School of Mathematics and Statistics - Research Publications

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Author: Scott, Clare × End date: 2012 × Type: Journal Article ×

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    Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
    Craddock, N ; Hurles, ME ; Cardin, N ; Pearson, RD ; Plagnol, V ; Robson, S ; Vukcevic, D ; Barnes, C ; Conrad, DF ; Giannoulatou, E ; Holmes, C ; Marchini, JL ; Stirrups, K ; Tobin, MD ; Wain, LV ; Yau, C ; Aerts, J ; Ahmad, T ; Andrews, TD ; Arbury, H ; Attwood, A ; Auton, A ; Ball, SG ; Balmforth, AJ ; 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 ; Clee, CM ; Coffey, AJ ; Connell, JMC ; 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 ; Feuk, L ; Fitzgerald, T ; Flynn, E ; Forbes, A ; Forty, L ; Franklyn, JA ; Freathy, RM ; Gibbs, P ; Gilbert, P ; Gokumen, O ; 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 ; 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 ; Martin, P ; Massey, DCO ; McArdle, WL ; McGuffin, P ; McLay, KE ; Mentzer, A ; Mimmack, ML ; Morgan, AE ; Morris, AP ; Mowat, C ; Myers, S ; Newman, W ; Nimmo, ER ; O'Donovan, MC ; Onipinla, A ; Onyiah, I ; Ovington, NR ; Owen, MJ ; Palin, K ; Parnell, K ; Pernet, D ; Perry, JRB ; Phillips, A ; Pinto, D ; Prescott, NJ ; Prokopenko, I ; Quail, MA ; Rafelt, S ; Rayner, NW ; Redon, R ; Reid, DM ; Renwick, A ; Ring, SM ; Robertson, N ; Russell, E ; St Clair, D ; Sambrook, JG ; Sanderson, JD ; Schuilenburg, H ; Scott, CE ; Scott, R ; Seal, S ; Shaw-Hawkins, S ; Shields, BM ; Simmonds, MJ ; Smyth, DJ ; Somaskantharajah, E ; Spanova, K ; Steer, S ; Stephens, J ; Stevens, HE ; Stone, MA ; Su, Z ; Symmons, DPM ; Thompson, JR ; Thomson, W ; Travers, ME ; Turnbull, C ; Valsesia, A ; Walker, M ; Walker, NM ; Wallace, C ; Warren-Perry, M ; Watkins, NA ; Webster, J ; Weedon, MN ; Wilson, AG ; Woodburn, M ; Wordsworth, BP ; Young, AH ; Zeggini, E ; Carter, NP ; Frayling, TM ; Lee, C ; McVean, G ; Munroe, PB ; Palotie, A ; Sawcer, SJ ; Scherer, SW ; Strachan, DP ; Tyler-Smith, C ; 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 ; Deloukas, P ; Duncanson, A ; Kwiatkowski, DP ; McCarthy, MI ; Ouwehand, WH ; Parkes, M ; Rahman, N ; Todd, JA ; Samani, NJ ; Donnelly, P (NATURE PORTFOLIO, 2010-04-01)
    Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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    Neither loss of Bik alone, nor combined loss of Bik and Noxa, accelerate murine lymphoma development or render lymphoma cells resistant to DNA damaging drugs
    Happo, L ; Phipson, B ; Smyth, GK ; Strasser, A ; Scott, CL (NATURE PUBLISHING GROUP, 2012-05)
    The pro-apoptotic BH3-only protein, BIK, is widely expressed and although many critical functions in developmental or stress-induced death have been ascribed to this protein, mice lacking Bik display no overt abnormalities. It has been postulated that Bik can serve as a tumour suppressor, on the basis that its deficiency and loss of apoptotic function have been reported in many human cancers, including lymphoid malignancies. Evasion of apoptosis is a major factor contributing to c-Myc-induced tumour development, but despite this, we found that Bik deficiency did not accelerate Eμ-Myc-induced lymphomagenesis. Co-operation between BIK and NOXA, another BH3-only protein, has been previously described, and was attributed to their complementary binding specificities to distinct subsets of pro-survival BCL-2 family proteins. Nevertheless, combined deficiency of Bik and Noxa did not alter the onset of Eμ-Myc transgene induced lymphoma development. Moreover, although p53-mediated induction of Bik has been reported, neither Eμ-Myc/Bik(-/-) nor Eμ-Myc/Bik(-/-)Noxa(-/-) lymphomas were more resistant than control Eμ-Myc lymphomas to killing by DNA damaging drugs, either in vitro or in vivo. These results suggest that Bik, even in combination with Noxa, is not a potent suppressor of c-Myc-driven tumourigenesis or critical for chemotherapeutic drug-induced killing of Myc-driven tumours.