ALBERT

Description: 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892339/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892339/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wellcome Trust Case Control Consortium -- Craddock, Nick -- Hurles, Matthew E -- Cardin, Niall -- Pearson, Richard D -- Plagnol, Vincent -- Robson, Samuel -- Vukcevic, Damjan -- Barnes, Chris -- Conrad, Donald F -- Giannoulatou, Eleni -- Holmes, Chris -- Marchini, Jonathan L -- Stirrups, Kathy -- Tobin, Martin D -- Wain, Louise V -- Yau, Chris -- Aerts, Jan -- Ahmad, Tariq -- Andrews, T Daniel -- Arbury, Hazel -- Attwood, Anthony -- Auton, Adam -- Ball, Stephen G -- Balmforth, Anthony J -- Barrett, Jeffrey C -- Barroso, Ines -- Barton, Anne -- Bennett, Amanda J -- Bhaskar, Sanjeev -- Blaszczyk, Katarzyna -- Bowes, John -- Brand, Oliver J -- Braund, Peter S -- Bredin, Francesca -- Breen, Gerome -- Brown, Morris J -- Bruce, Ian N -- Bull, Jaswinder -- Burren, Oliver S -- Burton, John -- Byrnes, Jake -- Caesar, Sian -- Clee, Chris M -- Coffey, Alison J -- Connell, John M C -- Cooper, Jason D -- Dominiczak, Anna F -- Downes, Kate -- Drummond, Hazel E -- Dudakia, Darshna -- Dunham, Andrew -- Ebbs, Bernadette -- Eccles, Diana -- Edkins, Sarah -- Edwards, Cathryn -- Elliot, Anna -- Emery, Paul -- Evans, David M -- Evans, Gareth -- Eyre, Steve -- Farmer, Anne -- Ferrier, I Nicol -- Feuk, Lars -- Fitzgerald, Tomas -- Flynn, Edward -- Forbes, Alistair -- Forty, Liz -- Franklyn, Jayne A -- Freathy, Rachel M -- Gibbs, Polly -- Gilbert, Paul -- Gokumen, Omer -- Gordon-Smith, Katherine -- Gray, Emma -- Green, Elaine -- Groves, Chris J -- Grozeva, Detelina -- Gwilliam, Rhian -- Hall, Anita -- Hammond, Naomi -- Hardy, Matt -- Harrison, Pile -- Hassanali, Neelam -- Hebaishi, Husam -- Hines, Sarah -- Hinks, Anne -- Hitman, Graham A -- Hocking, Lynne -- Howard, Eleanor -- Howard, Philip -- Howson, Joanna M M -- Hughes, Debbie -- Hunt, Sarah -- Isaacs, John D -- Jain, Mahim -- Jewell, Derek P -- Johnson, Toby -- Jolley, Jennifer D -- Jones, Ian R -- Jones, Lisa A -- Kirov, George -- Langford, Cordelia F -- Lango-Allen, Hana -- Lathrop, G Mark -- Lee, James -- Lee, Kate L -- Lees, Charlie -- Lewis, Kevin -- Lindgren, Cecilia M -- Maisuria-Armer, Meeta -- Maller, Julian -- Mansfield, John -- Martin, Paul -- Massey, Dunecan C O -- McArdle, Wendy L -- McGuffin, Peter -- McLay, Kirsten E -- Mentzer, Alex -- Mimmack, Michael L -- Morgan, Ann E -- Morris, Andrew P -- Mowat, Craig -- Myers, Simon -- Newman, William -- Nimmo, Elaine R -- O'Donovan, Michael C -- Onipinla, Abiodun -- Onyiah, Ifejinelo -- Ovington, Nigel R -- Owen, Michael J -- Palin, Kimmo -- Parnell, Kirstie -- Pernet, David -- Perry, John R B -- Phillips, Anne -- Pinto, Dalila -- Prescott, Natalie J -- Prokopenko, Inga -- Quail, Michael A -- Rafelt, Suzanne -- Rayner, Nigel W -- Redon, Richard -- Reid, David M -- Renwick -- Ring, Susan M -- Robertson, Neil -- Russell, Ellie -- St Clair, David -- Sambrook, Jennifer G -- Sanderson, Jeremy D -- Schuilenburg, Helen -- Scott, Carol E -- Scott, Richard -- Seal, Sheila -- Shaw-Hawkins, Sue -- Shields, Beverley M -- Simmonds, Matthew J -- Smyth, Debbie J -- Somaskantharajah, Elilan -- Spanova, Katarina -- Steer, Sophia -- Stephens, Jonathan -- Stevens, Helen E -- Stone, Millicent A -- Su, Zhan -- Symmons, Deborah P M -- Thompson, John R -- Thomson, Wendy -- Travers, Mary E -- Turnbull, Clare -- Valsesia, Armand -- Walker, Mark -- Walker, Neil M -- Wallace, Chris -- Warren-Perry, Margaret -- Watkins, Nicholas A -- Webster, John -- Weedon, Michael N -- Wilson, Anthony G -- Woodburn, Matthew -- Wordsworth, B Paul -- Young, Allan H -- Zeggini, Eleftheria -- Carter, Nigel P -- Frayling, Timothy M -- Lee, Charles -- McVean, Gil -- Munroe, Patricia B -- Palotie, Aarno -- Sawcer, Stephen J -- Scherer, Stephen W -- Strachan, David P -- Tyler-Smith, Chris -- Brown, Matthew A -- Burton, Paul R -- Caulfield, Mark J -- Compston, Alastair -- Farrall, Martin -- Gough, Stephen C L -- Hall, Alistair S -- Hattersley, Andrew T -- Hill, Adrian V S -- Mathew, Christopher G -- Pembrey, Marcus -- Satsangi, Jack -- Stratton, Michael R -- Worthington, Jane -- Deloukas, Panos -- Duncanson, Audrey -- Kwiatkowski, Dominic P -- McCarthy, Mark I -- Ouwehand, Willem -- Parkes, Miles -- Rahman, Nazneen -- Todd, John A -- Samani, Nilesh J -- Donnelly, Peter -- 061858/Wellcome Trust/United Kingdom -- 083948/Wellcome Trust/United Kingdom -- 089989/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 17552/Arthritis Research UK/United Kingdom -- CZB/4/540/Chief Scientist Office/United Kingdom -- ETM/137/Chief Scientist Office/United Kingdom -- ETM/75/Chief Scientist Office/United Kingdom -- G0000934/Medical Research Council/United Kingdom -- G0400874/Medical Research Council/United Kingdom -- G0500115/Medical Research Council/United Kingdom -- G0501942/Medical Research Council/United Kingdom -- G0600329/Medical Research Council/United Kingdom -- G0600705/Medical Research Council/United Kingdom -- G0700491/Medical Research Council/United Kingdom -- G0701003/Medical Research Council/United Kingdom -- G0701420/Medical Research Council/United Kingdom -- G0701810/Medical Research Council/United Kingdom -- G0701810(85517)/Medical Research Council/United Kingdom -- G0800383/Medical Research Council/United Kingdom -- G0800509/Medical Research Council/United Kingdom -- G0800759/Medical Research Council/United Kingdom -- G19/9/Medical Research Council/United Kingdom -- G90/106/Medical Research Council/United Kingdom -- G9521010/Medical Research Council/United Kingdom -- MC_UP_A390_1107/Medical Research Council/United Kingdom -- RG/09/012/28096/British Heart Foundation/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Apr 1;464(7289):713-20. doi: 10.1038/nature08979.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20360734" target="_blank"〉PubMed〈/a〉

Description: Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case-control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 x 10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 x 10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 x 10(-9)). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759028/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759028/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ruark, Elise -- Snape, Katie -- Humburg, Peter -- Loveday, Chey -- Bajrami, Ilirjana -- Brough, Rachel -- Rodrigues, Daniel Nava -- Renwick, Anthony -- Seal, Sheila -- Ramsay, Emma -- Duarte, Silvana Del Vecchio -- Rivas, Manuel A -- Warren-Perry, Margaret -- Zachariou, Anna -- Campion-Flora, Adriana -- Hanks, Sandra -- Murray, Anne -- Ansari Pour, Naser -- Douglas, Jenny -- Gregory, Lorna -- Rimmer, Andrew -- Walker, Neil M -- Yang, Tsun-Po -- Adlard, Julian W -- Barwell, Julian -- Berg, Jonathan -- Brady, Angela F -- Brewer, Carole -- Brice, Glen -- Chapman, Cyril -- Cook, Jackie -- Davidson, Rosemarie -- Donaldson, Alan -- Douglas, Fiona -- Eccles, Diana -- Evans, D Gareth -- Greenhalgh, Lynn -- Henderson, Alex -- Izatt, Louise -- Kumar, Ajith -- Lalloo, Fiona -- Miedzybrodzka, Zosia -- Morrison, Patrick J -- Paterson, Joan -- Porteous, Mary -- Rogers, Mark T -- Shanley, Susan -- Walker, Lisa -- Gore, Martin -- Houlston, Richard -- Brown, Matthew A -- Caufield, Mark J -- Deloukas, Panagiotis -- McCarthy, Mark I -- Todd, John A -- Breast and Ovarian Cancer Susceptibility Collaboration -- Wellcome Trust Case Control Consortium -- Turnbull, Clare -- Reis-Filho, Jorge S -- Ashworth, Alan -- Antoniou, Antonis C -- Lord, Christopher J -- Donnelly, Peter -- Rahman, Nazneen -- 068545/Z/02/Wellcome Trust/United Kingdom -- 083948/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 090532/Z/09/Z/Wellcome Trust/United Kingdom -- 091157/Wellcome Trust/United Kingdom -- 095552/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- 100140/Wellcome Trust/United Kingdom -- 11174/Cancer Research UK/United Kingdom -- C12292/A11174/Cancer Research UK/United Kingdom -- CZB/4/540/Chief Scientist Office/United Kingdom -- ETM/137/Chief Scientist Office/United Kingdom -- ETM/75/Chief Scientist Office/United Kingdom -- G0000934/Medical Research Council/United Kingdom -- G0600329/Medical Research Council/United Kingdom -- G0800759/Medical Research Council/United Kingdom -- G0900747 91070/Medical Research Council/United Kingdom -- G9521010/Medical Research Council/United Kingdom -- MR/K006584/1/Medical Research Council/United Kingdom -- England -- Nature. 2013 Jan 17;493(7432):406-10. doi: 10.1038/nature11725. Epub 2012 Dec 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Genetics & Epidemiology, The Institute of Cancer Research, Sutton SM2 5NG, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23242139" target="_blank"〉PubMed〈/a〉

Description: A small proportion of breast cancer, in particular those cases arising at a young age, is due to the inheritance of dominant susceptibility genes conferring a high risk of the disease. A genomic linkage search was performed with 15 high-risk breast cancer families that were unlinked to the BRCA1 locus on chromosome 17q21. This analysis localized a second breast cancer susceptibility locus, BRCA2, to a 6-centimorgan interval on chromosome 13q12-13. Preliminary evidence suggests that BRCA2 confers a high risk of breast cancer but, unlike BRCA1, does not confer a substantially elevated risk of ovarian cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wooster, R -- Neuhausen, S L -- Mangion, J -- Quirk, Y -- Ford, D -- Collins, N -- Nguyen, K -- Seal, S -- Tran, T -- Averill, D -- CA-48711/CA/NCI NIH HHS/ -- CN-05222/CN/NCI NIH HHS/ -- HG-00571/HG/NHGRI NIH HHS/ -- etc. -- New York, N.Y. -- Science. 1994 Sep 30;265(5181):2088-90.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Section of Molecular Carcinogenesis, Institute of Cancer Research, Sutton, Surrey, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8091231" target="_blank"〉PubMed〈/a〉

Description: Infectious bovine rhinotracheitis virus was isolated from the soft-shelled tick (Ornithodoros coriaceus). Serological identification of the isolated viruses was confirmed by restriction endonuclease digestion of purified virus DNA. These isolations indicate that the soft-shelled tick may be a vector for infectious bovine rhinotracheitis virus. This may be the first reported isolation of mammalian herpesvirus from an arthropod vector.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Taylor, R E -- Seal, B S -- St Jeor, S -- New York, N.Y. -- Science. 1982 Apr 16;216(4543):300-1.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/6278596" target="_blank"〉PubMed〈/a〉