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: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182531/" 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/PMC3182531/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉International Multiple Sclerosis Genetics Consortium -- Wellcome Trust Case Control Consortium 2 -- Sawcer, Stephen -- Hellenthal, Garrett -- Pirinen, Matti -- Spencer, Chris C A -- Patsopoulos, Nikolaos A -- Moutsianas, Loukas -- Dilthey, Alexander -- Su, Zhan -- Freeman, Colin -- Hunt, Sarah E -- Edkins, Sarah -- Gray, Emma -- Booth, David R -- Potter, Simon C -- Goris, An -- Band, Gavin -- Oturai, Annette Bang -- Strange, Amy -- Saarela, Janna -- Bellenguez, Celine -- Fontaine, Bertrand -- Gillman, Matthew -- Hemmer, Bernhard -- Gwilliam, Rhian -- Zipp, Frauke -- Jayakumar, Alagurevathi -- Martin, Roland -- Leslie, Stephen -- Hawkins, Stanley -- Giannoulatou, Eleni -- D'alfonso, Sandra -- Blackburn, Hannah -- Martinelli Boneschi, Filippo -- Liddle, Jennifer -- Harbo, Hanne F -- Perez, Marc L -- Spurkland, Anne -- Waller, Matthew J -- Mycko, Marcin P -- Ricketts, Michelle -- Comabella, Manuel -- Hammond, Naomi -- Kockum, Ingrid -- McCann, Owen T -- Ban, Maria -- Whittaker, Pamela -- Kemppinen, Anu -- Weston, Paul -- Hawkins, Clive -- Widaa, Sara -- Zajicek, John -- Dronov, Serge -- Robertson, Neil -- Bumpstead, Suzannah J -- Barcellos, Lisa F -- Ravindrarajah, Rathi -- Abraham, Roby -- Alfredsson, Lars -- Ardlie, Kristin -- Aubin, Cristin -- Baker, Amie -- Baker, Katharine -- Baranzini, Sergio E -- Bergamaschi, Laura -- Bergamaschi, Roberto -- Bernstein, Allan -- Berthele, Achim -- Boggild, Mike -- Bradfield, Jonathan P -- Brassat, David -- Broadley, Simon A -- Buck, Dorothea -- Butzkueven, Helmut -- Capra, Ruggero -- Carroll, William M -- Cavalla, Paola -- Celius, Elisabeth G -- Cepok, Sabine -- Chiavacci, Rosetta -- Clerget-Darpoux, Francoise -- Clysters, Katleen -- Comi, Giancarlo -- Cossburn, Mark -- Cournu-Rebeix, Isabelle -- Cox, Mathew B -- Cozen, Wendy -- Cree, Bruce A C -- Cross, Anne H -- Cusi, Daniele -- Daly, Mark J -- Davis, Emma -- de Bakker, Paul I W -- Debouverie, Marc -- D'hooghe, Marie Beatrice -- Dixon, Katherine -- Dobosi, Rita -- Dubois, Benedicte -- Ellinghaus, David -- Elovaara, Irina -- Esposito, Federica -- Fontenille, Claire -- Foote, Simon -- Franke, Andre -- Galimberti, Daniela -- Ghezzi, Angelo -- Glessner, Joseph -- Gomez, Refujia -- Gout, Olivier -- Graham, Colin -- Grant, Struan F A -- Guerini, Franca Rosa -- Hakonarson, Hakon -- Hall, Per -- Hamsten, Anders -- Hartung, Hans-Peter -- Heard, Rob N -- Heath, Simon -- Hobart, Jeremy -- Hoshi, Muna -- Infante-Duarte, Carmen -- Ingram, Gillian -- Ingram, Wendy -- Islam, Talat -- Jagodic, Maja -- Kabesch, Michael -- Kermode, Allan G -- Kilpatrick, Trevor J -- Kim, Cecilia -- Klopp, Norman -- Koivisto, Keijo -- Larsson, Malin -- Lathrop, Mark -- Lechner-Scott, Jeannette S -- Leone, Maurizio A -- Leppa, Virpi -- Liljedahl, Ulrika -- Bomfim, Izaura Lima -- Lincoln, Robin R -- Link, Jenny -- Liu, Jianjun -- Lorentzen, Aslaug R -- Lupoli, Sara -- Macciardi, Fabio -- Mack, Thomas -- Marriott, Mark -- Martinelli, Vittorio -- Mason, Deborah -- McCauley, Jacob L -- Mentch, Frank -- Mero, Inger-Lise -- Mihalova, Tania -- Montalban, Xavier -- Mottershead, John -- Myhr, Kjell-Morten -- Naldi, Paola -- Ollier, William -- Page, Alison -- Palotie, Aarno -- Pelletier, Jean -- Piccio, Laura -- Pickersgill, Trevor -- Piehl, Fredrik -- Pobywajlo, Susan -- Quach, Hong L -- Ramsay, Patricia P -- Reunanen, Mauri -- Reynolds, Richard -- Rioux, John D -- Rodegher, Mariaemma -- Roesner, Sabine -- Rubio, Justin P -- Ruckert, Ina-Maria -- Salvetti, Marco -- Salvi, Erika -- Santaniello, Adam -- Schaefer, Catherine A -- Schreiber, Stefan -- Schulze, Christian -- Scott, Rodney J -- Sellebjerg, Finn -- Selmaj, Krzysztof W -- Sexton, David -- Shen, Ling -- Simms-Acuna, Brigid -- Skidmore, Sheila -- Sleiman, Patrick M A -- Smestad, Cathrine -- Sorensen, Per Soelberg -- Sondergaard, Helle Bach -- Stankovich, Jim -- Strange, Richard C -- Sulonen, Anna-Maija -- Sundqvist, Emilie -- Syvanen, Ann-Christine -- Taddeo, Francesca -- Taylor, Bruce -- Blackwell, Jenefer M -- Tienari, Pentti -- Bramon, Elvira -- Tourbah, Ayman -- Brown, Matthew A -- Tronczynska, Ewa -- Casas, Juan P -- Tubridy, Niall -- Corvin, Aiden -- Vickery, Jane -- Jankowski, Janusz -- Villoslada, Pablo -- Markus, Hugh S -- Wang, Kai -- Mathew, Christopher G -- Wason, James -- Palmer, Colin N A -- Wichmann, H-Erich -- Plomin, Robert -- Willoughby, Ernest -- Rautanen, Anna -- Winkelmann, Juliane -- Wittig, Michael -- Trembath, Richard C -- Yaouanq, Jacqueline -- Viswanathan, Ananth C -- Zhang, Haitao -- Wood, Nicholas W -- Zuvich, Rebecca -- Deloukas, Panos -- Langford, Cordelia -- Duncanson, Audrey -- Oksenberg, Jorge R -- Pericak-Vance, Margaret A -- Haines, Jonathan L -- Olsson, Tomas -- Hillert, Jan -- Ivinson, Adrian J -- De Jager, Philip L -- Peltonen, Leena -- Stewart, Graeme J -- Hafler, David A -- Hauser, Stephen L -- McVean, Gil -- Donnelly, Peter -- Compston, Alastair -- 068545/Z/02/Wellcome Trust/United Kingdom -- 075491/Z/04/Z/Wellcome Trust/United Kingdom -- 084702/Wellcome Trust/United Kingdom -- 085475/Wellcome Trust/United Kingdom -- 085475/B/08/Z/Wellcome Trust/United Kingdom -- 085475/Z/08/Z/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 898/Multiple Sclerosis Society/United Kingdom -- AI076544/AI/NIAID NIH HHS/ -- CA104021/CA/NCI NIH HHS/ -- G0100594/Medical Research Council/United Kingdom -- G0400017/Medical Research Council/United Kingdom -- G0700061/Medical Research Council/United Kingdom -- G0901310/Medical Research Council/United Kingdom -- G0901461/Medical Research Council/United Kingdom -- G19/2/Medical Research Council/United Kingdom -- K23N/S048869/PHS HHS/ -- NS032830/NS/NINDS NIH HHS/ -- NS049477/NS/NINDS NIH HHS/ -- NS049510/NS/NINDS NIH HHS/ -- NS067305/NS/NINDS NIH HHS/ -- NS19142/NS/NINDS NIH HHS/ -- NS26799/NS/NINDS NIH HHS/ -- NS43559/NS/NINDS NIH HHS/ -- PDA/02/06/016/Department of Health/United Kingdom -- R01 NS026799/NS/NINDS NIH HHS/ -- R01 NS049477/NS/NINDS NIH HHS/ -- R01 NS049477-06A1/NS/NINDS NIH HHS/ -- RR020092/RR/NCRR NIH HHS/ -- RR024992/RR/NCRR NIH HHS/ -- UL1 TR000448/TR/NCATS NIH HHS/ -- Medical Research Council/United Kingdom -- England -- Nature. 2011 Aug 10;476(7359):214-9. doi: 10.1038/nature10251.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21833088" target="_blank"〉PubMed〈/a〉