buchanan, T.A., Valle, T.T., Rotter, J.I., Penninx, B.W., Boomsma, D.I., Cao, A., Scuteri, A., Schlessinger, D., Uda, M., Ruokonen, A., Jarvelin, M.R., Peltonen, L., Mooser, V., Musunuru, K., Smith, A.V., Edmondson, A.C., Stylianou, I.M., Koseki, M., Pirruccello, J.P., Chasman, D.I., Johansen, C.T., Fouchier, S.W., Peloso, G.M., Barbalic, M., Ricketts, S.L., Bis, J.C., Feitosa, M.F., Orho-Melander, M., Melander, O., Li, X., Cho, Y.S., Go, M.J., Kim, Y.J., Lee, J.Y., Park, T., Kim, K., Sim, X., Ong, R.T., Croteau-Chonka, D.C., Lange, L.A., Smith, J.D., Ziegler, A., Zhang, W., Zee, R.Y., Whitfield, J.B., Thompson, J.R., Surakka, I., Smit, J.H., Sinisalo, J., Scott, J., Saharinen, J., Sabatti, C., Rose, L.M., Roberts, R., Rieder, M., Parker, A.N., Pare, G., O'Donnell, C.J., Nieminen, M.S., Nickerson, D.A., Montgomery, G.W., McArdle, W., Masson, D., Martin, N.G., Marroni, F., Lucas, G., Luben, R., Lokki, M.L., Lettre, G., Launer, L.J., Lakatta, E.G., Laaksonen, R., König, I.R., Khaw, K.T., Kaplan, L.M., Johansson, Å., Janssens, A.C., Igl, W., Hovingh, G.K., Hengstenberg, C., Havulinna, A.S., Hastie, N.D., Harris, T.B., Haritunians, T., Hall, A.S., Groop, L.C., Gonzalez, E., Freimer, N.B., Erdmann, J., Ejebe, K.G., Döring, A., Dominiczak, A.F., Demissie, S., de Faire, U., Caulfield, M.J., Boekholdt, S.M., Assimes, T.L., Quertermous, T., Seielstad, M., Wong, T.Y., Tai, E.S., Feranil, A.B., Kuzawa, C.W., Taylor, H.A., Gabriel, S.B., Holm, H., Gudnason, V., Krauss, R.M., Ordovas, J.M., Munroe, P.B., Kooner, J.S., Tall, A.R., Hegele, R.A., Kastelein, J.J., Schadt, E.E., Strachan, D.P., Reilly, M.P., Samani, N.J., Schunkert, H., Cupples, L.A., Sandhu, M.S., Ridker, P.M., Rader, D.J., and Kathiresan, S.

Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

Published
2012

40. Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Author

Bown, M.J., Jones, G.T., Harrison, S.C., Wright, B.J., Bumpstead, S., Baas, A.F., Gretarsdottir, S., Badger, S.A., Bradley, D.T., Burnand, K., Child, A.H., Clough, R.E., Cockerill, G., Hafez, H., Scott, D.J., Futers, S., Johnson, A., Sohrabi, S., Smith, A., Thompson, M.M., Bockxmeer, F.M. van, Waltham, M., Matthiasson, S.E., Thorleifsson, G., Thorsteinsdottir, U., Blankensteijn, J.D., Teijink, J.A., Wijmenga, C., Graaf, J. de, Kiemeney, L.A.L.M., Assimes, T.L., McPherson, R., Folkersen, L., Franco-Cereceda, A., Palmen, J., Smith, A.J., Sylvius, N., Wild, J.B., Refstrup, M., Edkins, S., Gwilliam, R., Hunt, S.E., Potter, S., Lindholt, J.S., Frikke-Schmidt, R., Tybjaerg-Hansen, A., Hughes, A.E., Golledge, J., Norman, P.E., Rij, A. van, Powell, J.T., Eriksson, P., Stefansson, K., Thompson, J.R., Humphries, S.E., Sayers, R.D., Deloukas, P., Samani, N.J., Bown, M.J., Jones, G.T., Harrison, S.C., Wright, B.J., Bumpstead, S., Baas, A.F., Gretarsdottir, S., Badger, S.A., Bradley, D.T., Burnand, K., Child, A.H., Clough, R.E., Cockerill, G., Hafez, H., Scott, D.J., Futers, S., Johnson, A., Sohrabi, S., Smith, A., Thompson, M.M., Bockxmeer, F.M. van, Waltham, M., Matthiasson, S.E., Thorleifsson, G., Thorsteinsdottir, U., Blankensteijn, J.D., Teijink, J.A., Wijmenga, C., Graaf, J. de, Kiemeney, L.A.L.M., Assimes, T.L., McPherson, R., Folkersen, L., Franco-Cereceda, A., Palmen, J., Smith, A.J., Sylvius, N., Wild, J.B., Refstrup, M., Edkins, S., Gwilliam, R., Hunt, S.E., Potter, S., Lindholt, J.S., Frikke-Schmidt, R., Tybjaerg-Hansen, A., Hughes, A.E., Golledge, J., Norman, P.E., Rij, A. van, Powell, J.T., Eriksson, P., Stefansson, K., Thompson, J.R., Humphries, S.E., Sayers, R.D., Deloukas, P., and Samani, N.J.

Abstract

Contains fulltext : 97601.pdf (publisher's version ) (Closed access), Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 x 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 x 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 x 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.

Published
2011

41. Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Author

Bown, M.J. (Matthew), Jones, G.T. (Gregory), Harrison, S.C. (Seamus), Wright, B.J. (Benjamin), Bumpstead, S. (Suzannah), Baas, A.F. (Annette), Gretarsdottir, S. (Solveig), Badger, J.H. (Jonathan), Bradley, D.T. (Declan), Burnand, K. (Kevin), Badger, S.A. (Stephen), Child, A.H. (Anne), Clough, R.E. (Rachel), Cockerill, G. (Gillian), Hafez, H. (Hany), Scott, D.J.A. (Julian), Futers, S. (Simon), Johnson, A. (Anne), Sohrabi, S. (Soroush), Smith, A. (Alberto), Thompson, M.J. (Matthew), Bockxmeer, F.M. (Frank) van, Waltham, M. (Matthew), Matthiasson, S.E. (Stefan), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Blankensteijn, J.D. (Jan), Teijink, J.A.W. (Joep), Wijmenga, C. (Cisca), Graaf, J. (Jacqueline) de, Kiemeney, L.A.L.M. (Bart), Assimes, T.L. (Themistocles), McPherson, R. (Ruth), Folkersen, L. (Lasse), Franco-Cereceda, A. (Anders), Palmen, J. (Jutta), Smith, A.J. (Andrew), Sylvius, N. (Nicolas), Wild, J.B. (John), Refstrup, M. (Mette), Edkins, S. (Sarah), Gwilliam, R. (Rhian), Hunt, S.E. (Sarah), Potter, S.C. (Simon), Lindholt, J.S. (Jes), Frikke-Schmidt, R. (Ruth), Tybjaerg-Hansen, A. (Anne), Hughes, A.E. (Anne), Golledge, J. (Jonathan), Norman, P.E. (Paul), Rij, A.M. (Andre) van, Powell, J.T. (Janet), Eriksson, P. (Per), Stefansson, K. (Kari), Thompson, J.R. (John), Humphries, S.E. (Steve), Sayers, R.E. (Robert), Deloukas, P. (Panos), Samani, N.J. (Nilesh), Bown, M.J. (Matthew), Jones, G.T. (Gregory), Harrison, S.C. (Seamus), Wright, B.J. (Benjamin), Bumpstead, S. (Suzannah), Baas, A.F. (Annette), Gretarsdottir, S. (Solveig), Badger, J.H. (Jonathan), Bradley, D.T. (Declan), Burnand, K. (Kevin), Badger, S.A. (Stephen), Child, A.H. (Anne), Clough, R.E. (Rachel), Cockerill, G. (Gillian), Hafez, H. (Hany), Scott, D.J.A. (Julian), Futers, S. (Simon), Johnson, A. (Anne), Sohrabi, S. (Soroush), Smith, A. (Alberto), Thompson, M.J. (Matthew), Bockxmeer, F.M. (Frank) van, Waltham, M. (Matthew), Matthiasson, S.E. (Stefan), Thorleifsson, G. (Gudmar), Thorsteinsdottir, U. (Unnur), Blankensteijn, J.D. (Jan), Teijink, J.A.W. (Joep), Wijmenga, C. (Cisca), Graaf, J. (Jacqueline) de, Kiemeney, L.A.L.M. (Bart), Assimes, T.L. (Themistocles), McPherson, R. (Ruth), Folkersen, L. (Lasse), Franco-Cereceda, A. (Anders), Palmen, J. (Jutta), Smith, A.J. (Andrew), Sylvius, N. (Nicolas), Wild, J.B. (John), Refstrup, M. (Mette), Edkins, S. (Sarah), Gwilliam, R. (Rhian), Hunt, S.E. (Sarah), Potter, S.C. (Simon), Lindholt, J.S. (Jes), Frikke-Schmidt, R. (Ruth), Tybjaerg-Hansen, A. (Anne), Hughes, A.E. (Anne), Golledge, J. (Jonathan), Norman, P.E. (Paul), Rij, A.M. (Andre) van, Powell, J.T. (Janet), Eriksson, P. (Per), Stefansson, K. (Kari), Thompson, J.R. (John), Humphries, S.E. (Steve), Sayers, R.E. (Robert), Deloukas, P. (Panos), and Samani, N.J. (Nilesh)

Published
2011
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42. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

Author

Anderson, CA, Boucher, G, Lees, CW, Franke, A, D'Amato, M, Taylor, KD, Lee, JC, Goyette, P, Imielinski, M, Latiano, A, Lagace, C, Scott, R, Amininejad, L, Bumpstead, S, Baidoo, L, Baldassano, RN, Barclay, M, Bayless, TM, Brand, S, Buening, C, Colombel, J-F, Denson, LA, De Vos, M, Dubinsky, M, Edwards, C, Ellinghaus, D, Fehrmann, RSN, Floyd, JAB, Florin, T, Franchimont, D, Franke, L, Georges, M, Glas, J, Glazer, NL, Guthery, SL, Haritunians, T, Hayward, NK, Hugot, J-P, Jobin, G, Laukens, D, Lawrance, I, Lemann, M, Levine, A, Libioulle, C, Louis, E, McGovern, DP, Milla, M, Montgomery, GW, Morley, KI, Mowat, C, Ng, A, Newman, W, Ophoff, RA, Papi, L, Palmieri, O, Peyrin-Biroulet, L, Panes, J, Phillips, A, Prescott, NJ, Proctor, DD, Roberts, R, Russell, R, Rutgeerts, P, Sanderson, J, Sans, M, Schumm, P, Seibold, F, Sharma, Y, Simms, LA, Seielstad, M, Steinhart, AH, Targan, SR, van den Berg, LH, Vatn, M, Verspaget, H, Walters, T, Wijmenga, C, Wilson, DC, Westra, H-J, Xavier, RJ, Zhao, ZZ, Ponsioen, CY, Andersen, V, Torkvist, L, Gazouli, M, Anagnou, NP, Karlsen, TH, Kupcinskas, L, Sventoraityte, J, Mansfield, JC, Kugathasan, S, Silverberg, MS, Halfvarson, J, Rotter, JI, Mathew, CG, Griffiths, AM, Gearry, R, Ahmad, T, Brant, SR, Chamaillard, M, Satsangi, J, Cho, JH, Schreiber, S, Daly, MJ, Barrett, JC, Parkes, M, Annese, V, Hakonarson, H, Radford-Smith, G, Duerr, RH, Vermeire, S, Weersma, RK, Rioux, JD, Anderson, CA, Boucher, G, Lees, CW, Franke, A, D'Amato, M, Taylor, KD, Lee, JC, Goyette, P, Imielinski, M, Latiano, A, Lagace, C, Scott, R, Amininejad, L, Bumpstead, S, Baidoo, L, Baldassano, RN, Barclay, M, Bayless, TM, Brand, S, Buening, C, Colombel, J-F, Denson, LA, De Vos, M, Dubinsky, M, Edwards, C, Ellinghaus, D, Fehrmann, RSN, Floyd, JAB, Florin, T, Franchimont, D, Franke, L, Georges, M, Glas, J, Glazer, NL, Guthery, SL, Haritunians, T, Hayward, NK, Hugot, J-P, Jobin, G, Laukens, D, Lawrance, I, Lemann, M, Levine, A, Libioulle, C, Louis, E, McGovern, DP, Milla, M, Montgomery, GW, Morley, KI, Mowat, C, Ng, A, Newman, W, Ophoff, RA, Papi, L, Palmieri, O, Peyrin-Biroulet, L, Panes, J, Phillips, A, Prescott, NJ, Proctor, DD, Roberts, R, Russell, R, Rutgeerts, P, Sanderson, J, Sans, M, Schumm, P, Seibold, F, Sharma, Y, Simms, LA, Seielstad, M, Steinhart, AH, Targan, SR, van den Berg, LH, Vatn, M, Verspaget, H, Walters, T, Wijmenga, C, Wilson, DC, Westra, H-J, Xavier, RJ, Zhao, ZZ, Ponsioen, CY, Andersen, V, Torkvist, L, Gazouli, M, Anagnou, NP, Karlsen, TH, Kupcinskas, L, Sventoraityte, J, Mansfield, JC, Kugathasan, S, Silverberg, MS, Halfvarson, J, Rotter, JI, Mathew, CG, Griffiths, AM, Gearry, R, Ahmad, T, Brant, SR, Chamaillard, M, Satsangi, J, Cho, JH, Schreiber, S, Daly, MJ, Barrett, JC, Parkes, M, Annese, V, Hakonarson, H, Radford-Smith, G, Duerr, RH, Vermeire, S, Weersma, RK, and Rioux, JD

Abstract

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

Published
2011

43. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Author

Dupuis, J. (Josée), Langenberg, C. (Claudia), Prokopenko, I. (Inga), Saxena, R. (Richa), Soranzo, N. (Nicole), Jackson, A.U. (Anne), Wheeler, E. (Eleanor), Glazer, N.L. (Nicole), Bouatia-Naji, N. (Nabila), Gloyn, A.L. (Anna), Lindgren, C.M. (Cecilia), Mägi, R. (Reedik), Morris, A.P. (Andrew), Randall, J.C. (Joshua), Johnson, T. (Toby), Elliott, P. (Paul), Rybin, D. (Denis), Thorleifsson, G. (Gudmar), Steinthorsdottir, V. (Valgerdur), Henneman, P. (Peter), Grallert, H. (Harald), Dehghan, A. (Abbas), JanHottenga, J. (Jouke), Franklin, C.S. (Christopher), Navarro, P. (Pau), Song, K. (Kijoung), Goel, A. (Anuj), Perry, J.R.B. (John), Egan, J.M. (Josephine), Lajunen, T. (Taina), Grarup, N. (Niels), Sparsø, T. (Thomas), Doney, A.S.F. (Alex), Voight, B.F. (Benjamin), Stringham, H.M. (Heather), Li, M. (Man), Kanoni, S. (Stavroula), Shrader, P. (Peter), Cavalcanti-Proença, C. (Christine), Kumari, M. (Meena), Qi, L. (Lu), Timpson, N.J. (Nicholas), Gieger, C. (Christian), Zabena, C. (Carina), Rocheleau, G. (Ghislain), Ingelsson, E. (Erik), An, P. (Ping), O´Connell, J.R., Luan, J., McCarroll, S.A. (Steven), Payne, F. (Felicity), Roccasecca, R.M., Pattou, F. (François), Sethupathy, P. (Praveen), Ardlie, K.G. (Kristin), Ariyurek, Y. (Yavuz), Balkau, B. (Beverley), Barter, P. (Phil), Beilby, J.P. (John), Ben-Shlomo, Y., Benediktsson, R. (Rafn), Bennett, A.J. (Amanda), Bergmann, S.M. (Sven), Bochud, M. (Murielle), Boerwinkle, E.A. (Eric), Bonnefond, A. (Amélie), Bonnycastle, L.L. (Lori), Borch-Johnsen, K., Böttcher, Y. (Yvonne), Brunner, E. (Eric), Bumpstead, S. (Suzannah), Charpentier, G. (Guillaume), IdaChen, Y. (Yii) der, Chines, P.S. (Peter), Clarke, R., McOin, L.J. (Lachlan), Cooper, M.N. (Matthew), Cornelis, M. (Marilyn), Crawford, G. (Gabe), Crisponi, L. (Laura), Day, I.N.M. (Ian), Geus, E.J.C. (Eco) de, Delplanque, J. (Jerome), Dina, C. (Christian), Erdos, M.R. (Michael), Fedson, A.C. (Annette), Fischer-Rosinsky, A. (Antje), Forouhi, N.G. (Nita), Fox, C.S. (Caroline), Frants, R.R. (Rune), GraziaFranzosi, M. (Maria), Galan, P. (Pilar), Goodarzi, M. (Mark), Graessler, J. (Jürgen), Groves, C.J. (Christopher), Grundy, S.M. (Scott), Gwilliam, R. (Rhian), Gyllensten, U. (Ulf), Hadjadj, S. (Samy), Hallmans, G. (Göran), Hammond, N. (Naomi), Han, X. (Xijing), Hartikainen, A.-L. (Anna-Liisa), Hassanali, N. (Neelam), Hayward, C. (Caroline), Heath, S.C. (Simon), Hercberg, S. (Serge), Herder, C. (Christian), Hicks, A.A. (Andrew), Hillman, D.R. (David), Hingorani, A. (Aroon), Hofman, A. (Albert), Hui, J. (Jennie), Hung, J. (Judy), Isomaa, B. (Bo), Jørgensen, T. (Torben), Jula, A. (Antti), Kaakinen, M. (Marika), Kaprio, J. (Jaakko), AnteroKesaniemi, Y., Kivimaki, M. (Mika), Knight, B. (Beatrice), Koskinen, S. (Seppo), Kovacs, P. (Peter), Kyvik, K.O. (Kirsten Ohm), Lathrop, G.M. (Mark), Lawlor, D.A. (Debbie), Bacquer, O.L. (Olivier), Lecoeur, C. (Cécile), Lyssenko, V. (Valeriya), Mahley, R. (Robert), Mangino, M. (Massimo), Manning, A.K. (Alisa), TeresaMartínez-Larrad, M. (María), McAteer, J.B. (Jarred), McCulloch, L.J. (Laura), McPherson, R. (Ruth), Meisinger, C. (Christa), Melzer, D. (David), Meyre, D. (David), Mitchell, B.D. (Braxton), Morken, M.A. (Mario), Mukherjee, S. (Sutapa), Naitza, S. (Silvia), Narisu, N. (Narisu), Neville, M.J. (Matthew), Oostra, B.A. (Ben), Orrù, M. (Marco), Pakyz, R. (Ruth), Palmer, C.N.A. (Colin), Paolisso, G. (Giuseppe), Pattaro, C. (Cristian), Pearson, D. (Daniel), Peden, J. (John), Pedersen, N.L. (Nancy), Perola, M. (Markus), Pfeiffer, A.F.H. (Andreas), Pichler, I. (Irene), Polasek, O. (Ozren), Posthuma, D. (Danielle), Potter, S.C. (Simon), Pouta, A. (Anneli), Province, M.A. (Mike), Psaty, B.M. (Bruce), Rathmann, W. (Wolfgang), Rayner, N.W. (Nigel William), Rice, K. (Kenneth), Ripatti, S. (Samuli), Rivadeneira Ramirez, F. (Fernando), Roden, M. (Michael), Rolandsson, O. (Olov), Sandbaek, A. (Annelli), Sandhu, M.S. (Manjinder), Sanna, S. (Serena), Sayer, A.A., Scheet, P. (Paul), Scott, L.J. (Laura), Seedorf, U. (Udo), Sharp, S.J. (Stephen), Shields, B.M. (Beverley), Sigursson, G. (Gunnar), Sijbrands, E.J.G. (Eric), Silveira, A. (Angela), Simpson, L. (Laila), Singleton, A. (Andrew), Smith, N.L. (Nicholas), Sovio, U. (Ulla), Swift, A.J. (Amy), Syddall, H. (Holly), Syvänen, A.-C. (Ann-Christine), Tanaka, T. (Toshiko), Thorand, B. (Barbara), Tichet, J. (Jean), Tönjes, A. (Anke), Tuomi, T. (Tiinamaija), Uitterlinden, A.G. (André), Willems van Dijk, J.A.P. (Ko), Hoek, M. (Mandy) van, Varma, D. (Dhiraj), Visvikis-Siest, S. (Sophie), Vitart, V. (Veronique), Vogelzangs, N. (Nicole), Waeber, G. (Gérard), Wagner, P.J. (Peter), Walley, A. (Andrew), BragiWalters, G., Ward, K.L. (Kim), Watkins, H. (Hugh), Weedon, M.N. (Michael), Wild, S.H. (Sarah), Willemsen, G.A.H.M. (Gonneke), Witteman, J.C.M. (Jacqueline), GYarnell, J.W. (John), Zeggini, E. (Eleftheria), Zelenika, D. (Diana), Zethelius, B. (Björn), Zhai, G. (Guangju), Zhao, J.H. (Jing Hua), Zillikens, M.C. (Carola), Borecki, I.B. (Ingrid), Loos, R.J.F. (Ruth), Meneton, P. (Pierre), Magnusson, P.K. (Patrik), Nathan, D.M. (David), Williams, G.H. (Gordon), Hattersley, A.T. (Andrew), Silander, K. (Kaisa), Salomaa, V. (Veikko), Bornstein, S.R. (Stefan), Schwarz, P. (Peter), Spranger, J. (Jürgen), Karpe, F. (Fredrik), Shuldiner, A.R. (Alan), Dedoussis, G.V. (George), Serrano-Ríos, M. (Manuel), Lind, L. (Lars), Palmer, C. (Cameron), Hu, F.B. (Frank), Franks, P.W. (Paul), Ebrahim, S. (Shanil), Marmot, M. (Michael), Kao, W.-H.L. (Linda), Pankow, J.S. (James), Sampson, M.J. (Michael), Kuusisto, J. (Johanna), Laakso, M. (Markku), Hansen, T. (Torben), Pramstaller, P.P. (Peter Paul), Wichmann, H.E. (Erich), Illig, T. (Thomas), Rudan, I. (Igor), Wright, A.F. (Alan), Stumvoll, M. (Michael), Campbell, H. (Harry), Wilson, J.F. (James), Bergman, R.N. (Richard), Buchanan, T.A. (Thomas), Collins, F.S. (Francis), Mohlke, K.L. (Karen), Tuomilehto, J. (Jaakko), Valle, T.T. (Timo), Altshuler, D. (David), Rotter, J.I. (Jerome), Siscovick, D.S. (David), Penninx, B.W.J.H. (Brenda), Boomsma, D.I. (Dorret), Deloukas, P. (Panagiotis), Spector, T.D. (Timothy), Frayling, T.M. (Timothy), Ferrucci, L. (Luigi), Kong, A. (Augustine), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Tikka-Kleemola, P. (Päivi), Aulchenko, Y.S. (Yurii), Cao, A. (Antonio), Scuteri, A. (Angelo), Schlessinger, D. (David), Uda, M. (Manuela), Ruokonen, A. (Aimo), Jarvelin, M.-R. (Marjo-Riitta), Waterworth, D. (Dawn), Vollenweider, P. (Peter), Peltonen, L. (Leena Johanna), Mooser, V. (Vincent), Abecasis, G.R. (Gonçalo), Wareham, N.J. (Nick), Sladek, R. (Rob), Froguel, P. (Philippe), Meigs, J.B. (James), Groop, L. (Leif), Watanabe, R.M. (Richard), Boehnke, M. (Michael), McCarthy, M.I. (Mark), Florez, J.C. (Jose), Barroso, I.E. (Inês), Dupuis, J. (Josée), Langenberg, C. (Claudia), Prokopenko, I. (Inga), Saxena, R. (Richa), Soranzo, N. (Nicole), Jackson, A.U. (Anne), Wheeler, E. (Eleanor), Glazer, N.L. (Nicole), Bouatia-Naji, N. (Nabila), Gloyn, A.L. (Anna), Lindgren, C.M. (Cecilia), Mägi, R. (Reedik), Morris, A.P. (Andrew), Randall, J.C. (Joshua), Johnson, T. (Toby), Elliott, P. (Paul), Rybin, D. (Denis), Thorleifsson, G. (Gudmar), Steinthorsdottir, V. (Valgerdur), Henneman, P. (Peter), Grallert, H. (Harald), Dehghan, A. (Abbas), JanHottenga, J. (Jouke), Franklin, C.S. (Christopher), Navarro, P. (Pau), Song, K. (Kijoung), Goel, A. (Anuj), Perry, J.R.B. (John), Egan, J.M. (Josephine), Lajunen, T. (Taina), Grarup, N. (Niels), Sparsø, T. (Thomas), Doney, A.S.F. (Alex), Voight, B.F. (Benjamin), Stringham, H.M. (Heather), Li, M. (Man), Kanoni, S. (Stavroula), Shrader, P. (Peter), Cavalcanti-Proença, C. (Christine), Kumari, M. (Meena), Qi, L. (Lu), Timpson, N.J. (Nicholas), Gieger, C. (Christian), Zabena, C. (Carina), Rocheleau, G. (Ghislain), Ingelsson, E. (Erik), An, P. (Ping), O´Connell, J.R., Luan, J., McCarroll, S.A. (Steven), Payne, F. (Felicity), Roccasecca, R.M., Pattou, F. (François), Sethupathy, P. (Praveen), Ardlie, K.G. (Kristin), Ariyurek, Y. (Yavuz), Balkau, B. (Beverley), Barter, P. (Phil), Beilby, J.P. (John), Ben-Shlomo, Y., Benediktsson, R. (Rafn), Bennett, A.J. (Amanda), Bergmann, S.M. (Sven), Bochud, M. (Murielle), Boerwinkle, E.A. (Eric), Bonnefond, A. (Amélie), Bonnycastle, L.L. (Lori), Borch-Johnsen, K., Böttcher, Y. (Yvonne), Brunner, E. (Eric), Bumpstead, S. (Suzannah), Charpentier, G. (Guillaume), IdaChen, Y. (Yii) der, Chines, P.S. (Peter), Clarke, R., McOin, L.J. (Lachlan), Cooper, M.N. (Matthew), Cornelis, M. (Marilyn), Crawford, G. (Gabe), Crisponi, L. (Laura), Day, I.N.M. (Ian), Geus, E.J.C. (Eco) de, Delplanque, J. (Jerome), Dina, C. (Christian), Erdos, M.R. (Michael), Fedson, A.C. (Annette), Fischer-Rosinsky, A. (Antje), Forouhi, N.G. (Nita), Fox, C.S. (Caroline), Frants, R.R. (Rune), GraziaFranzosi, M. (Maria), Galan, P. (Pilar), Goodarzi, M. (Mark), Graessler, J. (Jürgen), Groves, C.J. (Christopher), Grundy, S.M. (Scott), Gwilliam, R. (Rhian), Gyllensten, U. (Ulf), Hadjadj, S. (Samy), Hallmans, G. (Göran), Hammond, N. (Naomi), Han, X. (Xijing), Hartikainen, A.-L. (Anna-Liisa), Hassanali, N. (Neelam), Hayward, C. (Caroline), Heath, S.C. (Simon), Hercberg, S. (Serge), Herder, C. (Christian), Hicks, A.A. (Andrew), Hillman, D.R. (David), Hingorani, A. (Aroon), Hofman, A. (Albert), Hui, J. (Jennie), Hung, J. (Judy), Isomaa, B. (Bo), Jørgensen, T. (Torben), Jula, A. (Antti), Kaakinen, M. (Marika), Kaprio, J. (Jaakko), AnteroKesaniemi, Y., Kivimaki, M. (Mika), Knight, B. (Beatrice), Koskinen, S. (Seppo), Kovacs, P. (Peter), Kyvik, K.O. (Kirsten Ohm), Lathrop, G.M. (Mark), Lawlor, D.A. (Debbie), Bacquer, O.L. (Olivier), Lecoeur, C. (Cécile), Lyssenko, V. (Valeriya), Mahley, R. (Robert), Mangino, M. (Massimo), Manning, A.K. (Alisa), TeresaMartínez-Larrad, M. (María), McAteer, J.B. (Jarred), McCulloch, L.J. (Laura), McPherson, R. (Ruth), Meisinger, C. (Christa), Melzer, D. (David), Meyre, D. (David), Mitchell, B.D. (Braxton), Morken, M.A. (Mario), Mukherjee, S. (Sutapa), Naitza, S. (Silvia), Narisu, N. (Narisu), Neville, M.J. (Matthew), Oostra, B.A. (Ben), Orrù, M. (Marco), Pakyz, R. (Ruth), Palmer, C.N.A. (Colin), Paolisso, G. (Giuseppe), Pattaro, C. (Cristian), Pearson, D. (Daniel), Peden, J. (John), Pedersen, N.L. (Nancy), Perola, M. (Markus), Pfeiffer, A.F.H. (Andreas), Pichler, I. (Irene), Polasek, O. (Ozren), Posthuma, D. (Danielle), Potter, S.C. (Simon), Pouta, A. (Anneli), Province, M.A. (Mike), Psaty, B.M. (Bruce), Rathmann, W. (Wolfgang), Rayner, N.W. (Nigel William), Rice, K. (Kenneth), Ripatti, S. (Samuli), Rivadeneira Ramirez, F. (Fernando), Roden, M. (Michael), Rolandsson, O. (Olov), Sandbaek, A. (Annelli), Sandhu, M.S. (Manjinder), Sanna, S. (Serena), Sayer, A.A., Scheet, P. (Paul), Scott, L.J. (Laura), Seedorf, U. (Udo), Sharp, S.J. (Stephen), Shields, B.M. (Beverley), Sigursson, G. (Gunnar), Sijbrands, E.J.G. (Eric), Silveira, A. (Angela), Simpson, L. (Laila), Singleton, A. (Andrew), Smith, N.L. (Nicholas), Sovio, U. (Ulla), Swift, A.J. (Amy), Syddall, H. (Holly), Syvänen, A.-C. (Ann-Christine), Tanaka, T. (Toshiko), Thorand, B. (Barbara), Tichet, J. (Jean), Tönjes, A. (Anke), Tuomi, T. (Tiinamaija), Uitterlinden, A.G. (André), Willems van Dijk, J.A.P. (Ko), Hoek, M. (Mandy) van, Varma, D. (Dhiraj), Visvikis-Siest, S. (Sophie), Vitart, V. (Veronique), Vogelzangs, N. (Nicole), Waeber, G. (Gérard), Wagner, P.J. (Peter), Walley, A. (Andrew), BragiWalters, G., Ward, K.L. (Kim), Watkins, H. (Hugh), Weedon, M.N. (Michael), Wild, S.H. (Sarah), Willemsen, G.A.H.M. (Gonneke), Witteman, J.C.M. (Jacqueline), GYarnell, J.W. (John), Zeggini, E. (Eleftheria), Zelenika, D. (Diana), Zethelius, B. (Björn), Zhai, G. (Guangju), Zhao, J.H. (Jing Hua), Zillikens, M.C. (Carola), Borecki, I.B. (Ingrid), Loos, R.J.F. (Ruth), Meneton, P. (Pierre), Magnusson, P.K. (Patrik), Nathan, D.M. (David), Williams, G.H. (Gordon), Hattersley, A.T. (Andrew), Silander, K. (Kaisa), Salomaa, V. (Veikko), Bornstein, S.R. (Stefan), Schwarz, P. (Peter), Spranger, J. (Jürgen), Karpe, F. (Fredrik), Shuldiner, A.R. (Alan), Dedoussis, G.V. (George), Serrano-Ríos, M. (Manuel), Lind, L. (Lars), Palmer, C. (Cameron), Hu, F.B. (Frank), Franks, P.W. (Paul), Ebrahim, S. (Shanil), Marmot, M. (Michael), Kao, W.-H.L. (Linda), Pankow, J.S. (James), Sampson, M.J. (Michael), Kuusisto, J. (Johanna), Laakso, M. (Markku), Hansen, T. (Torben), Pramstaller, P.P. (Peter Paul), Wichmann, H.E. (Erich), Illig, T. (Thomas), Rudan, I. (Igor), Wright, A.F. (Alan), Stumvoll, M. (Michael), Campbell, H. (Harry), Wilson, J.F. (James), Bergman, R.N. (Richard), Buchanan, T.A. (Thomas), Collins, F.S. (Francis), Mohlke, K.L. (Karen), Tuomilehto, J. (Jaakko), Valle, T.T. (Timo), Altshuler, D. (David), Rotter, J.I. (Jerome), Siscovick, D.S. (David), Penninx, B.W.J.H. (Brenda), Boomsma, D.I. (Dorret), Deloukas, P. (Panagiotis), Spector, T.D. (Timothy), Frayling, T.M. (Timothy), Ferrucci, L. (Luigi), Kong, A. (Augustine), Thorsteinsdottir, U. (Unnur), Zwart, J-A. (John-Anker), Tikka-Kleemola, P. (Päivi), Aulchenko, Y.S. (Yurii), Cao, A. (Antonio), Scuteri, A. (Angelo), Schlessinger, D. (David), Uda, M. (Manuela), Ruokonen, A. (Aimo), Jarvelin, M.-R. (Marjo-Riitta), Waterworth, D. (Dawn), Vollenweider, P. (Peter), Peltonen, L. (Leena Johanna), Mooser, V. (Vincent), Abecasis, G.R. (Gonçalo), Wareham, N.J. (Nick), Sladek, R. (Rob), Froguel, P. (Philippe), Meigs, J.B. (James), Groop, L. (Leif), Watanabe, R.M. (Richard), Boehnke, M. (Michael), McCarthy, M.I. (Mark), Florez, J.C. (Jose), and Barroso, I.E. (Inês)

Abstract

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Published
2010
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44. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

Author

Voight, B.F. (Benjamin), Scott, L.J. (Laura), Steinthorsdottir, V. (Valgerdur), Morris, A.D. (Andrew), Dina, C. (Christian), Welch, R.P. (Ryan), Zeggini, E. (Eleftheria), Huth, C. (Cornelia), Aulchenko, Y.S. (Yurii), Thorleifsson, G. (Gudmar), McCulloch, L.J. (Laura), Ferreira, T. (Teresa), Grallert, H. (Harald), Amin, N. (Najaf), Wu, G. (Guanming), Willer, C.J. (Cristen), Raychaudhuri, S. (Soumya), McCarroll, S.A. (Steven), Langenberg, C. (Claudia), Hofmann, O.M. (Oliver), Dupuis, J. (Josée), Qi, L. (Lu), Segrè, A.V. (Ayellet), Hoek, M. (Mandy) van, Navarro, P. (Pau), Ardlie, K.G. (Kristin), Balkau, B. (Beverley), Benediktsson, R. (Rafn), Bennett, A.J. (Amanda), Blagieva, R. (Roza), Boerwinkle, E.A. (Eric), Bonnycastle, L.L. (Lori), Boström, K.B. (Kristina Bengtsson), Bravenboer, B. (Bert), Bumpstead, S. (Suzannah), Burtt, N.P. (Noël), Charpentier, G. (Guillaume), Chines, P.S. (Peter), Cornelis, M. (Marilyn), Couper, D.J. (David), Crawford, G. (Gabe), Doney, A.S.F. (Alex), Elliott, K.S. (Katherine), Erdos, M.R. (Michael), Fox, C.S. (Caroline), Franklin, C.S. (Christopher), Ganser, M. (Martha), Gieger, C. (Christian), Grarup, N. (Niels), Green, T. (Todd), Griffin, S. (Simon), Groves, C.J. (Christopher), Guiducci, C. (Candace), Hadjadj, S. (Samy), Hassanali, N. (Neelam), Herder, C. (Christian), Isomaa, B. (Bo), Jackson, A.U. (Anne), Johnson, P.R.V. (Paul), Jørgensen, T. (Torben), Kao, W.H.L. (Wen), Klopp, N. (Norman), Kong, A. (Augustine), Kraft, P. (Peter), Kuusisto, J. (Johanna), Lauritzen, T. (Torsten), Li, M. (Man), Lieverse, A.G. (Aloysius), Lindgren, C.M. (Cecilia), Lyssenko, V. (Valeriya), Marre, M. (Michel), Meitinger, T. (Thomas), Midthjell, K. (Kristian), Morken, M.A. (Mario), Narisu, N. (Narisu), Nilsson, P. (Peter), Owen, K.R. (Katharine), Payne, F. (Felicity), Perry, J.R.B. (John), Petersen, A.K., Platou, C. (Carl), Proença, C. (Christine), Prokopenko, I. (Inga), Rathmann, W. (Wolfgang), Rayner, N.W. (Nigel William), Robertson, N.R. (Neil), Rocheleau, G. (Ghislain), Roden, M. (Michael), Sampson, M.J. (Michael), Saxena, R. (Richa), Shields, B.M. (Beverley), Shrader, P. (Peter), Sigurdsson, G. (Gunnar), Sparsø, T. (Thomas), Strassburger, K. (Klaus), Stringham, H.M. (Heather), Sun, Q. (Qi), Swift, A.J. (Amy), Thorand, B. (Barbara), Tichet, J. (Jean), Tuomi, T. (Tiinamaija), Dam, R.M. (Rob) van, Haeften, T.W. (Timon) van, Herpt, T.W. (Thijs) van, Vliet-Ostaptchouk, J.V. (Jana) van, Walters, G.B. (Bragi), Weedon, M.N. (Michael), Wijmenga, C. (Cisca), Witteman, J.C.M. (Jacqueline), Bergman, R.N. (Richard), Cauchi, S. (Stephane), Collins, F.S. (Francis), Gloyn, A.L. (Anna), Gyllensten, U. (Ulf), Hansen, T. (Torben), Hide, W.A. (Winston), Hitman, G.A. (Graham), Hofman, A. (Albert), Hunter, D. (David), Hveem, K. (Kristian), Laakso, M. (Markku), Mohlke, K.L. (Karen), Palmer, C.N.A. (Colin), Pramstaller, P.P. (Peter Paul), Rudan, I. (Igor), Sijbrands, E.J.G. (Eric), Stein, L.D. (Lincoln), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Walker, M. (Mark), Wareham, N.J. (Nick), Abecasis, G.R. (Gonçalo), Boehm, B.O. (Bernhard), Campbell, H. (Harry), Daly, M.J. (Mark), Hattersley, A.T. (Andrew), Hu, F.B. (Frank), Meigs, J.B. (James), Pankow, J.S. (James), Pedersen, O. (Oluf), Wichmann, H.E. (Erich), Barroso, I.E. (Inês), Florez, J.C. (Jose), Frayling, T.M. (Timothy), Groop, L. (Leif), Sladek, R. (Rob), Thorsteinsdottir, U. (Unnur), Wilson, J.F. (James), Illig, T. (Thomas), Froguel, P. (Philippe), Tikka-Kleemola, P. (Päivi), Zwart, J-A. (John-Anker), Altshuler, D. (David), Boehnke, M. (Michael), McCarthy, M.I. (Mark), Watanabe, R.M. (Richard), Voight, B.F. (Benjamin), Scott, L.J. (Laura), Steinthorsdottir, V. (Valgerdur), Morris, A.D. (Andrew), Dina, C. (Christian), Welch, R.P. (Ryan), Zeggini, E. (Eleftheria), Huth, C. (Cornelia), Aulchenko, Y.S. (Yurii), Thorleifsson, G. (Gudmar), McCulloch, L.J. (Laura), Ferreira, T. (Teresa), Grallert, H. (Harald), Amin, N. (Najaf), Wu, G. (Guanming), Willer, C.J. (Cristen), Raychaudhuri, S. (Soumya), McCarroll, S.A. (Steven), Langenberg, C. (Claudia), Hofmann, O.M. (Oliver), Dupuis, J. (Josée), Qi, L. (Lu), Segrè, A.V. (Ayellet), Hoek, M. (Mandy) van, Navarro, P. (Pau), Ardlie, K.G. (Kristin), Balkau, B. (Beverley), Benediktsson, R. (Rafn), Bennett, A.J. (Amanda), Blagieva, R. (Roza), Boerwinkle, E.A. (Eric), Bonnycastle, L.L. (Lori), Boström, K.B. (Kristina Bengtsson), Bravenboer, B. (Bert), Bumpstead, S. (Suzannah), Burtt, N.P. (Noël), Charpentier, G. (Guillaume), Chines, P.S. (Peter), Cornelis, M. (Marilyn), Couper, D.J. (David), Crawford, G. (Gabe), Doney, A.S.F. (Alex), Elliott, K.S. (Katherine), Erdos, M.R. (Michael), Fox, C.S. (Caroline), Franklin, C.S. (Christopher), Ganser, M. (Martha), Gieger, C. (Christian), Grarup, N. (Niels), Green, T. (Todd), Griffin, S. (Simon), Groves, C.J. (Christopher), Guiducci, C. (Candace), Hadjadj, S. (Samy), Hassanali, N. (Neelam), Herder, C. (Christian), Isomaa, B. (Bo), Jackson, A.U. (Anne), Johnson, P.R.V. (Paul), Jørgensen, T. (Torben), Kao, W.H.L. (Wen), Klopp, N. (Norman), Kong, A. (Augustine), Kraft, P. (Peter), Kuusisto, J. (Johanna), Lauritzen, T. (Torsten), Li, M. (Man), Lieverse, A.G. (Aloysius), Lindgren, C.M. (Cecilia), Lyssenko, V. (Valeriya), Marre, M. (Michel), Meitinger, T. (Thomas), Midthjell, K. (Kristian), Morken, M.A. (Mario), Narisu, N. (Narisu), Nilsson, P. (Peter), Owen, K.R. (Katharine), Payne, F. (Felicity), Perry, J.R.B. (John), Petersen, A.K., Platou, C. (Carl), Proença, C. (Christine), Prokopenko, I. (Inga), Rathmann, W. (Wolfgang), Rayner, N.W. (Nigel William), Robertson, N.R. (Neil), Rocheleau, G. (Ghislain), Roden, M. (Michael), Sampson, M.J. (Michael), Saxena, R. (Richa), Shields, B.M. (Beverley), Shrader, P. (Peter), Sigurdsson, G. (Gunnar), Sparsø, T. (Thomas), Strassburger, K. (Klaus), Stringham, H.M. (Heather), Sun, Q. (Qi), Swift, A.J. (Amy), Thorand, B. (Barbara), Tichet, J. (Jean), Tuomi, T. (Tiinamaija), Dam, R.M. (Rob) van, Haeften, T.W. (Timon) van, Herpt, T.W. (Thijs) van, Vliet-Ostaptchouk, J.V. (Jana) van, Walters, G.B. (Bragi), Weedon, M.N. (Michael), Wijmenga, C. (Cisca), Witteman, J.C.M. (Jacqueline), Bergman, R.N. (Richard), Cauchi, S. (Stephane), Collins, F.S. (Francis), Gloyn, A.L. (Anna), Gyllensten, U. (Ulf), Hansen, T. (Torben), Hide, W.A. (Winston), Hitman, G.A. (Graham), Hofman, A. (Albert), Hunter, D. (David), Hveem, K. (Kristian), Laakso, M. (Markku), Mohlke, K.L. (Karen), Palmer, C.N.A. (Colin), Pramstaller, P.P. (Peter Paul), Rudan, I. (Igor), Sijbrands, E.J.G. (Eric), Stein, L.D. (Lincoln), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Walker, M. (Mark), Wareham, N.J. (Nick), Abecasis, G.R. (Gonçalo), Boehm, B.O. (Bernhard), Campbell, H. (Harry), Daly, M.J. (Mark), Hattersley, A.T. (Andrew), Hu, F.B. (Frank), Meigs, J.B. (James), Pankow, J.S. (James), Pedersen, O. (Oluf), Wichmann, H.E. (Erich), Barroso, I.E. (Inês), Florez, J.C. (Jose), Frayling, T.M. (Timothy), Groop, L. (Leif), Sladek, R. (Rob), Thorsteinsdottir, U. (Unnur), Wilson, J.F. (James), Illig, T. (Thomas), Froguel, P. (Philippe), Tikka-Kleemola, P. (Päivi), Zwart, J-A. (John-Anker), Altshuler, D. (David), Boehnke, M. (Michael), McCarthy, M.I. (Mark), and Watanabe, R.M. (Richard)

Abstract

By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P 5 × 10 8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap

Published
2010
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45. Genome-wide and fine-resolution association analysis of malaria in West Africa

Author

Jallow, M, Teo, Y, Small, K, Rockett, K, Deloukas, P, Clark, T, Kivinen, K, Bojang, K, Conway, D, Pinder, M, Sirugo, G, Sisay-Joof, F, Usen, S, Auburn, Sarah, SJ Bumpstead, S, Campino, S, Coffey, A, Dunham, A, Fry, A, Green, A, Gwilliam, R, Hunt, S, Inouye, M, Jeffreys, A, Mendy, A, Palotie, A, Potter, S, Ragoussis, J, Rogers, J, Rowlands, K, Somaskantharajah, E, Whittaker, P, Widden, C, Donnelly, P, Howie, B, Marchini, J, Morris, A, Sanjoaquin, M, Achidi, E, Agbenyega, T, Allen, A, Amodu, O, Corran, P, Djimde, A, Dolo, A, Doumbo, O, Drakeley, C, Dunstan, S, Evans, J, Farrar, J, Fernando, D, Hien, T, Horstmann, R, Ibrahim, M, Karunaweera, N, Kokwaro, G, Koram, K, Lemnge, M, Makani, J, Marsh, K, Michon, P, Modiano, D, Molyneux, M, Mueller, I, Parker, M, Peshu, N, Plowe, C, Puijalon, O, Reeder, J, Reyburn, H, Riley, E, Sakuntabhai, A, Singhasivanon, P, Sirima, S, Tall, A, Taylor, T, Thera, M, Troye-Blomberg, M, Williams, T, Wilson, M, Kwiatkowski, D, Jallow, M, Teo, Y, Small, K, Rockett, K, Deloukas, P, Clark, T, Kivinen, K, Bojang, K, Conway, D, Pinder, M, Sirugo, G, Sisay-Joof, F, Usen, S, Auburn, Sarah, SJ Bumpstead, S, Campino, S, Coffey, A, Dunham, A, Fry, A, Green, A, Gwilliam, R, Hunt, S, Inouye, M, Jeffreys, A, Mendy, A, Palotie, A, Potter, S, Ragoussis, J, Rogers, J, Rowlands, K, Somaskantharajah, E, Whittaker, P, Widden, C, Donnelly, P, Howie, B, Marchini, J, Morris, A, Sanjoaquin, M, Achidi, E, Agbenyega, T, Allen, A, Amodu, O, Corran, P, Djimde, A, Dolo, A, Doumbo, O, Drakeley, C, Dunstan, S, Evans, J, Farrar, J, Fernando, D, Hien, T, Horstmann, R, Ibrahim, M, Karunaweera, N, Kokwaro, G, Koram, K, Lemnge, M, Makani, J, Marsh, K, Michon, P, Modiano, D, Molyneux, M, Mueller, I, Parker, M, Peshu, N, Plowe, C, Puijalon, O, Reeder, J, Reyburn, H, Riley, E, Sakuntabhai, A, Singhasivanon, P, Sirima, S, Tall, A, Taylor, T, Thera, M, Troye-Blomberg, M, Williams, T, Wilson, M, and Kwiatkowski, D

Published
2009

46. Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution

Author

Lindgren, C.M. (Cecilia), Heid, I.M. (Iris), Randall, J.C. (Joshua), Lamina, C. (Claudia), Steinthorsdottir, V. (Valgerdur), Qi, L. (Lu), Speliotes, E.K. (Elizabeth), Thorleifsson, G. (Gudmar), Willer, C.J. (Cristen), Herrera, B.M. (Blanca), Jackson, A.U. (Anne), Lim, N. (Noha), Scheet, P. (Paul), Soranzo, N. (Nicole), Amin, N. (Najaf), Aulchenko, Y.S. (Yurii), Chambers, J.C. (John), Drong, A. (Alexander), Luan, J., Lyon, H.N. (Helen), Rivadeneira Ramirez, F. (Fernando), Sanna, S. (Serena), Timpson, N.J. (Nicholas), Zillikens, M.C. (Carola), Jing, H.Z., Almgren, P. (Peter), Bandinelli, S. (Stefania), Bennett, A.J. (Amanda), Bergman, R.N. (Richard), Bonnycastle, L.L. (Lori), Bumpstead, S. (Suzannah), Chanock, S.J. (Stephen), Cherkas, L. (Lynn), Chines, P.S. (Peter), Coin, L. (Lachlan), Cooper, C. (Charles), Crawford, G. (Gabe), Doering, A. (Angela), Dominiczak, A. (Anna), Doney, A.S.F. (Alex), Ebrahim, S. (Shanil), Elliott, P. (Paul), Erdos, M.R. (Michael), Estrada Gil, K. (Karol), Ferrucci, L. (Luigi), Fischer, G. (Guido), Forouhi, N.G. (Nita), Gieger, C. (Christian), Grallert, H. (Harald), Groves, C.J. (Christopher), Grundy, S.M. (Scott), Guiducci, C. (Candace), Hadley, D. (David), Hamsten, A. (Anders), Havulinna, A.S. (Aki), Hofman, A. (Albert), Holle, R. (Rolf), Holloway, J.W. (John), Illig, T. (Thomas), Isomaa, B. (Bo), Jacobs, L.C. (Leonie), Jameson, K. (Karen), Jousilahti, P. (Pekka), Karpe, F. (Fredrik), Kuusisto, J. (Johanna), Laitinen, J. (Jaana), Lathrop, G.M. (Mark), Lawlor, D.A. (Debbie), Mangino, M. (Massimo), McArdle, W.L. (Wendy), Meitinger, T. (Thomas), Morken, M.A. (Mario), Morris, A.P. (Andrew), Munroe, P. (Patricia), Narisu, N. (Narisu), Nordström, A. (Anna), Oostra, B.A. (Ben), Palmer, C.N.A. (Colin), Payne, F. (Felicity), Peden, J. (John), Prokopenko, I. (Inga), Renström, F. (Frida), Ruokonen, A. (Aimo), Salomaa, V. (Veikko), Sandhu, M.S. (Manjinder), Scott, L.J. (Laura), Scuteri, A. (Angelo), Silander, K. (Kaisa), Song, K. (Kijoung), Yuan, X. (Xin), Stringham, H.M. (Heather), Swift, A.J. (Amy), Tuomi, T. (Tiinamaija), Uda, M. (Manuela), Vollenweider, P. (Peter), Waeber, G. (Gérard), Wallace, C. (Chris), Walters, G.B. (Bragi), Weedon, M.N. (Michael), Witteman, J.C.M. (Jacqueline), Zhang, C. (Cuilin), Caulfield, M. (Mark), Collins, F.S. (Francis), Smith, A.V. (Davey), Day, I.N.M. (Ian), Franks, P.W. (Paul), Hattersley, A.T. (Andrew), Hu, F.B. (Frank), Jarvelin, M.-R. (Marjo-Riitta), Kong, A. (Augustine), Kooner, J.S. (Jaspal), Laakso, M. (Markku), Lakatta, E. (Edward), Mooser, V. (Vincent), Peltonen, L. (Leena Johanna), Samani, N.J. (Nilesh), Spector, T.D. (Timothy), Strachan, D.P. (David), Tanaka, T. (Toshiko), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Tikka-Kleemola, P. (Päivi), Wareham, N.J. (Nick), Watkins, H. (Hugh), Waterworth, D. (Dawn), Boehnke, M. (Michael), Deloukas, P. (Panagiotis), Groop, L. (Leif), Hunter, D.J. (David), Thorsteinsdottir, U. (Unnur), Schlessinger, D. (David), Wichmann, H.E. (Erich), Frayling, T.M. (Timothy), Abecasis, G.R. (Gonçalo), Hirschhorn, J.N. (Joel), Loos, R.J.F. (Ruth), Zwart, J-A. (John-Anker), Mohlke, K.L. (Karen), Barroso, I.E. (Inês), McCarthy, M.I. (Mark), Lindgren, C.M. (Cecilia), Heid, I.M. (Iris), Randall, J.C. (Joshua), Lamina, C. (Claudia), Steinthorsdottir, V. (Valgerdur), Qi, L. (Lu), Speliotes, E.K. (Elizabeth), Thorleifsson, G. (Gudmar), Willer, C.J. (Cristen), Herrera, B.M. (Blanca), Jackson, A.U. (Anne), Lim, N. (Noha), Scheet, P. (Paul), Soranzo, N. (Nicole), Amin, N. (Najaf), Aulchenko, Y.S. (Yurii), Chambers, J.C. (John), Drong, A. (Alexander), Luan, J., Lyon, H.N. (Helen), Rivadeneira Ramirez, F. (Fernando), Sanna, S. (Serena), Timpson, N.J. (Nicholas), Zillikens, M.C. (Carola), Jing, H.Z., Almgren, P. (Peter), Bandinelli, S. (Stefania), Bennett, A.J. (Amanda), Bergman, R.N. (Richard), Bonnycastle, L.L. (Lori), Bumpstead, S. (Suzannah), Chanock, S.J. (Stephen), Cherkas, L. (Lynn), Chines, P.S. (Peter), Coin, L. (Lachlan), Cooper, C. (Charles), Crawford, G. (Gabe), Doering, A. (Angela), Dominiczak, A. (Anna), Doney, A.S.F. (Alex), Ebrahim, S. (Shanil), Elliott, P. (Paul), Erdos, M.R. (Michael), Estrada Gil, K. (Karol), Ferrucci, L. (Luigi), Fischer, G. (Guido), Forouhi, N.G. (Nita), Gieger, C. (Christian), Grallert, H. (Harald), Groves, C.J. (Christopher), Grundy, S.M. (Scott), Guiducci, C. (Candace), Hadley, D. (David), Hamsten, A. (Anders), Havulinna, A.S. (Aki), Hofman, A. (Albert), Holle, R. (Rolf), Holloway, J.W. (John), Illig, T. (Thomas), Isomaa, B. (Bo), Jacobs, L.C. (Leonie), Jameson, K. (Karen), Jousilahti, P. (Pekka), Karpe, F. (Fredrik), Kuusisto, J. (Johanna), Laitinen, J. (Jaana), Lathrop, G.M. (Mark), Lawlor, D.A. (Debbie), Mangino, M. (Massimo), McArdle, W.L. (Wendy), Meitinger, T. (Thomas), Morken, M.A. (Mario), Morris, A.P. (Andrew), Munroe, P. (Patricia), Narisu, N. (Narisu), Nordström, A. (Anna), Oostra, B.A. (Ben), Palmer, C.N.A. (Colin), Payne, F. (Felicity), Peden, J. (John), Prokopenko, I. (Inga), Renström, F. (Frida), Ruokonen, A. (Aimo), Salomaa, V. (Veikko), Sandhu, M.S. (Manjinder), Scott, L.J. (Laura), Scuteri, A. (Angelo), Silander, K. (Kaisa), Song, K. (Kijoung), Yuan, X. (Xin), Stringham, H.M. (Heather), Swift, A.J. (Amy), Tuomi, T. (Tiinamaija), Uda, M. (Manuela), Vollenweider, P. (Peter), Waeber, G. (Gérard), Wallace, C. (Chris), Walters, G.B. (Bragi), Weedon, M.N. (Michael), Witteman, J.C.M. (Jacqueline), Zhang, C. (Cuilin), Caulfield, M. (Mark), Collins, F.S. (Francis), Smith, A.V. (Davey), Day, I.N.M. (Ian), Franks, P.W. (Paul), Hattersley, A.T. (Andrew), Hu, F.B. (Frank), Jarvelin, M.-R. (Marjo-Riitta), Kong, A. (Augustine), Kooner, J.S. (Jaspal), Laakso, M. (Markku), Lakatta, E. (Edward), Mooser, V. (Vincent), Peltonen, L. (Leena Johanna), Samani, N.J. (Nilesh), Spector, T.D. (Timothy), Strachan, D.P. (David), Tanaka, T. (Toshiko), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Tikka-Kleemola, P. (Päivi), Wareham, N.J. (Nick), Watkins, H. (Hugh), Waterworth, D. (Dawn), Boehnke, M. (Michael), Deloukas, P. (Panagiotis), Groop, L. (Leif), Hunter, D.J. (David), Thorsteinsdottir, U. (Unnur), Schlessinger, D. (David), Wichmann, H.E. (Erich), Frayling, T.M. (Timothy), Abecasis, G.R. (Gonçalo), Hirschhorn, J.N. (Joel), Loos, R.J.F. (Ruth), Zwart, J-A. (John-Anker), Mohlke, K.L. (Karen), Barroso, I.E. (Inês), and McCarthy, M.I. (Mark)

Abstract

To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9×102-11) and MSRA (WC, P = 8.9×10-9). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6×10-8). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human

Published
2009
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47. Common variants at five new loci associated with early-onset inflammatory bowel disease.

Author

Imielinski, M, Baldassano, RN, Griffiths, Anne, Russell, RK, Annese, V, Dubinsky, M, Kugathasan, S, Bradfield, JP, Walters, TD, Sleiman, P, Kim, CE, Muise, A, Wang, K, Glessner, JT, Saeed, S, Zhang, H, Frackelton, EC, Hou, C, Flory, JH, Otieno, G, Chiavacci, RM, Grundmeier, R, Castro, Massimo, Latiano, A, Dallapiccola, B, Stempak, J, Abrams, DJ, Taylor, K, McGovern, D, Western Regional Alliance for Pediatric IBD, Silber, G, Wrobel, I, Quiros, A, International IBD Genetics Consortium, Barrett, J Carl, Hansoul, Sarah, Nicolae, DL, Cho, Judy H, Duerr, R H, Rioux, J D, Brant, S R, Silverberg, M S, Taylor, Kent D, Barmuda, MM, Bitton, A, Dassopoulos, T, Datta, LW, Green, T, Griffiths, Anne-Marie, Kistner, EO, Murtha, MT, Regueiro, Miguel, Rotter, J I, Schumm, L Philip, Steinhart, A H, Targan, SR, Xavier, RJ, NIDDK IBD Genetics Consortium, Libioulle, C, Sandor, Cynthia, Lathrop, Mark, Belaiche, Jacques, Gut, Ivo, Heath, Simon, Laukens, Debby, Mni, Myriam, Rutgeerts, Paul, Van Gossum, André, Zelenika, Diana, Franchimont, Denis, Hugot, JP, De Vos, M, Vermeire, Séverine, Louis, Edouard, Belgian-French IBD Consortium,, Wellcome Trust Case Control Consortium,, Cardon, LR, Anderson, CA, Drummond, H, Nimmo, Elaine R, Ahmad, T, Prescott, NJ, Onnie, CM, Fisher, SA, Marchini, J, Ghori, J, Bumpstead, S, Gwillam, R, Tremelling, M, Delukas, P, Mansfeld, J., Jewell, D, Satsangi, Jack, Mathew, CG, Parkes, M, Georges, M., Daly, M J, Heyman, MB, Ferry, GD, Kirschner, B, Lee, J, Essers, J, Grand, R, Stephens, M, Levine, A, Piccoli, D, Van Limbergen, J, Cucchiara, Salvatore, Monos, DS, Guthery, SL, Denson, L, Wilson, DC, Grant, SF, Dewit, Olivier, Imielinski, M, Baldassano, RN, Griffiths, Anne, Russell, RK, Annese, V, Dubinsky, M, Kugathasan, S, Bradfield, JP, Walters, TD, Sleiman, P, Kim, CE, Muise, A, Wang, K, Glessner, JT, Saeed, S, Zhang, H, Frackelton, EC, Hou, C, Flory, JH, Otieno, G, Chiavacci, RM, Grundmeier, R, Castro, Massimo, Latiano, A, Dallapiccola, B, Stempak, J, Abrams, DJ, Taylor, K, McGovern, D, Western Regional Alliance for Pediatric IBD, Silber, G, Wrobel, I, Quiros, A, International IBD Genetics Consortium, Barrett, J Carl, Hansoul, Sarah, Nicolae, DL, Cho, Judy H, Duerr, R H, Rioux, J D, Brant, S R, Silverberg, M S, Taylor, Kent D, Barmuda, MM, Bitton, A, Dassopoulos, T, Datta, LW, Green, T, Griffiths, Anne-Marie, Kistner, EO, Murtha, MT, Regueiro, Miguel, Rotter, J I, Schumm, L Philip, Steinhart, A H, Targan, SR, Xavier, RJ, NIDDK IBD Genetics Consortium, Libioulle, C, Sandor, Cynthia, Lathrop, Mark, Belaiche, Jacques, Gut, Ivo, Heath, Simon, Laukens, Debby, Mni, Myriam, Rutgeerts, Paul, Van Gossum, André, Zelenika, Diana, Franchimont, Denis, Hugot, JP, De Vos, M, Vermeire, Séverine, Louis, Edouard, Belgian-French IBD Consortium,, Wellcome Trust Case Control Consortium,, Cardon, LR, Anderson, CA, Drummond, H, Nimmo, Elaine R, Ahmad, T, Prescott, NJ, Onnie, CM, Fisher, SA, Marchini, J, Ghori, J, Bumpstead, S, Gwillam, R, Tremelling, M, Delukas, P, Mansfeld, J., Jewell, D, Satsangi, Jack, Mathew, CG, Parkes, M, Georges, M., Daly, M J, Heyman, MB, Ferry, GD, Kirschner, B, Lee, J, Essers, J, Grand, R, Stephens, M, Levine, A, Piccoli, D, Van Limbergen, J, Cucchiara, Salvatore, Monos, DS, Guthery, SL, Denson, L, Wilson, DC, Grant, SF, and Dewit, Olivier

Abstract

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 x 10(-9)), 22q12 (rs2412973, P = 1.55 x 10(-9)), 10q22 (rs1250550, P = 5.63 x 10(-9)), 2q37 (rs4676410, P = 3.64 x 10(-8)) and 19q13.11 (rs10500264, P = 4.26 x 10(-10)). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn's disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD., Journal Article, Research Support, N.I.H. Extramural, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
2009

48. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease.

Author

Barrett, J Carl, Hansoul, Sarah, Nicolae, DL, Cho, Judy H, Duerr, R H, Rioux, J D, Brant, S R, Silverberg, M S, Taylor, Kent D, Barmada, MM, Bitton, A, Dassopoulos, T, Datta, LW, Green, T, Griffiths, Anne-Marie, Kistner, EO, Murtha, MT, Regueiro, Miguel, Rotter, J I, Schumm, L Philip, Steinhart, A H, Targan, SR, Xavier, RJ, NIDDK IBD Genetics Consortium, Libioulle, C, Sandor, Cynthia, Lathrop, Mark, Belaiche, Jacques, Gut, Ivo, Heath, Simon, Laukens, Debby, Mni, Myriam, Rutgeerts, Paul, Van Gossum, André, Zelenika, Diana, Franchimont, Denis, Hugot, JP, De Vos, M, Vermeire, Séverine, Louis, Edouard, Belgian-French IBD Consortium,, Wellcome Trust Case Control Consortium,, Cardon, LR, Anderson, CA, Drummond, H, Nimmo, Elaine R, Ahmad, T, Prescott, NJ, Onnie, CM, Fisher, SA, Marchini, J, Ghori, J, Bumpstead, S, Gwillam, R, Tremelling, M, Delukas, P, Mansfeld, J., Jewell, D, Satsangi, Jack, Mathew, CG, Parkes, M, Georges, M., Daly, M J, Dewit, Olivier, Barrett, J Carl, Hansoul, Sarah, Nicolae, DL, Cho, Judy H, Duerr, R H, Rioux, J D, Brant, S R, Silverberg, M S, Taylor, Kent D, Barmada, MM, Bitton, A, Dassopoulos, T, Datta, LW, Green, T, Griffiths, Anne-Marie, Kistner, EO, Murtha, MT, Regueiro, Miguel, Rotter, J I, Schumm, L Philip, Steinhart, A H, Targan, SR, Xavier, RJ, NIDDK IBD Genetics Consortium, Libioulle, C, Sandor, Cynthia, Lathrop, Mark, Belaiche, Jacques, Gut, Ivo, Heath, Simon, Laukens, Debby, Mni, Myriam, Rutgeerts, Paul, Van Gossum, André, Zelenika, Diana, Franchimont, Denis, Hugot, JP, De Vos, M, Vermeire, Séverine, Louis, Edouard, Belgian-French IBD Consortium,, Wellcome Trust Case Control Consortium,, Cardon, LR, Anderson, CA, Drummond, H, Nimmo, Elaine R, Ahmad, T, Prescott, NJ, Onnie, CM, Fisher, SA, Marchini, J, Ghori, J, Bumpstead, S, Gwillam, R, Tremelling, M, Delukas, P, Mansfeld, J., Jewell, D, Satsangi, Jack, Mathew, CG, Parkes, M, Georges, M., Daly, M J, and Dewit, Olivier

Abstract

Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development., Journal Article, Meta-Analysis, Research Support, N.I.H. Extramural, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
2008

49. 378 THE arcOGEN CONSORTIUM: STAGE 1 OF A GENOME-WIDE ASSOCIATION SCAN FOR OSTEOARTHRITIS

Author

Panoutsopoulou, K., primary, Southam, L., additional, Rayner, W., additional, Zhai, G., additional, Beazley, C., additional, Arden, N., additional, Carr, A., additional, Chapman, K., additional, Deloukas, P., additional, Doherty, M., additional, McCaskie, A., additional, Oilier, W., additional, Ralston, S., additional, Spector, T., additional, Valdes, A., additional, Wallis, G., additional, Wilkinson, M., additional, Arden, E., additional, Battley, K., additional, Blackburn, H., additional, Blanco, F., additional, Bumpstead, S., additional, Cupples, A., additional, Day-Williams, A., additional, Dixon, K., additional, Doherty, S., additional, Elliott, K., additional, Evangelou, E., additional, Felson, D., additional, Gomez-Reino, J., additional, Gonzalez, A., additional, Gordon, A., additional, Gwilliam, R., additional, Hofman, A., additional, Hunt, S., additional, Ioannidis, J., additional, Jonsdottir, I., additional, Keen, R., additional, Kerkhof, H., additional, Kloppenburg, M., additional, Koller, N., additional, Lakenberg, N., additional, Lane, N., additional, Lee, A., additional, Meulenbelt, I., additional, Nevitt, M., additional, O'Neill, F., additional, Parimi, N., additional, Potter, S., additional, Rego-Perez, I., additional, Riancho, J., additional, Sherburn, K., additional, Slagboom, E., additional, Styrkarsdottir, U., additional, Sumillera, M., additional, Swift, D., additional, Tsezou, A., additional, Uitterlinden, A., additional, van Meurs, J., additional, Watkins, B., additional, Wheeler, M., additional, Mitchell, S., additional, Zhu, Y., additional, Zmuda, J., additional, Zeggini, E., additional, and Loughlin, J., additional

Published
2010
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50. Erratum: Corrigendum: Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

Author

Voight, BF, Scott, LJ, Steinthorsdottir, V, Morris, AP, Dina, C, Welch, RP, Zeggini, E, Huth, C, Aulchenko, YS, Thorleifsson, G, McCulloch, LJ, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, CJ, Raychaudhuri, S, McCarroll, SA, Langenberg, C, Hofmann, OM, Dupuis, J, Qi, L, Segrè, AV, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, AJ, Blagieva, R, Boerwinkle, E, Bonnycastle, LL, Boström, KB, Bravenboer, B, Bumpstead, S, Burtt, NP, Charpentier, G, Chines, PS, Cornelis, M, Couper, DJ, Crawford, G, Doney, AS, Elliott, KS, Elliott, AL, Erdos, MR, Fox, CS, Franklin, CS, Ganser, M, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, CJ, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Isomaa, B, Jackson, AU, Johnson, PR, Jørgensen, T, Kao, WH, Klopp, N, Kong, A, Kraft, P, Kuusisto, J, Lauritzen, T, Li, M, Lieverse, A, Lindgren, CM, Lyssenko, V, Marre, M, Meitinger, T, Midthjell, K, Morken, MA, Narisu, N, Nilsson, P, Owen, KR, Payne, F, Perry, JR, Petersen, AK, Platou, C, Proença, C, Prokopenko, I, Rathmann, W, Rayner, NW, Robertson, NR, Rocheleau, G, Roden, M, Sampson, MJ, Saxena, R, Shields, BM, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, HM, Sun, Q, Swift, AJ, Thorand, B, Tichet, J, Tuomi, T, van Dam, RM, van Haeften, TW, van Herpt, T, van Vliet-Ostaptchouk, JV, Walters, GB, Weedon, MN, Wijmenga, C, Witteman, J, Bergman, RN, Cauchi, S, Collins, FS, Gloyn, AL, Gyllensten, U, Hansen, T, Hide, WA, Hitman, GA, Hofman, A, Hunter, DJ, Hveem, K, Laakso, M, Mohlke, KL, Morris, AD, Palmer, CN, Pramstaller, PP, Rudan, I, Sijbrands, E, Stein, LD, Tuomilehto, J, Uitterlinden, A, Walker, M, Wareham, NJ, Watanabe, RM, Abecasis, GR, Boehm, BO, Campbell, H, Daly, MJ, Hattersley, AT, Hu, FB, Meigs, JB, Pankow, JS, Pedersen, O, Wichmann, HE, Barroso, I, Florez, JC, Frayling, TM, Groop, L, Sladek, R, Thorsteinsdottir, U, Wilson, JF, Illig, T, Froguel, P, van Duijn, CM, Stefansson, K, Altshuler, D, Boehnke, M, and McCarthy, MI

Subjects
Genetics, Scale (ratio), medicine, Susceptibility locus, Type 2 diabetes, Biology, medicine.disease, Genetic association
Published
2011
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