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1. A Method to Exploit the Structure of Genetic Ancestry Space to Enhance Case-Control Studies

Author: Corneliu A. Bodea, Benjamin M. Neale, Stephan Ripke, Mark J. Daly, Bernie Devlin, Kathryn Roeder, Murray Barclay, Laurent Peyrin-Biroulet, Mathias Chamaillard, Jean-Frederick Colombel, Mario Cottone, Anthony Croft, Renata D’Incà, Jonas Halfvarson, Katherine Hanigan, Paul Henderson, Jean-Pierre Hugot, Amir Karban, Nicholas A. Kennedy, Mohammed Azam Khan, Marc Lémann, Arie Levine, Dunecan Massey, Monica Milla, Grant W. Montgomery, Sok Meng Evelyn Ng, Ioannis Oikonomou, Harald Peeters, Deborah D. Proctor, Jean-Francois Rahier, Rebecca Roberts, Paul Rutgeerts, Frank Seibold, Laura Stronati, Kirstin M. Taylor, Leif Törkvist, Kullak Ublick, Johan Van Limbergen, Andre Van Gossum, Morten H. Vatn, Hu Zhang, Wei Zhang, Jane M. Andrews, Peter A. Bampton, Timothy H. Florin, Richard Gearry, Krupa Krishnaprasad, Ian C. Lawrance, Gillian Mahy, Graham Radford-Smith, Rebecca L. Roberts, Lisa A. Simms, Leila Amininijad, Isabelle Cleynen, Olivier Dewit, Denis Franchimont, Michel Georges, Debby Laukens, Emilie Theatre, André Van Gossum, Severine Vermeire, Guy Aumais, Leonard Baidoo, Arthur M. Barrie, Karen Beck, Edmond-Jean Bernard, David G. Binion, Alain Bitton, Steve R. Brant, Judy H. Cho, Albert Cohen, Kenneth Croitoru, Lisa W. Datta, Colette Deslandres, Richard H. Duerr, Debra Dutridge, John Ferguson, Joann Fultz, Philippe Goyette, Gordon R. Greenberg, Talin Haritunians, Gilles Jobin, Seymour Katz, Raymond G. Lahaie, Dermot P. McGovern, Linda Nelson, Sok Meng Ng, Kaida Ning, Pierre Paré, Miguel D. Regueiro, John D. Rioux, Elizabeth Ruggiero, L. Philip Schumm, Marc Schwartz, Regan Scott, Yashoda Sharma, Mark S. Silverberg, Denise Spears, A. Hillary Steinhart, Joanne M. Stempak, Jason M. Swoger, Constantina Tsagarelis, Clarence Zhang, Hongyu Zhao, Jan Aerts, Tariq Ahmad, Hazel Arbury, Anthony Attwood, Adam Auton, Stephen G. Ball, Anthony J. Balmforth, Chris Barnes, Jeffrey C. Barrett, Inês Barroso, Anne Barton, Amanda J. Bennett, Sanjeev Bhaskar, Katarzyna Blaszczyk, John Bowes, Oliver J. Brand, Peter S. Braund, Francesca Bredin, Gerome Breen, Morris J. Brown, Ian N. Bruce, Jaswinder Bull, Oliver S. Burren, John Burton, Jake Byrnes, Sian Caesar, Niall Cardin, Chris M. Clee, Alison J. Coffey, John M.C. Connell, Donald F. Conrad, Jason D. Cooper, Anna F. Dominiczak, Kate Downes, Hazel E. Drummond, Darshna Dudakia, Andrew Dunham, Bernadette Ebbs, Diana Eccles, Sarah Edkins, Cathryn Edwards, Anna Elliot, Paul Emery, David M. Evans, Gareth Evans, Steve Eyre, Anne Farmer, Nicol Ferrier, Edward Flynn, Alistair Forbes, Liz Forty, Jayne A. Franklyn, Timothy M. Frayling, Rachel M. Freathy, Eleni Giannoulatou, Polly Gibbs, Paul Gilbert, Katherine Gordon-Smith, Emma Gray, Elaine Green, Chris J. Groves, Detelina Grozeva, Rhian Gwilliam, Anita Hall, Naomi Hammond, Matt Hardy, Pile Harrison, Neelam Hassanali, Husam Hebaishi, Sarah Hines, Anne Hinks, Graham A. Hitman, Lynne Hocking, Chris Holmes, Eleanor Howard, Philip Howard, Joanna M.M. Howson, Debbie Hughes, Sarah Hunt, John D. Isaacs, Mahim Jain, Derek P. Jewell, Toby Johnson, Jennifer D. Jolley, Ian R. Jones, Lisa A. Jones, George Kirov, Cordelia F. Langford, Hana Lango-Allen, G. Mark Lathrop, James Lee, Kate L. Lee, Charlie Lees, Kevin Lewis, Cecilia M. Lindgren, Meeta Maisuria-Armer, Julian Maller, John Mansfield, Jonathan L. Marchini, Paul Martin, Dunecan C.O. Massey, Wendy L. McArdle, Peter McGuffin, Kirsten E. McLay, Gil McVean, Alex Mentzer, Michael L. Mimmack, Ann E. Morgan, Andrew P. Morris, Craig Mowat, Patricia B. Munroe, Simon Myers, William Newman, Elaine R. Nimmo, Michael C. O’Donovan, Abiodun Onipinla, Nigel R. Ovington, Michael J. Owen, Kimmo Palin, Aarno Palotie, Kirstie Parnell, Richard Pearson, David Pernet, John R.B. Perry, Anne Phillips, Vincent Plagnol, Natalie J. Prescott, Inga Prokopenko, Michael A. Quail, Suzanne Rafelt, Nigel W. Rayner, David M. Reid, Anthony Renwick, Susan M. Ring, Neil Robertson, Samuel Robson, Ellie Russell, David St Clair, Jennifer G. Sambrook, Jeremy D. Sanderson, Stephen J. Sawcer, Helen Schuilenburg, Carol E. Scott, Richard Scott, Sheila Seal, Sue Shaw-Hawkins, Beverley M. Shields, Matthew J. Simmonds, Debbie J. Smyth, Elilan Somaskantharajah, Katarina Spanova, Sophia Steer, Jonathan Stephens, Helen E. Stevens, Kathy Stirrups, Millicent A. Stone, David P. Strachan, Zhan Su, Deborah P.M. Symmons, John R. Thompson, Wendy Thomson, Martin D. Tobin, Mary E. Travers, Clare Turnbull, Damjan Vukcevic, Louise V. Wain, Mark Walker, Neil M. Walker, Chris Wallace, Margaret Warren-Perry, Nicholas A. Watkins, John Webster, Michael N. Weedon, Anthony G. Wilson, Matthew Woodburn, B. Paul Wordsworth, Chris Yau, Allan H. Young, Eleftheria Zeggini, Matthew A. Brown, Paul R. Burton, Mark J. Caulfield, Alastair Compston, Martin Farrall, Stephen C.L. Gough, Alistair S. Hall, Andrew T. Hattersley, Adrian V.S. Hill, Christopher G. Mathew, Marcus Pembrey, Jack Satsangi, Michael R. Stratton, Jane Worthington, Matthew E. Hurles, Audrey Duncanson, Willem H. Ouwehand, Miles Parkes, Nazneen Rahman, John A. Todd, Nilesh J. Samani, Dominic P. Kwiatkowski, Mark I. McCarthy, Nick Craddock, Panos Deloukas, Peter Donnelly, Jenefer M. Blackwell, Elvira Bramon, Juan P. Casas, Aiden Corvin, Janusz Jankowski, Hugh S. Markus, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Richard C. Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Chris C.A. Spencer, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Matti Pirinen, Amy Strange, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Matthew Gillman, Alagurevathi Jayakumar, Owen T. McCann, Jennifer Liddle, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (MGD) Service de gastro-entérologie, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, and Genomics of Neurological and Neuropsychiatric Disorders
Subjects: 0301 basic medicine, Heredity, Genetics, Genetics (clinical), Computer science, Genetic Linkage, Genome-wide association study, VARIANTS, 030105 genetics & heredity, computer.software_genre, Bayes' theorem, Gene Frequency, HISTORY, IMPUTATION, False positive paradox, Genetics(clinical), Disease, 0303 health sciences, education.field_of_study, 030305 genetics & heredity, Inheritance (genetic algorithm), Genotype, DATABASE, Genetic genealogy, POWER, Population, Genomics, POPULATION STRATIFICATION, Biology, INHERITANCE, Population stratification, Machine learning, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, Allele frequency, FAMILY-BASED ASSOCIATION, 030304 developmental biology, Genetic association, business.industry, Bayes Theorem, DISEASE ASSOCIATION, Human genetics, Hierarchical clustering, Genetics, Population, 030104 developmental biology, Case-Control Studies, 3111 Biomedicine, Artificial intelligence, business, computer, Software, Imputation (genetics)
Abstract: A. Palotie on työryhmän Int IBD Genetics Consortium jäsen. One goal of human genetics is to understand the genetic basis of disease, a challenge for diseases of complex inheritance because risk alleles are few relative to the vast set of benign variants. Risk variants are often sought by association studies in which allele frequencies in case subjects are contrasted with those from population-based samples used as control subjects. In an ideal world we would know population-level allele frequencies, releasing researchers to focus on case subjects. We argue this ideal is possible, at least theoretically, and we outline a path to achieving it in reality. If such a resource were to exist, it would yield ample savings and would facilitate the effective use of data repositories by removing administrative and technical barriers. We call this concept the Universal Control Repository Network (UNICORN), a means to perform association analyses without necessitating direct access to individual-level control data. Our approach to UNICORN uses existing genetic resources and various statistical tools to analyze these data, including hierarchical clustering with spectral analysis of ancestry; and empirical Bayesian analysis along with Gaussian spatial processes to estimate ancestry-specific allele frequencies. We demonstrate our approach using tens of thousands of control subjects from studies of Crohn disease, showing how it controls false positives, provides power similar to that achieved when all control data are directly accessible, and enhances power when control data are limiting or even imperfectly matched ancestrally. These results highlight how UNICORN can enable reliable, powerful, and convenient genetic association analyses without access to the individual-level data.
Published: 2016
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2. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Author: Nicholas G. Martin, René Höhn, Paul Mitchell, Gavin Band, Pamela Whittaker, Michelle Ricketts, Pirro G. Hysi, Jenefer M. Blackwell, Grant W. Montgomery, Elena Rochtchina, Manfred E. Beutel, Richard A. Mills, Anna Rautanen, Alagurevathi Jayakumar, Colin Freeman, Stephen Sawcer, Stuart MacGregor, Irene Schmidtmann, Cornelia M. van Duijn, Nicholas W. Wood, Sayoko E. Moroi, Jonathan L. Haines, Aniket Mishra, Ananth C. Viswanathan, Jie Jin Wang, Donald L. Budenz, Seyhan Yazar, Janey L. Wiggs, Garrett Hellenthal, Kathryn P. Burdon, Jerome I. Rotter, Jamie E Craig, Puya Gharahkhani, Juan P. Casas, R. Rand Allingham, Jost B. Jonas, Ozren Polasek, Julia E. Richards, Sarah Edkins, Rodney J. Scott, Abhishek Nag, Tanja Zeller, Rhian Gwilliam, Chris C. A. Spencer, David S. Friedman, Adriana I Iglesias, Radhi Ravindrarajah, Kent D. Taylor, Caroline Hayward, Eleni Giannoulatou, David A. Mackey, Michael A. Hauser, Paul J. Foster, Emma Gray, Audrey Duncanson, Yih Chung Tham, Murray H. Brilliant, Ching-Yu Cheng, William K. Scott, Robert N. Weinreb, Hugh S. Markus, Xueling Sim, David S. Siscovick, Matti Pirinen, John H. Fingert, Yelena Bykhovskaya, Louis R. Pasquale, Peter Donnelly, Donald J. Zack, Kuldev Singh, Cordelia Langford, Zhan Su, Céline Bellenguez, Joel S. Schuman, Peter Kraft, Christopher G. Mathew, Hannah Blackburn, Sara Widaa, Yuan Shi, Gabriel Cuellar-Partida, André G. Uitterlinden, Naomi Hammond, Panos Deloukas, Richard K. Lee, Robert Plomin, Jessica N. Cooke Bailey, Jae H. Kang, John Attia, Yutao Liu, Simon C. Potter, Jennifer Liddle, Matthew Gillman, Alex W. Hewitt, Margaret A. Pericak-Vance, James F. Wilson, Tien Yin Wong, Elvira Bramon, Janusz Jankowski, Henriët Springelkamp, Sarah E. Hunt, Anthony P Khawaja, Veronique Vitart, Xiaohui Li, Pieter W.M. Bonnemaijer, Damjan Vukcevic, Paul R. Lichter, Aiden Corvin, Sionne E. M. Lucas, Matthew Waller, Caroline C W Klaver, Douglas E. Gaasterland, Terry Gaasterland, Norbert Pfeiffer, Douglas Vollrath, Anthony Realini, Eranga N. Vithana, Gadi Wollstein, Thibaud Boutin, Owen T. McCann, Paul A. Weston, Lisa S. Kearns, Inês Barroso, Richard G. Pearson, Christopher J Hammond, Colin N. A. Palmer, Michael Inouye, Chiea Chuen Khor, Stephanie Loomis, Sandra E Staffieri, Yaron S. Rabinowitz, Richard C. Trembath, Tin Aung, William G. Christen, Paul N. Baird, Jing Xie, Elisabeth M. van Leeuwen, Serge Dronov, Arthur J. Sit, Colin E. Willoughby, Kang Zhang, Matthew A. Brown, Suzannah Bumpstead, Amy Strange, Elizabeth G. Holliday, Clinical Genetics, Epidemiology, Ophthalmology, Internal Medicine, Experimental Immunology, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Iglesias, Adriana I [0000-0001-5532-764X], Gharahkhani, Puya [0000-0002-4203-5952], Bailey, Jessica N Cooke [0000-0002-4001-8702], Li, Xiaohui [0000-0002-5037-3572], Khawaja, Anthony P [0000-0001-6802-8585], Haines, Jonathan L [0000-0002-4351-4728], Hayward, Caroline [0000-0002-9405-9550], Bonnemaijer, Pieter [0000-0001-5154-6765], Staffieri, Sandra E [0000-0003-3131-9359], Jonas, Jost B [0000-0003-2972-5227], Kang, Jae H [0000-0003-4812-0557], Wilson, James F [0000-0001-5751-9178], Foster, Paul J [0000-0002-4755-177X], Hysi, Pirro G [0000-0001-5752-2510], Hewitt, Alex W [0000-0002-5123-5999], Khor, Chiea Chuen [0000-0002-1128-4729], Pasquale, Louis R [0000-0002-5835-3496], Montgomery, Grant W [0000-0002-4140-8139], Klaver, Caroline CW [0000-0002-2355-5258], Hammond, Christopher J [0000-0002-3227-2620], Wiggs, Janey L [0000-0003-1890-3278], Burdon, Kathryn P [0000-0001-8217-1249], MacGregor, Stuart [0000-0001-6731-8142], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Lumican, Candidate gene, genetic structures, Fibrillin-1, Gene Expression, General Physics and Astronomy, Glaucoma, Genome-wide association study, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Corneal Diseases, Marfan Syndrome, Cornea, ADAMTS Proteins, 0302 clinical medicine, Myopia, lcsh:Science, Corneal Dystrophies, Hereditary, Genetics, Multidisciplinary, Eye Diseases, Hereditary, Mendelian Randomization Analysis, 3. Good health, medicine.anatomical_structure, Proteoglycans, Decorin, Glaucoma, Open-Angle, Keratoconus, Science, Quantitative Trait Loci, 610 Medicine & health, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, White People, General Biochemistry, Genetics and Molecular Biology, Transforming Growth Factor beta2, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Quantitative Trait, Heritable, Asian People, medicine, Humans, CHROMATIN STATES, GENE-EXPRESSION, RISK-FACTOR, MUTATIONS, LUMICAN, MOUSE, KERATOCONUS, DECORIN, POLYMORPHISMS, HERITABILITY, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Loeys-Dietz Syndrome, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Genome, Human, General Chemistry, medicine.disease, eye diseases, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030221 ophthalmology & optometry, lcsh:Q, Ehlers-Danlos Syndrome, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, sense organs, Genome-Wide Association Study
Abstract: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = −0.62, P = 5.30 × 10−5) but not between CCT and primary open-angle glaucoma (r = −0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
Published: 2018
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3. Discovery and development of exome-based, co-dominant single nucleotide polymorphism markers in hexaploid wheat (Triticum aestivumL.)

Author: Peter Jack, Paul A. Wilkinson, Rhian Gwilliam, Simon Berry, Keith J. Edwards, Peter Werner, Phil Robinson, James P. E. Melichar, Mark O. Winfield, Amanda J. Burridge, Jane McDougall, Jane A. Coghill, Cristobal Uauy, Simon Griffiths, Alexandra M. Allen, and Gary L A Barker
Subjects: Genetics, Chromosome Mapping, food and beverages, Locus (genetics), Single-nucleotide polymorphism, Plant Science, Biology, Polymorphism, Single Nucleotide, DNA sequencing, SNP genotyping, Polyploidy, Genotype, SNP, Exome, Agronomy and Crop Science, Genotyping, Triticum, Biotechnology
Abstract: Summary Globally, wheat is the most widely grown crop and one of the three most important crops for human and livestock feed. However, the complex nature of the wheat genome has, until recently, resulted in a lack of single nucleotide polymorphism (SNP)-based molecular markers of practical use to wheat breeders. Recently, large numbers of SNP-based wheat markers have been made available via the use of next-generation sequencing combined with a variety of genotyping platforms. However, many of these markers and platforms have difficulty distinguishing between heterozygote and homozygote individuals and are therefore of limited use to wheat breeders carrying out commercial-scale breeding programmes. To identify exome-based co-dominant SNP-based assays, which are capable of distinguishing between heterozygotes and homozygotes, we have used targeted re-sequencing of the wheat exome to generate large amounts of genomic sequences from eight varieties. Using a bioinformatics approach, these sequences have been used to identify 95 266 putative single nucleotide polymorphisms, of which 10 251 were classified as being putatively co-dominant. Validation of a subset of these putative co-dominant markers confirmed that 96% were true polymorphisms and 65% were co-dominant SNP assays. The new co-dominant markers described here are capable of genotypic classification of a segregating locus in polyploid wheat and can be used on a variety of genotyping platforms; as such, they represent a powerful tool for wheat breeders. These markers and related information have been made publically available on an interactive web-based database to facilitate their use on genotyping programmes worldwide.
Published: 2012
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4. Transferrin and HFE genes interact in Alzheimer's disease risk: the Epistasis Project

Author: Maaike Schuur, Reinhard Heun, Rhian Gwilliam, Monique M.B. Breteler, Alejandro Arias-Vásquez, D J Lehmann, Abderrahim Oulhaj, Naomi Hammond, Michael G Lehmann, Panos Deloukas, Olivia Belbin, Gordon K. Wilcock, Donald Warden, Ignacio Mateo, Onofre Combarros, M. Arfan Ikram, Patrick G. Kehoe, Christopher Morris, Mario Cortina-Borja, Eliecer Coto, Rachel Barker, Cornelia M. van Duijn, Yurii S. Aulchenko, Kevin Morgan, Kathryn J. H. Robson, Victoria Alvarez, A. David Smith, Kristelle Brown, Heike Kölsch, Neurology, Epidemiology, and Radiology & Nuclear Medicine
Subjects: Apolipoprotein E, Male, Risk, Aging, Iron Overload, DCN MP - Plasticity and memory, Apolipoprotein E4, Disease, DCN PAC - Perception action and control, Biology, Iron Chelating Agents, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, medicine, Humans, Allele, Hemochromatosis Protein, Hemochromatosis, 030304 developmental biology, Aged, Genetics, chemistry.chemical_classification, Aged, 80 and over, 0303 health sciences, Transferrin saturation, General Neuroscience, Histocompatibility Antigens Class I, Transferrin, Membrane Proteins, Epistasis, Genetic, Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], medicine.disease, 3. Good health, Oxidative Stress, chemistry, Immunology, Epistasis, Female, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Item does not contain fulltext Iron overload may contribute to the risk of Alzheimer's disease (AD). In the Epistasis Project, with 1757 cases of AD and 6295 controls, we studied 4 variants in 2 genes of iron metabolism: hemochromatosis (HFE) C282Y and H63D, and transferrin (TF) C2 and -2G/A. We replicated the reported interaction between HFE 282Y and TF C2 in the risk of AD: synergy factor, 1.75 (95% confidence interval, 1.1-2.8, p = 0.02) in Northern Europeans. The synergy factor was 3.1 (1.4-6.9; 0.007) in subjects with the APOEepsilon4 allele. We found another interaction, between HFE 63HH and TF -2AA, markedly modified by age. Both interactions were found mainly or only in Northern Europeans. The interaction between HFE 282Y and TF C2 has now been replicated twice, in altogether 2313 cases of AD and 7065 controls, and has also been associated with increased iron load. We therefore suggest that iron overload may be a causative factor in the development of AD. Treatment for iron overload might thus be protective in some cases. 01 januari 2012
Published: 2012
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5. Transcript-specific, single-nucleotide polymorphism discovery and linkage analysis in hexaploid bread wheat (Triticum aestivum L.)

Author: Anthony Hall, Neil McKenzie, Darren Waite, Susan Kirby, Rachel Brenchley, Alexandra M. Allen, Simon Berry, Rosalinda D’Amore, Rhian Gwilliam, Phil Robinson, Gary L A Barker, Jane A. Coghill, Keith J. Edwards, Michael W. Bevan, and Neil Hall
Subjects: Germplasm, Genetics, education.field_of_study, Genetic diversity, Expressed sequence tag, business.industry, Population, food and beverages, Single-nucleotide polymorphism, Plant Science, Biology, DNA sequencing, Biotechnology, Doubled haploidy, education, business, Agronomy and Crop Science, Genotyping
Abstract: Summary Food security is a global concern and substantial yield increases in cereal crops are required to feed the growing world population. Wheat is one of the three most important crops for human and livestock feed. However, the complexity of the genome coupled with a decline in genetic diversity within modern elite cultivars has hindered the application of marker-assisted selection (MAS) in breeding programmes. A crucial step in the successful application of MAS in breeding programmes is the development of cheap and easy to use molecular markers, such as single-nucleotide polymorphisms. To mine selected elite wheat germplasm for intervarietal single-nucleotide polymorphisms, we have used expressed sequence tags derived from public sequencing programmes and next-generation sequencing of normalized wheat complementary DNA libraries, in combination with a novel sequence alignment and assembly approach. Here, we describe the development and validation of a panel of 1114 single-nucleotide polymorphisms in hexaploid bread wheat using competitive allele-specific polymerase chain reaction genotyping technology. We report the genotyping results of these markers on 23 wheat varieties, selected to represent a broad cross-section of wheat germplasm including a number of elite UK varieties. Finally, we show that, using relatively simple technology, it is possible to rapidly generate a linkage map containing several hundred single-nucleotide polymorphism markers in the doubled haploid mapping population of Avalon · Cadenza.
Published: 2011
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6. Common Variants at Abca7, Ms4A6A/Ms4A4E, Epha1, Cd33 and Cd2Ap Are Associated with Alzheimer'S Disease

Author: Neill R. Graff-Radford, Caroline S. Widdowson, John Hardy, Simon Lovestone, Stefan Schreiber, Ana Frank-García, Amy Gerrish, Kevin Mayo, Alexandra Stretton, Michael John Owen, Minerva M. Carrasquillo, Seth Love, Jade Chapman, Vincent Chouraki, Monique M.B. Breteler, Francesco Panza, Emma R L C Vardy, Ronald C. Petersen, Harald Hampel, S. Nicolhaus, Lenore J. Launer, Michelle K. Lupton, Eckart Rüther, A. David Smith, David C. Rubinsztein, Rebecca Sims, Gill Livingston, Diana Zelenika, Simon Mead, Martin N. Rossor, Hilkka Soininen, Christine Van Broeckhoven, Kristel Sleegers, Thorlakur Jonsson, M. Arfan Ikram, Helen Beaumont, Michael Conlon O'Donovan, Federico Licastro, Sudha Seshadri, Alexander Richards, Nick C. Fox, Markus M. Nöthen, Claudine Berr, T. Feulner, Benedetta Nacmias, Carlos Cruchaga, Peter Passmore, Oscar L. Lopez, Julie Williams, Matthias Riemenschneider, Florence Pasquier, John Gallacher, Didier Hannequin, Sigrid Botne Sando, Jens Wiltfang, Charlene Thomas, Gabriele Siciliano, Maria Barcikowska, Mikko Hiltunen, Carol Brayne, Dobril Ivanov, Anita L. DeStefano, Bernadette McGuinness, Norman Klopp, Gordon K. Wilcock, Aoibhinn Lynch, Wolfgang Maier, Peter Holmans, H.-Erich Wichmann, Giorgio Annoni, Beatrice Arosio, Alison Goate, Sigurbjorn Bjornsson, Karl-Heinz Jöckel, Dan Rujescu, Hugh Gurling, Nigel M. Hooper, Clive Holmes, Andrew McQuillin, Patricia Friedrich, John Powell, Rhian Gwilliam, R. Heun, Jacques Epelbaum, Isabella Heuser, Magda Tsolaki, Dennis W. Dickson, Alberto Pilotto, Stephen Todd, Dominique Campion, Michael Krawczak, Jan O. Aasly, Olivier Hanon, Patrick G. Kehoe, Johannes Kornhuber, Marc Delepine, Peter Paul De Deyn, Britta Schürmann, Brian A. Lawlor, Christophe Tzourio, Richard Abraham, Petra Nowotny, Jean-François Dartigues, Heike Kölsch, Michelangelo Mancuso, Marian L. Hamshere, Zbigniew K. Wszolek, Paola Piccardi, Paolo Bosco, Jean-Charles Lambert, Denise Harold, Frank Jessen, Palmi V. Jonsson, Paola Bossù, Paul Hollingworth, Jon Snaedal, Michael Gill, Onofre Combarros, David M. A. Mann, John C. Morris, Annette L. Fitzpatrick, Christopher Shaw, Alexis Brice, Philippe Amouyel, Elio Scarpini, Lesley Jones, Sebastiaan Engelborghs, Daniela Galimberti, Vincenzo Solfrizzi, V. Shane Pankratz, John Collinge, María J. Bullido, Kristelle Brown, Nicholas Bass, Andrew B. Singleton, Jaspreet Singh Pahwa, Kari Stefansson, Lutz Frölich, Steven G. Younkin, Ignacio Mateo, Annick Alpérovitch, Benjamin Genier-Boley, Ina Giegling, Caterina Riehle, Kimberley Dowzell, Mark Lathrop, Hreinn Stefansson, Sandro Sorbi, Rita Guerreiro, Thomas W. Mühleisen, Karolien Bettens, Michael Hüll, Martin Dichgans, Petroula Proitsi, Panagiotis Deloukas, Valentina Moskvina, Cornelia M. van Duijn, Donald Warden, Victoria Alvarez, Eliecer Coto, Kevin Morgan, Susanne Moebus, Ammar Al-Chalabi, Elisa Porcellini, Stefan Wagenpfeil, Hendrik van den Bussche, John S. K. Kauwe, Stacy Steinberg, David Craig, Nicola Jones, Manuel Mayhaus, Davide Seripa, Neurology, NCA - Neurodegeneration, HOLLINGWORTH P, HAROLD D, SIMS R, GERRISH A, LAMBERT JC, CARRASQUILLO MM, ABRAHAM R, HAMSHERE ML, PAHWA JS, MOSKVINA V, DOWZELL K, JONES N, STRETTON A, THOMAS C, RICHARDS A, IVANOV D, WIDDOWSON C, CHAPMAN J, LOVESTONE S, POWELL J, PROITSI P, LUPTON MK, BRAYNE C, RUBINSZTEIN DC, GILL M, LAWLOR B, LYNCH A, BROWN KS, PASSMORE PA, CRAIG D, MCGUINNESS B, TODD S, HOLMES C, MANN D, SMITH AD, BEAUMONT H, WARDEN D, WILCOCK G, LOVE S, KEHOE PG, HOOPER NM, VARDY ER, HARDY J, MEAD S, FOX NC, ROSSOR M, COLLINGE J, MAIER W, JESSEN F, RÜTHER E, SCHÜRMANN B, HEUN R, KÖLSCH H, VAN DEN BUSSCHE H, HEUSER I, KORNHUBER J, WILTFANG J, DICHGANS M, FRÖLICH L, HAMPEL H, GALLACHER J, HÜLL M, RUJESCU D, GIEGLING I, GOATE AM, KAUWE JS, CRUCHAGA C, NOWOTNY P, MORRIS JC, MAYO K, SLEEGERS K, BETTENS K, ENGELBORGHS S, DE DEYN PP, VAN BROECKHOVEN C, LIVINGSTON G, BASS NJ, GURLING H, MCQUILLIN A, GWILLIAM R, DELOUKAS P, AL-CHALABI A, SHAW CE, TSOLAKI M, SINGLETON AB, GUERREIRO R, MÜHLEISEN TW, NÖTHEN MM, MOEBUS S, JÖCKEL KH, KLOPP N, WICHMANN HE, PANKRATZ VS, SANDO SB, AASLY JO, BARCIKOWSKA M, WSZOLEK ZK, DICKSON DW, GRAFF-RADFORD NR, PETERSEN RC, ALZHEIMER'S DISEASE NEUROIMAGING INITIATIVE, VAN DUIJN CM, BRETELER MM, IKRAM MA, DESTEFANO AL, FITZPATRICK AL, LOPEZ O, LAUNER LJ, SESHADRI S, CHARGE CONSORTIUM, BERR C, CAMPION D, EPELBAUM J, DARTIGUES JF, TZOURIO C, ALPÉROVITCH A, LATHROP M, EADI1 CONSORTIUM, FEULNER TM, FRIEDRICH P, RIEHLE C, KRAWCZAK M, SCHREIBER S, MAYHAUS M, NICOLHAUS S, WAGENPFEIL S, STEINBERG S, STEFANSSON H, STEFANSSON K, SNAEDAL J, BJÖRNSSON S, JONSSON PV, CHOURAKI V, GENIER-BOLEY B, HILTUNEN M, SOININEN H, COMBARROS O, ZELENIKA D, DELEPINE M, BULLIDO MJ, PASQUIER F, MATEO I, FRANK-GARCIA A, PORCELLINI E, HANON O, COTO E, ALVAREZ V, BOSCO P, SICILIANO G, MANCUSO M, PANZA F, SOLFRIZZI V, NACMIAS B, SORBI S, BOSSÙ P, PICCARDI P, AROSIO B, ANNONI G, SERIPA D, PILOTTO A, SCARPINI E, GALIMBERTI D, BRICE A, HANNEQUIN D, LICASTRO F, JONES L, HOLMANS PA, JONSSON T, RIEMENSCHNEIDER M, MORGAN K, YOUNKIN SG, OWEN MJ, O'DONOVAN M, AMOUYEL P, WILLIAMS J, Epidemiology, Radiology & Nuclear Medicine, Clinical sciences, Pathologic Biochemistry and Physiology, Hollingworth, P, Harold, D, Sims, R, Gerrish, A, Lambert, J, Carrasquillo, M, Abraham, R, Hamshere, M, Pahwa, J, Moskvina, V, Dowzell, K, Jones, N, Stretton, A, Thomas, C, Richards, A, Ivanov, D, Widdowson, C, Chapman, J, Lovestone, S, Powell, J, Proitsi, P, Lupton, M, Brayne, C, Rubinsztein, D, Gill, M, Lawlor, B, Lynch, A, Brown, K, Passmore, P, Craig, D, Mcguinness, B, Todd, S, Holmes, C, Mann, D, Smith, A, Beaumont, H, Warden, D, Wilcock, G, Love, S, Kehoe, P, Hooper, N, Vardy, E, Hardy, J, Mead, S, Fox, N, Rossor, M, Collinge, J, Maier, W, Jessen, F, Rüther, E, Schürmann, B, Heun, R, Kölsch, H, van den Bussche, H, Heuser, I, Kornhuber, J, Wiltfang, J, Dichgans, M, Frölich, L, Hampel, H, Gallacher, J, Hüll, M, Rujescu, D, Giegling, I, Goate, A, Kauwe, J, Cruchaga, C, Nowotny, P, Morris, J, Mayo, K, Sleegers, K, Bettens, K, Engelborghs, S, De Deyn, P, Van Broeckhoven, C, Livingston, G, Bass, N, Gurling, H, Mcquillin, A, Gwilliam, R, Deloukas, P, Al Chalabi, A, Shaw, C, Tsolaki, M, Singleton, A, Guerreiro, R, Mühleisen, T, Nöthen, M, Moebus, S, Jöckel, K, Klopp, N, Wichmann, H, Pankratz, V, Sando, S, Aasly, J, Barcikowska, M, Wszolek, Z, Dickson, D, Graff Radford, N, Petersen, R, van Duijn, C, Breteler, M, Ikram, M, Destefano, A, Fitzpatrick, A, Lopez, O, Launer, L, Seshadri, S, Berr, C, Campion, D, Epelbaum, J, Dartigues, J, Tzourio, C, Alpérovitch, A, Lathrop, M, Feulner, T, Friedrich, P, Riehle, C, Krawczak, M, Schreiber, S, Mayhaus, M, Nicolhaus, S, Wagenpfeil, S, Steinberg, S, Stefansson, H, Stefansson, K, Snædal, J, Björnsson, S, Jonsson, P, Chouraki, V, Genier Boley, B, Hiltunen, M, Soininen, H, Combarros, O, Zelenika, D, Delepine, M, Bullido, M, Pasquier, F, Mateo, I, Frank Garcia, A, Porcellini, E, Hanon, O, Coto, E, Alvarez, V, Bosco, P, Siciliano, G, Mancuso, M, Panza, F, Solfrizzi, V, Nacmias, B, Sorbi, S, Bossù, P, Piccardi, P, Arosio, B, Annoni, G, Seripa, D, Pilotto, A, Scarpini, E, Galimberti, D, Brice, A, Hannequin, D, Licastro, F, Jones, L, Holmans, P, Jonsson, T, Riemenschneider, M, Morgan, K, Younkin, S, Owen, M, O'Donovan, M, Amouyel, P, and Williams, J
Subjects: Male, ABCA7 protein, human, ATP-Binding Cassette Transporters/genetics, Sialic Acid Binding Ig-like Lectin 3, CD33, SORL1, Medizin, genetics [Alzheimer Disease], Adaptor Proteins, Signal Transducing/genetics, Disease, PICALM, ABCA7, Disease susceptibility, 0302 clinical medicine, genetics [Adaptor Proteins, Signal Transducing], Databases, Genetic, GWAS, GENE-EXPRESSION, Medicine(all), Aged, 80 and over, Genetics, 0303 health sciences, Alzheimer's disease, genetic predisposition, Receptor, EphA1, ALZHEIMER’S DISEASE, Antigens, CD/genetics, genetics [Receptor, EphA1], genetics [Membrane Proteins], Multigene Family, Female, genetics [Antigens, Differentiation, Myelomonocytic], APOE, Antigens, Differentiation, Myelomonocytic, Single-nucleotide polymorphism, Case-control studies, Cytoskeletal Proteins/genetics, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, CD33 protein, human, Alzheimer Disease, Antigens, CD, ddc:570, Humans, Genetic Predisposition to Disease, Membrane Proteins/genetics, CLUSTERIN, Aged, genetics [Cytoskeletal Proteins], Adaptor Proteins, Signal Transducing, 030304 developmental biology, Alzheimer Disease/genetics, Antigens, Differentiation, Myelomonocytic/genetics, Genetic Variation, Membrane Proteins, CD2-associated protein, genetics [Antigens, CD], Cytoskeletal Proteins, MS4A4E protein, human, Case-Control Studies, Susceptibility locus, biology.protein, ATP-Binding Cassette Transporters, Human medicine, genetics [ATP-Binding Cassette Transporters], aged, 80 and over, Receptor, EphA1/genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ĝ‰Currency sign 1 × 10 -5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10 -17; including ADGC data, meta P = 5.0 × 10 -21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10 -14; including ADGC data, meta P = 1.2 × 10 -16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10 -4; including ADGC data, meta P = 8.6 × 10 -9), CD33 (GERAD+, P = 2.2 × 10 -4; including ADGC data, meta P = 1.6 × 10 -9) and EPHA1 (GERAD+, P = 3.4 × 10 -4; including ADGC data, meta P = 6.0 × 10 -10). © 2011 Nature America, Inc. All rights reserved.
Published: 2011
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7. Genetic Determinants of Major Blood Lipids in Pakistanis Compared With Europeans

Author: Shahid Abbas, Nicole Soranzo, Nabi Shah, Muhammed Murtaza, Nadeem Hayat Mallick, Jawaid Hassan Niazi, Muhammad Salman Daood, Sarah L. Bray, Kishore Kumar, Stephen Kaptoge, Tanja B. Grammer, Ralph McGinnis, Adam S. Butterworth, Muhammad Azhar, Marcus E. Kleber, Syed Saadat Ali, Faisal Shahid, Willem H. Ouwehand, Moazzam Zaidi, Muhammad Ishaq, Simon C. Potter, Frank Dudbridge, Mustafa Hussain, Danish Saleheen, Shahzad Majeed Bhatti, Gurdeep S. Sagoo, Hubert Scharnagl, Kerstin Koch, Zia Yaqoob, Wilfried Renner, Simon G. Thompson, Abdus Samad, Aftab Alam Gul, Abdul Hakeem, Michael M. Hoffmann, Suzanna Bumpstead, Maria Samuel, Asim Saleem, Asif Rasheed, Usman Ahmad, Nasir Sheikh, Alexander M. W. Cargill Thompson, Myriam Alexander, Emanuele Di Angelantonio, Fazal-ur Rehman, Ali Raza Gardezi, Reeta Gobin, Nadeem Sarwar, Rashid Jooma, J. Stephens, Assadullah Kundi, Philippe M. Frossard, Khan Shah Zaman, Winfried März, Kishwar Kumar, Michael Inouye, Shajjia Razi Haider, Sarah E. Hunt, Nadeem Qamar, Fahim Muhammad, Panos Deloukas, Liaquat Ali Cheema, Anthony Attwood, Azhar Faruqui, Junaid Zafar, Syed Zahed Rasheed, Abdul Ghaffar, Bernhard O. Boehm, Rhian Gwilliam, Bernhard R. Winkelmann, John Danesh, Philip Haycock, and Nazir Ahmed Memon
Subjects: Adult, Male, Lipid Metabolism Disorders, Blood lipids, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, chemistry.chemical_compound, Meta-Analysis as Topic, Polymorphism (computer science), Genetics, Humans, Pakistan, Allele, Allele frequency, Genetics (clinical), Aged, Triglyceride, Case-control study, Middle Aged, Lipid Metabolism, Lipids, Genetic architecture, Europe, chemistry, Genetic Loci, Case-Control Studies, Female, Cardiology and Cardiovascular Medicine, Genome-Wide Association Study
Abstract: Background— Evidence is sparse about the genetic determinants of major lipids in Pakistanis. Methods and Results— Variants (n=45 000) across 2000 genes were assessed in 3200 Pakistanis and compared with 2450 Germans using the same gene array and similar lipid assays. We also did a meta-analysis of selected lipid-related variants in Europeans. Pakistani genetic architecture was distinct from that of several ethnic groups represented in international reference samples. Forty-one variants at 14 loci were significantly associated with levels of HDL-C, triglyceride, or LDL-C. The most significant lipid-related variants identified among Pakistanis corresponded to genes previously shown to be relevant to Europeans, such as CETP associated with HDL-C levels (rs711752; P −13 ), APOA5/ZNF259 (rs651821; P −13 ) and GCKR (rs1260326; P −13 ) with triglyceride levels; and CELSR2 variants with LDL-C levels (rs646776; P −9 ). For Pakistanis, these 41 variants explained 6.2%, 7.1%, and 0.9% of the variation in HDL-C, triglyceride, and LDL-C, respectively. Compared with Europeans, the allele frequency of rs662799 in APOA5 among Pakistanis was higher and its impact on triglyceride concentration was greater ( P -value for difference −4 ). Conclusions— Several lipid-related genetic variants are common to Pakistanis and Europeans, though they explain only a modest proportion of population variation in lipid concentration. Allelic frequencies and effect sizes of lipid-related variants can differ between Pakistanis and Europeans.
Published: 2010
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8. 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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9. Mosaic 22q13 deletions: evidence for concurrent mosaic segmental isodisomy and gene conversion

Author: Orsetta Zuffardi, A. Sensi, Stefania Bigoni, Panos Deloukas, Roberto Giorda, Antonella Capucci, Cristina De Agostini, Silvana Beri, Rhian Gwilliam, Ian Dunham, Maria Clara Bonaglia, and Anna Baroncini
Subjects: Adult, congenital, hereditary, and neonatal diseases and abnormalities, Chromosomes, Human, Pair 22, Gene Conversion, Germline mosaicism, Marker analysis, Biology, Genetics, medicine, Humans, Gene conversion, In Situ Hybridization, Fluorescence, Genetics (clinical), Isodisomy, Mosaicism, Karyotype, Articles, Uniparental Disomy, medicine.disease, Molecular biology, Phenotype, Uniparental disomy, Karyotyping, Microsatellite, Female, Chromosome Deletion
Abstract: Although 22q terminal deletions are well documented, very few patients with mosaicism have been reported. We describe two new cases with mosaic 22q13.2-qter deletion, detected by karyotype analysis, showing the neurological phenotype of 22q13.3 deletion syndrome. Case 1 represents an exceptional case of mosaicism for maternal 22q13.2-qter deletion (45% of cells) and 22q13.2-qter paternal segmental isodisomy (55% of cells). This complex situation was suspected because cytogenetic, FISH and array-CGH analyses showed the presence of an 8.8 Mb mosaic 22q13.2-qter deletion, whereas microsatellite marker analysis was consistent with maternal deletion without any evidence of mosaic deletion. Molecular analysis led to the definition of very close, but not coincident, deletion and uniparental disomy (UPD) break points. Furthermore, we demonstrated that the segmental UPD arose by gene conversion in the same region. In Case 2, mosaicism for a paternal 8.9 Mb 22q13.2-qter deletion (73% of cells) was detected. In both patients, the level of mosaicism was also verified in saliva samples. We propose possible causative mechanisms for both rearrangements. Although the size of the deletions was quite similar, the phenotype was more severe in Case 2 than in Case 1. As maternal UPD 22 has not been generally associated with any defects and as the size of the deletion is very similar in the two cases, phenotype severity is likely to depend entirely on the degree of mosaicism in each individual.
Published: 2008
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10. Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study

Author: Tomi Pastinen, Scott Wilson, Huib A.P. Pols, D Hart, Mario Falchi, P. Arp, Toby Andrew, Mila Jhamai, Pamela Whittaker, Nicole Soranzo, Kourosh R. Ahmadi, J. B. Richards, Ana M. Valdes, J.B. van Meurs, André G. Uitterlinden, M. Moorhouse, Rhian Gwilliam, Michael Inouye, Albert Hofman, Benjamin H. Mullin, Vasudev Kumanduri, Tim D. Spector, Guangju Zhai, Panos Deloukas, Bernet S. Kato, Feng Zhang, Dominique J. Verlaan, Fernando Rivadeneira, Internal Medicine, Pathology, and Epidemiology
Subjects: Genetic Markers, Male, Oncology, medicine.medical_specialty, Genotype, Bone density, Osteoporosis, Gene Expression, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, Fractures, Bone, 03 medical and health sciences, 0302 clinical medicine, Bone Density, Internal medicine, Fast track — Articles, Humans, media_common.cataloged_instance, Medicine, European union, Alleles, LDL-Receptor Related Proteins, 030304 developmental biology, media_common, Femoral neck, Genetics, Bone mineral, 0303 health sciences, Lumbar Vertebrae, Genome, Human, business.industry, Chromosomes, Human, Pair 11, Osteoprotegerin, General Medicine, Odds ratio, Middle Aged, medicine.disease, 3. Good health, Low Density Lipoprotein Receptor-Related Protein-5, medicine.anatomical_structure, Female, business, Chromosomes, Human, Pair 8
Abstract: Summary Background Osteoporosis is diagnosed by the measurement of bone mineral density, which is a highly heritable and multifactorial trait. We aimed to identify genetic loci that are associated with bone mineral density. Methods In this genome-wide association study, we identified the most promising of 314 075 single nucleotide polymorphisms (SNPs) in 2094 women in a UK study. We then tested these SNPs for replication in 6463 people from three other cohorts in western Europe. We also investigated allelic expression in lymphoblast cell lines. We tested the association between the replicated SNPs and osteoporotic fractures with data from two studies. Findings We identified genome-wide evidence for an association between bone mineral density and two SNPs (p −8 ). The SNPs were rs4355801, on chromosome 8, near to the TNFRSF11B (osteoprotegerin) gene, and rs3736228, on chromosome 11 in the LRP5 (lipoprotein-receptor-related protein) gene. A non-synonymous SNP in the LRP5 gene was associated with decreased bone mineral density (rs3736228, p=6·3×10 −12 for lumbar spine and p=1·9×10 −4 for femoral neck) and an increased risk of both osteoporotic fractures (odds ratio [OR] 1·3, 95% CI 1·09–1·52, p=0·002) and osteoporosis (OR 1·3, 1·08–1·63, p=0·008). Three SNPs near the TNFRSF11B gene were associated with decreased bone mineral density (top SNP, rs4355801: p=7·6×10 −10 for lumbar spine and p=3·3×10 −8 for femoral neck) and increased risk of osteoporosis (OR 1·2, 95% CI 1·01–1·42, p=0·038). For carriers of the risk allele at rs4355801, expression of TNFRSF11B in lymphoblast cell lines was halved (p=3·0×10 −6 ). 1883 (22%) of 8557 people were at least heterozygous for these risk alleles, and these alleles had a cumulative association with bone mineral density (trend p=2·3×10 −17 ). The presence of both risk alleles increased the risk of osteoporotic fractures (OR 1·3, 1·08–1·63, p=0·006) and this effect was independent of bone mineral density. Interpretation Two gene variants of key biological proteins increase the risk of osteoporosis and osteoporotic fracture. The combined effect of these risk alleles on fractures is similar to that of most well-replicated environmental risk factors, and they are present in more than one in five white people, suggesting a potential role in screening. Funding Wellcome Trust, European Commission, NWO Investments, Arthritis Research Campaign, Chronic Disease Research Foundation, Canadian Institutes of Health Research, European Society for Clinical and Economic Aspects of Osteoporosis, Genome Canada, Genome Quebec, Canada Research Chairs, National Health and Medical Research Council of Australia, and European Union.
Published: 2008

11. A haplotype map of the human genome

Author: Mark Leppert, Aravinda Chakravarti, Charmaine D.M. Royal, Sarah S. Murray, Renzong Qiu, Panos Deloukas, Renwu Wang, David A. Hinds, Barbara E. Stranger, Xiaoli Tang, Huanming Yang, John W. Belmont, Nigel P. Carter, Huy Nguyen, William Mak, Kazuto Kato, Shiran Pasternak, Chaohua Li, Jeffrey C. Barrett, Lon R. Cardon, Vincent Ferretti, Atsushi Nagashima, Peter E. Chen, Stephen F. Schaffner, Hongbo Fu, Zhu Chen, Siqi Liu, John Burton, Paul Hardenbol, Gudmundur A. Thorisson, Yusuke Nakamura, Mark Griffiths, Imtiaz Yakub, Eiko Suda, Gonçalo R. Abecasis, Carl S. Kashuk, Qingrun Zhang, Yoshimitsu Fukushima, Karen Kennedy, Sarah E. Hunt, Yi Wang, Norio Niikawa, Ichiro Matsuda, Lynn F. Zacharia, Lalitha Krishnan, Zhen Wang, Stéphanie Roumy, C M Clee, David J. Cutler, Albert V. Smith, Lincoln Stein, Simon Myers, Jane Peterson, Jun Zhou, Yozo Ohnishi, Weihua Guan, Matthew Stephens, Xiaoyan Xiong, Julian Maller, Houcan Zhang, Pui-Yan Kwok, Mark S. Guyer, Liuda Ziaugra, Jonathan Witonsky, Matthew C. Jones, Stacey Gabriel, You-Qiang Song, Daochang An, Haifeng Wang, Gilean McVean, Lawrence M. Sung, Zhijian Yao, Yan Shen, Yangfan Liu, George M. Weinstock, Ludmila Pawlikowska, Erica Sodergren, Mark T. Ross, Andrew Boudreau, Toshihiro Tanaka, Thomas D. Willis, Weitao Hu, Kelly A. Frazer, Li Jin, Robert W. Plumb, Paul I.W. de Bakker, Hongbin Zhao, Wei Lin, Sarah Sims, Richard A. Gibbs, Maura Faggart, Michael Feolo, Dennis G. Ballinger, Xun Chu, Lucinda Fulton, Marcos Delgado, Ellen Winchester, Wei Huang, Fuli Yu, Christianne R. Bird, Shaun Purcell, Jessica Roy, Dongmei Cai, Launa M. Galver, Bartha Maria Knoppers, Emmanouil T. Dermitzakis, Gao Yang, Takashi Morizono, Rachel Barry, Kirsten McLay, Daryl J. Thomas, Steve McCarroll, Jonathan Marchini, Daniel J. Richter, Andy Peiffer, Patricia Taillon-Miller, Richard K. Wilson, Stephen Kwok-Wing Tsui, Jian-Bing Fan, Lisa D. Brooks, Laura L. Stuve, Paul L'Archevêque, David M. Evans, Clémentine Sallée, Peter Donnelly, Hong Xue, Hui Zhao, Charles N. Rotimi, Jean E. McEwen, J. Tze Fei Wong, Hao Pan, Alastair Kent, Brendan Blumenstiel, Qing Li, Weiwei Sun, L. Kang, Colin Freeman, John Stewart, Chibuzor Nkwodimmah, Morris W. Foster, Don Powell, Leonardo Bottolo, Raymond D. Miller, Stephen T. Sherry, Francis S. Collins, Donna M. Muzny, Jun Yu, Ike Ajayi, Hua Han, Pardis C. Sabeti, Hongguang Wang, Takahisa Kawaguchi, Tatsuhiko Tsunoda, Guy Bellemare, Zhaohui S. Qin, H. B. Hu, Jane Rogers, Thomas J. Hudson, Mark J. Daly, Andrew P. Morris, Supriya Gupta, Ming Xiao, Patrick Varilly, Nick Patterson, Akihiro Sekine, Chris C. A. Spencer, Jonathan Morrison, Missy Dixon, Paul K.H. Tam, Jian Wang, Matthew Defelice, Susana Eyheramendy, Michael Shi, Yungang He, Ellen Wright Clayton, Richa Saxena, Heather M. Munro, Arthur L. Holden, Yayun Shen, Christine P. Bird, Bruce W. Birren, Itsik Pe'er, David R. Bentley, Lynne V. Nazareth, Pamela Whittaker, Pak C. Sham, Amy L. Camargo, David A. Wheeler, Koji Saeki, Martin Godbout, David Altshuler, Liang Xu, Ying Wang, David Willey, Alexandre Montpetit, Shin Lin, Michael S. Phillips, Changqing Zeng, Clement Adebamowo, John C. Wallenburg, Mark S. Chee, Ben Fry, Erich Stahl, Melissa Parkin, Rhian Gwilliam, Andrei Verner, Patrick J. Nailer, Lap-Chee Tsui, Bo Zhang, Fanny Chagnon, David R. Cox, Jack Spiegel, Jamie Moore, Vivian Ota Wang, Patricia A. Marshall, Takuya Kitamoto, Bruce S. Weir, Darryl Macer, Geraldine M. Clarke, Robert C. Onofrio, Mary M.Y. Waye, Wei Wang, Suzanne M. Leal, James C. Mullikin, Toyin Aniagwu, Daniel C. Koboldt, Mary Goyette, Martin Leboeuf, Isaac F. Adewole, Ruth Jamieson, Arnold Oliphant, Jessica Watkin, and Jean François Olivier
Subjects: Linkage disequilibrium, Biology, DNA, Mitochondrial, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, Structural variation, Gene Frequency, Humans, Selection, Genetic, International HapMap Project, Genetic association, Haplotypes - genetics, Recombination, Genetic, Genetics, Chromosomes, Human, Y, Multidisciplinary, Genome, Human, DNA, Mitochondrial - genetics, Haplotype, Tag SNP, Polymorphism, Single Nucleotide - genetics, Haplotypes, Human genome, Haplotype estimation, Chromosomes, Human, Y - genetics
Abstract: Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution. © 2005 Nature Publishing Group., link_to_OA_fulltext
Published: 2005
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12. The DNA sequence of the human X chromosome

Author: Gernot Glöckner, Karen Thomas, Christine Lloyd, Huda Y. Zoghbi, Adrienne Hunt, Fiona Francis, Annemarie Poustka, George M. Weinstock, Xuehong Wei, Alan Tracey, Gabriele Nordsiek, Ines Müller, Graham Clarke, Oliver Beasley, John Sulston, Alfred Beck, Christian J. Buhay, Thomas Meitinger, Manjula Maheshwari, Yvonne Ramsey, Kirsten McLay, Shannon Dugan-Rocha, James G. R. Gilbert, Louisa Faulkner, Sidney Morris, Margaret Morgan, Huntington F. Willard, Leni S. Jacob, Hermela Loulseged, K M Porter, T. Daniel Andrews, Cordelia Langford, Paul Wray, Guan Chen, Juliane Ramser, Nigel P. Carter, Georgina Warry, Ruby Banerjee, Graeme Bethel, LaDeana W. Hillier, Anne Hodgson, Stephen M. J. Searle, K F Barlow, David R. Bentley, Paul E. Tabor, Kathryn L. Evans, Russell J. Grocock, Rebecca Woodmansey, Alex V Pearce, Christie Kovar-Smith, Angela Williamson, Dean Chavez, Roy Storey, Kevin L. Howe, Zhijian J. Chen, Lesette Perez, Richard A. Gibbs, Michele D'Urso, Karen N Bates, Jackie Bye, Shirin S. Joseph, Bernd Hinzmann, Paul Heath, Susan H. Kelly, Jennifer Hume, Paula E. Burch, David Buck, Mark T. Ross, David A. Wheeler, Matthew C. Jones, A K Babbage, Erica Sodergren, Sophie Palmer, Jie Ma, Elizabeth C. Sotheran, Margaret A. Leversha, Cerissa Hamilton, Hans Lehrach, Swaroop Aradhya, Michael L. Metzker, S. M. Clegg, Elizabeth J. Huckle, Audrey Fraser, Sarah Bray-Allen, C. D. Skuce, Petra Galgoczy, Richard K. Wilson, Patrick Minx, Richard E Connor, Tamsin Eades, Alfons Meindl, Michelle Smith, John M. Davis, André Rosenthal, Stuart McLaren, Geoffery Okwuonu, M. Vaudin, Laura Carrel, Ryan J. Lozado, Harminder Sehra, Richard Pandian, Sue Y Clark, Anna Kosiura, Wen Liu, Simon G. Gregory, A Tromans, Alexandra Emery-Cohen, Charles Shaw-Smith, Donna Villasana, Joseph Chako, Katja Heitmann, Robert G. David, Jennifer L. Ashurst, Craig Chinault, S Lawlor, Paul Havlak, Jane E. Loveland, Lucy Matthews, Jianling Zhou, S. Whitehead, Paul Hunt, E Sheridan, Richard Reinhardt, Tim Hubbard, Mary G. Schueler, Patrick Meidl, Helen Beasley, David Beare, Donna M. Muzny, Kerry A Ridler, Joanne C Chapman, Jennifer McDowall, Andrew Dunham, Anne Bridgeman, Gabrielle Williams, Amanda McMurray, Stefan Taudien, Matthew E. Hurles, Helen Williamson, Preethi H. Gunaratne, Alfredo Ciccodicola, R Ainscough, Alison J. Coffey, Charlotte G. Cole, Stephan Beck, Frances L Lovell, Alan Coulson, Qiaoyan Wang, Sally Jones, Charles A. Steward, Michael Hoffs, Kim C. Worley, Sarah Pelan, David Bonnin, David Schlessinger, Mathew N Whiteley, Graham Scott, Christopher N O'Dell, Tineace Taylor, Susan Rhodes, Anthony P. West, E. Hart, Ian P. Barrett, Andrea Thorpe, D. Pearson, Huyen Dinh, Susan M. Gribble, Andrew J Knights, Laurens G. Wilming, N Corby, Steven E. Scherer, Pawandeep Dhami, Gerald Nyakatura, J Lovell, M. Ali Ansari-Lari, Kerstin P. Clerc-Blankenburg, David Swarbreck, Sara Zorilla, Yanghong Gu, Karin Blechschmidt, Matthew Dunn, Andrew Brown, Kirsten M. Timms, Darren Grafham, Yan Ding, Elspeth A. Bruford, Leanne Williams, Melanie M. Wall, Hua Shen, Dina Patel, Joanne K Kershaw, Rachel Gill, Yuan Chen, Joy Davies, D C Burford, John Burton, Vicky Cobley, R I S Ashwell, Nicola Brady, Ellson Y. Chen, Ngoc Nguyen, Gaiping Wen, Gavin K. Laird, Julia E. Parrish, Carol Scott, C Griffiths, Ratna Shownkeen, Ralf Sudbrak, Denise R. DeShazo, Shiran Pasternak, Ireena Dutta, Brian Teague, Rachael Lyne, David Parker, Jane Rogers, Steve Dodsworth, Mary J. Brown, Gary E Barker, Steve Trevanion, Joanne Burgess, Jane E. Wilkinson, James T. Warren, Jen S. Conquer, R Mark Swann, Oliver Delgado, Heather R. Draper, Shailesh L Mistry, Chris Clee, Richard Durbin, Karen Clifford, John Frankland, Sarah E. Hunt, David Steffen, Christine Burrows, Daniel Verduzco, C Carder, Robert H. Waterston, Stephen Richards, Andrea Ballabio, Catherine M. Rice, David Willey, Helen Errington, Andrew Cree, K. James Durbin, Lora Lewis, D. M. Lloyd, Helen E. Steingruber, Adam Whittaker, K D Ambrose, Rhian Gwilliam, Adam Frankish, Robert S. Fulton, Judith Hernandez, Claire L Bagguley, Pieter J. de Jong, Jennifer Yen, Matthew Ellwood, Christine P. Bird, Rui Chen, Sarah Milne, Clay Davis, Alicia Hawes, Jing Lu, Sven Klages, David L. Nelson, Wayne Burrill, Jingkun Zhang, Judith Isherwood, Kathrin Reichwald, Lenee Waldron, Rebecca Deadman, Steffen Hennig, Ziad Khan, Sarah Ho, Matthias Platzer, Gareth R. Howell, Stephen Keenan, Petra Kioschis, Phillip J Howden, George Miner, David W. Johnson, and James C. Mullikin
Subjects: Male, Genetic Linkage, Genetics, Medical, Centromere, HUMAN GENOME SEQUENCE, Biology, Y chromosome, Polymorphism, Single Nucleotide, Article, Evolution, Molecular, Contig Mapping, Chromosome 16, Antigens, Neoplasm, Dosage Compensation, Genetic, Sequence Homology, Nucleic Acid, Chromosome 19, Testis, Animals, Humans, Crossing Over, Genetic, X chromosome, Repetitive Sequences, Nucleic Acid, Genetics, Chromosomes, Human, X, Chromosomes, Human, Y, Multidisciplinary, INACTIVATION CENTER, LINKED MENTAL-RETARDATION, Genomics, Sequence Analysis, DNA, REPEAT HYPOTHESIS, MAMMALIAN Y-CHROMOSOME, Chromosome 4, Chromosome 3, RNA, Female, Chromosome 21, Chromosome 22
Abstract: The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.
Published: 2005
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13. Genomic Organization of Human CDS2 and Evaluation as a Candidate Gene for Corneal Hereditary Endothelial Dystrophy 2 on Chromosome 20p13

Author: Stephanie Halford, Neil D. Ebenezer, David M. Hunt, Rhian Gwilliam, Pauline Spencer, Moin D. Mohamed, and Suzanne L. Inglis
Subjects: Candidate gene, Chromosomes, Human, 19-20, Molecular Sequence Data, Gene Expression, Corneal dystrophy, Biology, Polymerase Chain Reaction, Cornea, Mice, Cellular and Molecular Neuroscience, medicine, Animals, Humans, In Situ Hybridization, Genomic organization, Corneal Dystrophies, Hereditary, Cloning, Genetics, Chromosome Mapping, Dystrophy, Chromosome, Exons, medicine.disease, Introns, Sensory Systems, Ophthalmology, Diacylglycerol Cholinephosphotransferase
Published: 2002
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14. Analysis of 41 kb of the DNA sequence from the right arm of chromosome II ofSchizosaccharomyces pombe

Author: Rachel Lyne, Sergio Moreno, Carol Churcher, Valerie Wood, José L. Revuelta, Richard Reinhardt, Angel Domínguez, Rhian Gwilliam, Alfred Beck, Marie-Adèle Rajandream, K. Borzym, Bart Barrell, Francisco Escobar del Rey, Manuel Calderon De La Barca Sanchez, and Jason Skelton
Subjects: Genetics, biology, Protein subunit, Bioengineering, biology.organism_classification, Applied Microbiology and Biotechnology, Biochemistry, Molecular biology, Open reading frame, Complete sequence, Schizosaccharomyces pombe, Cosmid, Nuclear protein, ORFS, Gene, Biotechnology
Abstract: We report the complete sequence of cosmid c18A7 (41 046 bp insert), located on the right arm of chromosome II of the Schizosaccharomyces pombe genome. The sequence, which partially overlaps with cosmids SPBC4F6 and SPBC336, contains 16 open reading frames (ORFs) capable of coding for proteins of at least 100 amino acid residues in length (one partial) and one small nucleolar RNA (snoRNA). Four known genes were found: swi10 (encoding a mating-type switching protein also involved in nucleotide excision repair); dim1 (encoding a dimethyladenosine transferase); arf1 (encoding ADP-ribosylation factor 1); and pol3 (cdc6) the partial fragment, encoding the 125 kDa catalytic subunit of the DNA polymerase type B. Six ORFs similar to known proteins were found. They include a transporter of the major facilitator superfamily class, a vacuolar sorting protein, an asparagine synthase, a nuclear protein, a reticulum oxidoreductin and a heat shock protein. Each protein product of the other six ORFs has conserved domains and can be assigned a molecular, but not a biological, function. The sequence has been submitted to the EMBL database under Accession No. AL080287. Copyright © 2001 John Wiley & Sons, Ltd.
Published: 2001
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15. Subtelomeric sequence from the right arm ofSchizosaccharomyces pombe chromosome I contains seven permease genes

Author: Stephen J. Aves, Rachel C. McDougall, Valerie Wood, Rhian Gwilliam, M. Lyne, Maire‐Adèle Rajandream, Zheng Xiang, Karen Moore, Cherryl Hunt, Suzanne M. Hurst, and Barclay G. Barrell
Subjects: Transposable element, Genetics, biology, Permease, Intron, Bioengineering, biology.organism_classification, Applied Microbiology and Biotechnology, Biochemistry, Amino acid permease, Open reading frame, Schizosaccharomyces pombe, ORFS, Gene, Biotechnology
Abstract: The sequence has been determined of 80 888 bp of contiguous subtelomeric DNA, including the isp5 gene, from the right arm of chromosome I of Schizosaccharomyces pombe; 27 open reading frames (ORFs) longer than 100 codons are present, giving a density of one gene per 3.0 kb. Seven of the predicted proteins are members of the major facilitator superfamily (MFS) of transport proteins, including four amino acid permease homologues, bringing this family of amino acid permease sequences to 17 in Sz. pombe, and a phylogenetic analysis is presented. Also encoded is an allantoate permease homologue, a sulphate permease homologue and a probable urea active transporter. Predicted non-membrane proteins include a 1-aminocyclopropane-1-carboxylate deaminase (ACC deaminase), a class III aminotransferase, serine acetyltransferase, protein-L-isoaspartate O-methyltransferase, α-glucosidase, α-galactosidase, esterase/lipase, oxidoreductase of the short-chain dehydrogenase/reductase (SDR) family, aldehyde dehydrogenase, formamidase, amidase, flavohaemoprotein, a putative translation initiation inhibitor and a protein with similarity to a filamentous fungal conidiation-specific protein. The remaining six ORFs are likely to encode proteins, either because they have sequence similarity with hypothetical proteins or because they are known to be transcribed. Introns are scarce in the sequenced region: only three ORFs contain introns, with only one having multiple introns. The sequenced region also contains a single Tf1 transposon long terminal repeat (LTR). The sequence is derived from cosmid clones c869, c922 and c1039 and has been submitted to the EMBL database under entries SPAC869 (Accession No. AL132779), SPAC922 (AL133522) and SPAC1039 (AL133521). Copyright © 2001 John Wiley & Sons, Ltd.
Published: 2001
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16. Analysis of 114 kb of DNA sequence from fission yeast chromosome 2 immediately centromere-distal tohis5

Author: Karen Devlin, Valerie Wood, Jason Skelton, Rhian Gwilliam, Zheng Xiang, Kim Rutherford, Karen Moore, Maire‐Adèle Rajandream, Barclay G. Barrell, M. Lyne, Stephen J. Aves, and Carol Churcher
Subjects: Genetics, Peptidylprolyl isomerase, Intron, Aminodeoxychorismate lyase, Bioengineering, Biology, Applied Microbiology and Biotechnology, Biochemistry, RNA Helicase A, Molecular biology, Transport protein, Cosmid, ORFS, Gene, Biotechnology
Abstract: One hundred and fourteen kilobase pairs (kb) of contiguous genomic sequence have been determined immediately distal to the his5 genetic marker located about 0.9 Mb from the centromere on the long arm of Schizosaccharomyces pombe chromosome 2. The sequence is contained in overlapping cosmid clones c16H5, c12D12, c24C6 and c19G7, of which 20 kb are identical to previously reported sequence from clone c21H7. The remaining 93 781 bp of sequence contains 10 known genes (cdc14, cdm1, cps1, gpa1, msh2, pck2, rip1, rps30-2, sad1 and ubl1), 32 open reading frames (ORFs) capable of coding for proteins of at least 100 amino acid residues in length, one 5S rRNA gene, one tRNA(Pro) gene, one lone Tf1-type long terminal repeat (LTR) and one lone Tf2-type LTR. There is a density of one protein-coding gene per 2.2 kb and 22 of the 42 ORFs (52%) incorporate one or more introns. Twenty-one of the novel ORFs show sequence similarities which suggest functions of their products, including a cyclin C, a MADS box transcription factor, mad2-like protein, telomere binding protein, topoisomerase II-associated protein, ATP-dependent DEAH box RNA helicase, G10 protein, ubiquitin-activating e1-like enzyme, nucleoporin, prolyl-tRNA synthetase, peptidylprolyl isomerase, delta-1-pyrroline-5-carboxylate dehydrogenase, protein transport protein, coatomer epsilon, TCP-1 chaperonin, beta-subunit of 6-phosphofructokinase, aminodeoxychorismate lyase, a phosphate transport protein and a thioredoxin.
Published: 2000
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17. High-Resolution Landmark Framework for the Sequence-Ready Mapping of Xq23–q26.1

Author: Gareth Maslen, Elizabeth C. Sotheran, Rhian Gwilliam, Pawandeep Dhami, Margaret A. Leversha, Carol Scott, S. M. Clegg, Mark T. Ross, Alison J. Coffey, Andrew Dunham, Sarah E. Hunt, David R. Bentley, Gareth R. Howell, Elizabeth J. Huckle, Cari Soderlund, Helen E. Steingruber, and Paul Hunt
Subjects: Genetic Markers, Yeast artificial chromosome, Letter, X Chromosome, Sequence analysis, Computational biology, Biology, Contig Mapping, Genetics, medicine, Humans, Chromosomes, Artificial, Yeast, In Situ Hybridization, Fluorescence, Genetics (clinical), X chromosome, medicine.diagnostic_test, Contig, Chromosome Mapping, Sequence Analysis, DNA, Electrophoresis, Gel, Pulsed-Field, Blotting, Southern, Genetic marker, Female, Human genome, Fluorescence in situ hybridization
Abstract: We have established a landmark framework map over 20–25 Mb of the long arm of the human X chromosome using yeast artificial chromosome (YAC) clones. The map has approximately one landmark per 45 kb of DNA and stretches from DXS7531 in proximal Xq23 to DXS895 in proximal Xq26, connecting to published framework maps on its proximal and distal sides. There are three gaps in the framework map resulting from the failure to obtain clone coverage from the YAC resources available. Estimates of the maximum sizes of these gaps have been obtained. The four YAC contigs have been positioned and oriented using somatic-cell hybrids and fluorescence in situ hybridization, and the largest is estimated to cover ∼15 Mb of DNA. The framework map is being used to assemble a sequence-ready map in large-insert bacterial clones, as part of an international effort to complete the sequence of the X chromosome. PAC and BAC contigs currently cover 18 Mb of the region, and from these, 12 Mb of finished sequence is available.
Published: 1999
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18. A Detailed Physical and Transcriptional Map of the Region of Chromosome 20 That Is Deleted in Myeloproliferative Disorders and Refinement of the Common Deleted Region

Author: David R. Bentley, Panos Deloukas, Fotios A. Asimakopoulos, Anthony R. Green, Micheala A. Aldred, Sean Humphray, Rhian Gwilliam, James G. R. Gilbert, Anthony J. Bench, and Kim Champion
Subjects: Genetic Markers, Genotype, Transcription, Genetic, T-Lymphocytes, Centromere, Chromosomes, Human, Pair 20, chemical and pharmacologic phenomena, Biology, Loss of heterozygosity, Myeloproliferative Disorders, Gene mapping, Genetics, Humans, Family, Chromosomes, Artificial, Yeast, Polycythemia Vera, Gene, Contig, Homozygote, Chromosome Mapping, DNA, Genetic marker, Microsatellite, Chromosome Deletion, Chromosome 20, Granulocytes, Microsatellite Repeats
Abstract: Acquired deletions of the long arm of chromosome 20 are the most common chromosomal abnormality seen in polycythemia vera and are also associated with other myeloid malignancies. Such deletions are believed to mark the site of one or more tumor suppressor genes, loss of which perturbs normal hematopoiesis. A common deleted region (CDR) has previously been identified on 20q. We have now constructed the most detailed physical map of this region to date—a YAC contig that encompasses the entire CDR and spans 23 cM (11 Mb). This contig contains 140 DNA markers and 65 unique expressed sequences. Our data represent a first step toward a complete transcriptional map of the CDR. The high marker density within the physical map permitted two complementary approaches to reducing the size of the CDR. Microsatellite PCR refined the centromeric boundary of the CDR to D20S465 and was used to search for homozygous deletions in 28 patients using 32 markers. No such deletions were detected. Genetic changes on the remaining chromosome 20 may therefore be too small to be detected or may occur in a subpopulation of cells.
Published: 1998
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19. From Long Range Mapping to Sequence-Ready Contigs on Human Chromosome 6

Author: Nigel P. Carter, Mark T. Ross, L Baron, Carol Scott, R. W. Heathcott, Carol Soderlund, Ian Dunham, Adam Butler, Panagiotis Deloukas, Sarah E. Hunt, Cordelia Langford, E. Holloway, A I Peck, Y. H. Ramsey, P Harrison, S. M. Clegg, Austin Smith, G. L. Maslen, C M Clee, M.A. Leversha, Andrew J. Mungall, Sean Humphray, S. A. Ranby, E. J. Huckle, A. J. Theaker, Carol A. Edwards, David R. Bentley, L D Green, Rhian Gwilliam, and C. M. Rice
Subjects: clone (Java method), Genetics, Databases, Factual, Gene map, Contig, Sequence Analysis, DNA, Biology, Biochemistry, DNA sequencing, Sequence-tagged site, Contig Mapping, Restriction enzyme, Endocrinology, Chromosome (genetic algorithm), Humans, Chromosomes, Human, Pair 6, Molecular Biology, Sequence (medicine)
Abstract: Our aim is to construct physical clone maps covering those regions of chromosome 6 that are not currently extensively mapped, and use these to determine the DNA sequence of the whole chromosome. The strategy we are following involves establishing a high density framework map of the order of 15 markers per Megabase using radiation hybrid (RH) mapping. The markers are then used to identify large-insert genomic bacterial clones covering the chromosome, which are assembled into sequence-ready contigs by restriction enzyme fingerprinting and sequence tagged site (STS) content analysis. Contig gap closure is performed by walking experiments using STSs developed from the end sequences of the clone inserts.
Published: 1997
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20. A variant in LDLR is associated with abdominal aortic aneurysm

Author: Frank M. van Bockxmeer, S Sohrabi, Janet T. Powell, Robert A. S. Ariëns, Anne Johnson, Seamus C. Harrison, Hany Hafez, Matthew M. Thompson, Matthew Waltham, Jacqueline de Graaf, Gillian Cockerill, D. Julian A. Scott, A H Child, Lambertus A. Kiemeney, Jan D. Blankensteijn, Jonathan Golledge, Rhian Gwilliam, Stephen A. Badger, Joep A.W. Teijink, kevin Burnand, Rachel E. Clough, Anne E. Hughes, Robert D. Sayers, Alberto Smith, Declan Bradley, Suzannah Bumpstead, Paul Norman, Gregory T. Jones, Benjamin J. Wright, John R Thompson, Simon C. Potter, Sarah E. Hunt, Jes S. Lindholt, Steve E. Humphries, Annette F. Baas, Stefan E Matthiasson, J.B. Wild, Unnur Thorsteinsdottir, Matthew J. Bown, Kari Stefansson, Andre M. van Rij, Nilesh J. Samani, Panos Deloukas, Per Eriksson, Gudmar Thorleifsson, Solveig Gretarsdottir, Cisca Wijmenga, Sarah Edkins, Surgery, ICaR - Ischemia and repair, Epidemiologie, RS: CAPHRI School for Public Health and Primary Care, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Department of Health and Life Sciences
Subjects: Male, Heart disease, LOCI, Genome-wide association study, Aetiology, screening and detection [ONCOL 5], Coronary artery disease, Cohort Studies, Risk Factors, Odds Ratio, Myocardial infarction, Genetics (clinical), COMMON VARIANTS, Middle Aged, Abdominal aortic aneurysm, Lipoproteins, LDL, Cohort, cardiovascular system, Regression Analysis, CORONARY-ARTERY-DISEASE, Female, Cardiology and Cardiovascular Medicine, Adult, medicine.medical_specialty, Genotype, HEART-DISEASE, Polymorphism, Single Nucleotide, LDL, lipids, Aneurysm, Internal medicine, Genetics, medicine, Humans, cardiovascular diseases, GENOME-WIDE ASSOCIATION, METAANALYSIS, POLYMORPHISMS, Health aging / healthy living Cardiovascular diseases [IGMD 5], Molecular epidemiology Aetiology, screening and detection [NCEBP 1], genome-wide association study, business.industry, cholesterol, Odds ratio, medicine.disease, Surgery, MYOCARDIAL-INFARCTION, SEQUENCE VARIANT, RISK-FACTORS, aneurysm, business, Aortic Aneurysm, Abdominal
Abstract: 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 −4 were carried through to in silico replication in 1292 AAA cases and 30 503 controls. One single-nucleotide polymorphism associated with P 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 =2.08×10 −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
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21. The Role of Variation at A beta PP, PSEN1, PSEN2, and MAPT in Late Onset Alzheimer's Disease

Author: Nicola Jones, Kevin Morgan, Susanne Moebus, Denise Harold, Ammar Al-Chalabi, David M. A. Mann, Frank Jessen, Ian J. Deary, Clive Holmes, Isabella Heuser, V. Shane Pankratz, Jens Wiltfang, Harald Hampel, John M. Starr, Rebecca Sims, Patrick G. Kehoe, H-Erich Wichmann, Simon Mead, Alison Goate, Aoibhinn Lynch, Michael Conlon O'Donovan, Bernadette McGuinness, Norman Klopp, Janet A. Johnston, Rita Guerreiro, Markus M. Nöthen, Lesley Jones, Hendrik van den Bussche, Reinhard Heun, John S. K. Kauwe, Petra Nowotny, A. David Smith, David Craig, John Powell, Michael Gill, Johannes Kornhuber, Stephen Todd, Seth Love, Thomas W. Mühleisen, Hugh Gurling, Kimberley Dowzell, John C. Morris, Alexander Richards, Marian L. Hamshere, Charlene Thomas, John Collinge, Christopher Shaw, Gill Livingston, Simon Lovestone, Wolfgang Maier, Amy Williams, Lutz Frölich, Jade Chapman, Steven G. Younkin, Karl-Heinz Jöckel, Dobril Ivanov, Brian A. Lawlor, Nick C. Fox, Carlos Cruchaga, Andrew B. Singleton, Gail Davies, Petroula Proitsi, Andrew McQuillin, Michael Hüll, Dan Rujescu, Jaspreet Singh Pahwa, Panagiotis Deloukas, Heike Kölsch, Britta Schürmann, Kevin Mayo, Peter Holmans, Rhian Gwilliam, Magda Tsolaki, Kristelle Brown, Sarah E. Harris, Nicholas Bass, John Hardy, Minerva M. Carrasquillo, Martin N. Rossor, Michael John Owen, Angharad R. Morgan, Paul Hollingworth, Peter Passmore, Giancarlo Russo, Amy Gerrish, Carol Brayne, David C. Rubinsztein, Michelle K. Lupton, Martin Dichgans, Valentina Moskvina, Alexandra Stretton, Richard Abraham, Julie Williams, Neurology, and NCA - Neurodegeneration
Subjects: Male, Genotype, Medizin, Genome-wide association study, tau Proteins, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Presenilin, Article, Progressive supranuclear palsy, Amyloid beta-Protein Precursor, Meta-Analysis as Topic, Alzheimer Disease, PSEN2, Presenilin-2, medicine, PSEN1, Odds Ratio, Presenilin-1, Corticobasal degeneration, Humans, Genetic Predisposition to Disease, Aged, Genetics, Aged, 80 and over, General Neuroscience, Haplotype, General Medicine, medicine.disease, Psychiatry and Mental health, Clinical Psychology, Female, Alzheimer's disease, Geriatrics and Gerontology, Genome-Wide Association Study
Abstract: Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.
Published: 2012
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22. Population genetic analysis of Plasmodium falciparum parasites using a customized Illumina GoldenGate genotyping assay

Author: Abdoulaye Djimde, Peter Siba, Hongying Jiang, Xin-zhuan Su, Steven M. Kiara, Duong Socheat, Bronwyn MacInnis, Kirk A. Rockett, Alexis Nzila, Nicholas J. White, François Nosten, Chris I. Newbold, Issaka Zongo, Ogobara K. Doumbo, Chanaki Amaratunga, Kevin Marsh, Katja Kivinen, Susana Campino, Rick M. Fairhurst, Jean-Bosco Ouédraogo, Taane G. Clark, Rhian Gwilliam, Steffen Borrmann, Panos Deloukas, Valentina D. Mangano, Sarah Auburn, Mallika Imwong, Dominic P. Kwiatkowski, Tim J. Anderson, Pascal Michon, and Ivo Mueller
Subjects: Time Factors, DIVERSITY, lcsh:Medicine, Protozoology, 0302 clinical medicine, Genotype, Malaria, Falciparum, lcsh:Science, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, biology, High-Throughput Nucleotide Sequencing, 3. Good health, GENOME, PCR, Infectious Diseases, Microsatellite, Medicine, MULTIPLE DISPLACEMENT AMPLIFICATION, Research Article, Cloning, Organism, MICROSATELLITE, 030231 tropical medicine, Population, Plasmodium falciparum, SEQUENCE, Polymorphism, Single Nucleotide, Microbiology, 03 medical and health sciences, Culture Techniques, parasitic diseases, Parasitic Diseases, Genetic variability, education, Genotyping, Biology, ANTIMALARIAL-DRUG RESISTANCE, 030304 developmental biology, Genetic diversity, IDENTIFICATION, Population Biology, lcsh:R, MALARIA, Multiple displacement amplification, Computational Biology, Tropical Diseases (Non-Neglected), DNA, Protozoan, biology.organism_classification, Malaria, Genetic Loci, Genetic Polymorphism, Parastic Protozoans, lcsh:Q, Laboratories, Population Genetics
Abstract: The diversity in the Plasmodium falciparum genome can be used to explore parasite population dynamics, with practical applications to malaria control. The ability to identify the geographic origin and trace the migratory patterns of parasites with clinically important phenotypes such as drug resistance is particularly relevant. With increasing single-nucleotide polymorphism (SNP) discovery from ongoing Plasmodium genome sequencing projects, a demand for high SNP and sample throughput genotyping platforms for large-scale population genetic studies is required. Low parasitaemias and multiple clone infections present a number of challenges to genotyping P. falciparum. We addressed some of these issues using a custom 384-SNP Illumina GoldenGate assay on P. falciparum DNA from laboratory clones (long-term cultured adapted parasite clones), short-term cultured parasite isolates and clinical (non-cultured isolates) samples from East and West Africa, Southeast Asia and Oceania. Eighty percent of the SNPs (n = 306) produced reliable genotype calls on samples containing as little as 2 ng of total genomic DNA and on whole genome amplified DNA. Analysis of artificial mixtures of laboratory clones demonstrated high genotype calling specificity and moderate sensitivity to call minor frequency alleles. Clear resolution of geographically distinct populations was demonstrated using Principal Components Analysis (PCA), and global patterns of population genetic diversity were consistent with previous reports. These results validate the utility of the platform in performing population genetic studies of P. falciparum.
Published: 2010

23. P4‐133: Genome‐wide association study of age at onset of Alzheimer's disease

Author: Kevin Morgan, Ammar Al-Chalabi, Alison Goate, Denise Harold, Peter Holmans, Julie Williams, Gill Livingston, Nicola Bass, Paul Hollingworth, Steven G. Younkin, Michael John Owen, Panos Deloukas, Wolfgang Maier, Richard Abraham, Rebecca Sims, Michael Gill, Rhian Gwilliam, Amy Gerrish, Carol Brayne, Brian A. Lawlor, Marian L. Hamshere, Simon Lovestone, Peter Passmore, Michael Conlon O'Donovan, and Markus M. Nöthen
Subjects: Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Genome-wide association study, Neurology (clinical), Disease, Geriatrics and Gerontology, Biology
Published: 2009
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24. P4‐121: Genome‐wide association study of Alzheimer's with psychotic symptoms

Author: Gill Livingston, Wolfgang Mayer, N Bass, Denise Harold, Kevin Morgan, Ammar Al-Chalabi, Paul Hollingworth, Michael Gill, Marian L. Hamshere, Steve Younkin, Rebecca Sims, Michael John Owen, Brian A. Lawlor, Amy Gerrish, Alison Goate, Rhian Gwilliam, Simon Lovestone, Peter Passmore, Peter Holmans, Carol Brayne, Michael Conlon O'Donovan, Markus M. Nöthen, Panos Deloukas, Julie Williams, and Richard Abraham
Subjects: Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Genome-wide association study, Neurology (clinical), Geriatrics and Gerontology, Biology
Published: 2009
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25. P4‐124: An examination of previously reported Alzheimer candidate genes within a large genome‐wide association dataset

Author: Carol Brayne, Julie Williams, Amy Gerrish, Denise Harold, Steve Younkin, Michael Gill, Michael John Owen, Rebecca Sims, Richard Abraham, Michael Conlon O'Donovan, Markus M. Nöthen, Marian L. Hamshere, Panos Deloukas, Gill Livingston, Paul Hollingworth, Kevin Morgan, Wolfgang Mayer, Alison Goate, Simon Lovestone, Peter Passmore, Ammar Al-Chalabi, N Bass, Rhian Gwilliam, Brian A. Lawlor, and Peter Holmans
Subjects: Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Candidate gene, Developmental Neuroscience, Epidemiology, Health Policy, Genome-wide association study, Neurology (clinical), Geriatrics and Gerontology, Biology
Published: 2009
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26. Linkage disequilibrium mapping of the replicated type 2 diabetes linkage signal on chromosome 1q

Author: Leslie J. Baier, Swapan K Das, Clifton Bogardus, Mark I. McCarthy, Alan R. Shuldiner, Cheng Hu, Braxton D. Mitchell, Panos Deloukas, M Vaxillaire, Lincoln Stein, Eleftheria Zeggini, Juliana C.N. Chan, Steven C. Elbein, Philippe Froguel, N. William Rayner, Robert L. Hanson, Colin N. A. Palmer, Congrong Wang, Maggie C.Y. Ng, Mao Fu, Timothy M. Frayling, Inga Prokopenko, Rhian Gwilliam, Benjamin F. Voight, Laura J. Scott, Christopher J. Groves, Andrew T. Hattersley, Pelin Akan, Andrew D. Morris, Marcela K. Tello-Ruiz, Weiping Jia, Katherine S. Elliott, and Medical Research Council (MRC)
Subjects: Linkage disequilibrium, SAMPLES, Endocrinology, Diabetes and Metabolism, LOCI, Genome-wide association study, SUSCEPTIBILITY, VARIANTS, Linkage Disequilibrium, 0302 clinical medicine, Gene Frequency, Reference Values, Ethnicity, International Type 2 Diabetes 1q Consortium, Association mapping, POPULATION, RISK, Genetics, 0303 health sciences, GK RAT, Linkage Disequilibrium Mapping, NUCLEAR FACTOR-4-ALPHA GENE, Chromosome Mapping, 11 Medical And Health Sciences, Tag SNP, DNA-Binding Proteins, Chromosomes, Human, Pair 1, DISEASES, Original Article, Life Sciences & Biomedicine, ENDOCRINOLOGY & METABOLISM, European Continental Ancestry Group, Ethnic Groups, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Risk Assessment, White People, 03 medical and health sciences, Genetic linkage, Internal Medicine, Humans, GENOME-WIDE ASSOCIATION, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Science & Technology, Genetic Variation, Histone-Lysine N-Methyltransferase, Diabetes Mellitus, Type 2, Imputation (genetics), Transcription Factors
Abstract: OBJECTIVE Linkage of the chromosome 1q21–25 region to type 2 diabetes has been demonstrated in multiple ethnic groups. We performed common variant fine-mapping across a 23-Mb interval in a multiethnic sample to search for variants responsible for this linkage signal. RESEARCH DESIGN AND METHODS In all, 5,290 single nucleotide polymorphisms (SNPs) were successfully genotyped in 3,179 type 2 diabetes case and control subjects from eight populations with evidence of 1q linkage. Samples were ascertained using strategies designed to enhance power to detect variants causal for 1q linkage. After imputation, we estimate ∼80% coverage of common variation across the region (r 2 > 0.8, Europeans). Association signals of interest were evaluated through in silico replication and de novo genotyping in ∼8,500 case subjects and 12,400 control subjects. RESULTS Association mapping of the 23-Mb region identified two strong signals, both of which were restricted to the subset of European-descent samples. The first mapped to the NOS1AP (CAPON) gene region (lead SNP: rs7538490, odds ratio 1.38 [95% CI 1.21–1.57], P = 1.4 × 10−6, in 999 case subjects and 1,190 control subjects); the second mapped within an extensive region of linkage disequilibrium that includes the ASH1L and PKLR genes (lead SNP: rs11264371, odds ratio 1.48 [1.18–1.76], P = 1.0 × 10−5, under a dominant model). However, there was no evidence for association at either signal on replication, and, across all data (>24,000 subjects), there was no indication that these variants were causally related to type 2 diabetes status. CONCLUSIONS Detailed fine-mapping of the 23-Mb region of replicated linkage has failed to identify common variant signals contributing to the observed signal. Future studies should focus on identification of causal alleles of lower frequency and higher penetrance.
Published: 2009
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27. Meta-Analysis of Genome-Wide Scans for Human Adult Stature Identifies Novel Loci and Associations with Measures of Skeletal Frame Size

Author: Jonathan Stephens, Huibert A. P. Pols, Deborah J. Hart, Mohammed J. R. Ghori, Ida Malkina, Wendy L. McArdle, Simon C. Potter, Rhian Gwilliam, David P. Strachan, Alexandra C. Nica, Kourosh R. Ahmadi, Radhi Ravindrarajah, Michael Inouye, Albert Hofman, Tim D. Spector, Karol Estrada, Lisette Stolk, Frances M K Williams, Gregory Livshits, Eleanor Wheeler, Naomi Hammond, P. Mila Jhamai, Sergey Ermakov, Usha Chinappen-Horsley, Pascal P. Arp, André G. Uitterlinden, Emmanouil T. Dermitzakis, Panos Deloukas, Nicholas J. Wareham, Ruth J. F. Loos, Amy Chaney, Inês Barroso, J. Brent Richards, Willem H. Ouwehand, Joyce B. J. van Meurs, Nicole Soranzo, Fernando Rivadeneira, Manjinder S. Sandhu, Internal Medicine, and Epidemiology
Subjects: Adult, Male, Cancer Research, Adolescent, lcsh:QH426-470, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Biology, Genetics and Genomics/Complex Traits, Polymorphism, Single Nucleotide, Bone and Bones, White People, Rheumatology/Cartilage Biology and Osteoarthritis, Body Height, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Genetics, Humans, Femur, ddc:576.5, Bone and Bones/*chemistry, Genome-Wide Association Study, Human height, European Continental Ancestry Group/genetics, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, Skeleton, 030304 developmental biology, Aged, Aged, 80 and over, 0303 health sciences, Genetics and Genomics, Rheumatology/Bone and Mineral Metabolism, Middle Aged, Trunk, lcsh:Genetics, Meta-analysis, Expression quantitative trait loci, Female, 030217 neurology & neurosurgery, Research Article
Abstract: Recent genome-wide (GW) scans have identified several independent loci affecting human stature, but their contribution through the different skeletal components of height is still poorly understood. We carried out a genome-wide scan in 12,611 participants, followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with GW-significant association with height. Of these, two are entirely novel (rs11809207 in CATSPER4, combined P-value = 6.1×10−8 and rs910316 in TMED10, P-value = 1.4×10−7) and two had previously been described with weak statistical support (rs10472828 in NPR3, P-value = 3×10−7 and rs849141 in JAZF1, P-value = 3.2×10−11). One locus (rs1182188 at GNA12) identifies the first height eQTL. We also assessed the contribution of height loci to the upper- (trunk) and lower-body (hip axis and femur) skeletal components of height. We find evidence for several loci associated with trunk length (including rs6570507 in GPR126, P-value = 4×10−5 and rs6817306 in LCORL, P-value = 4×10−4), hip axis length (including rs6830062 at LCORL, P-value = 4.8×10−4 and rs4911494 at UQCC, P-value = 1.9×10−4), and femur length (including rs710841 at PRKG2, P-value = 2.4×10−5 and rs10946808 at HIST1H1D, P-value = 6.4×10−6). Finally, we used conditional analyses to explore a possible differential contribution of the height loci to these different skeletal size measurements. In addition to validating four novel loci controlling adult stature, our study represents the first effort to assess the contribution of genetic loci to three skeletal components of height. Further statistical tests in larger numbers of individuals will be required to verify if the height loci affect height preferentially through these subcomponents of height., Author Summary The first genetic association studies of adult height have confirmed a role of many common variants in influencing human height, but to date, the genetic basis of differences between different skeletal components of height have not been addressed. Here, we take advantage of recent technical and methodological advances to examine the role of common genetic variants on both height and skeletal components of height. By examining nearly 20,000 individuals from the UK and the Netherlands, we provide statistically significant evidence that 17 genomic regions are associated with height, including four novel regions. We also examine, for the first time, the association of these 17 regions with skeletal size measurements of spine, femur, and hip axis length, a measurement of hip geometry known to influence the risk of osteoporotic fractures. We find that some height loci are also associated with these skeletal components, although further statistical tests will be required to verify if these genetic variants act differentially on the individual skeletal measurements. The knowledge generated by this and other studies will not only inform the genetics of human quantitative variation, but will also lead to the potential discovery of many medically important polymorphisms.
Published: 2009

28. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease

Author: Kimberley Dowzell, Rita Guerreiro, Peter Passmore, Brian A. Lawlor, Isabella Heuser, Frank Jessen, Patrick G. Kehoe, Britta Schürmann, Thomas W. Mühleisen, Charlene Thomas, Lutz Frölich, Steven G. Younkin, John Hardy, Johannes Kornhuber, Peter Paul De Deyn, Minerva M. Carrasquillo, Jens Wiltfang, Michael Hüll, Kristel Sleegers, Alison Goate, Michael Conlon O'Donovan, Petroula Proitsi, Carol Brayne, Markus M. Nöthen, Martin N. Rossor, Marian L. Hamshere, Peter Holmans, Sebastiaan Engelborghs, Amy Gerrish, Panagiotis Deloukas, Hugh Gurling, Denise Harold, Karolien Bettens, Amy L. Williams, Andrew McQuillin, Rhian Gwilliam, David M. A. Mann, Martin Dichgans, Magda Tsolaki, Valentina Moskvina, Wolfgang Maier, Karl-Heinz Jöckel, Gill Livingston, David C. Rubinsztein, H-Erich Wichmann, Simon Lovestone, Hendrik van den Bussche, A. David Smith, Dan Rujescu, John S. K. Kauwe, John Powell, Aoibhinn Lynch, Alexandra Stretton, Nick C. Fox, John Collinge, David Craig, Carlos Cruchaga, Paul Hollingworth, Stephen Todd, Andrew B. Singleton, Nicola L. Jones, Clive Holmes, Jaspreet Singh Pahwa, Petra Nowotny, Michelle K. Lupton, Christopher Shaw, Angharad R. Morgan, Julie Williams, Michael John Owen, Christine Van Broeckhoven, Kevin Mayo, Seth Love, Richard Abraham, Kristelle Brown, Nicholas Bass, V. Shane Pankratz, Kevin Morgan, Susanne Moebus, Ammar Al-Chalabi, Michael Gill, John C. Morris, Harald Hampel, Simon Mead, Bernadette McGuinness, Norman Klopp, Rebecca Sims, Neurology, NCA - Neurodegeneration, and Clinical sciences
Subjects: Apolipoprotein E, SORL1, Single-nucleotide polymorphism, Genome-wide association study, Biology, Monomeric Clathrin Assembly Proteins/genetics, Polymorphism, Single Nucleotide, Article, PICALM, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, PSEN2, Genetics, Chromosomes, Human, Humans, Genetic Predisposition to Disease, 030304 developmental biology, Medicine(all), Alzheimer Disease/genetics, 0303 health sciences, Genome, Human, Phosphatidylinositol binding, Odds ratio, Clusterin, Monomeric Clathrin Assembly Proteins, Human medicine, Clusterin/genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 × 10−157) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 × 10−9) and 5′ to the PICALM gene (rs3851179, P = 1.9 × 10−8). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 × 10−10, odds ratio = 0.86; rs3851179, P = 1.3 × 10−9, odds ratio = 0.86).
Published: 2009
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29. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease

Author: Andrew Keniry, Radhi Ravindrarajah, Michael Inouye, Natalie J. Prescott, Elaine R. Nimmo, Carl A. Anderson, John C. Mansfield, Mark Tremelling, Panos Deloukas, Nicholas A. Watkins, Sheila A. Fisher, Willem H. Ouwehand, Jeffrey C. Barrett, Derek P. Jewell, Hazel E. Drummond, Carlo Berzuini, Suzannah Bumpstead, Sarah E. Hunt, Lon R. Cardon, Miles Parkes, Charlie W. Lees, Fraser Cummings, Clive M. Onnie, Catherine Hanson, Alastair Forbes, Jack Satsangi, Christopher G. Mathew, Dunecan Massey, Alan J Lobo, Katarzyna Blaszczyk, M J Carter, Philip Ewels, Rhian Gwilliam, Chris Johnson, Cathryn M. Lewis, and Jeremy D. Sanderson
Subjects: Nod2 Signaling Adaptor Protein, Autophagy-Related Proteins, Genome-wide association study, Biology, Protein Serine-Threonine Kinases, Inflammatory bowel disease, Polymorphism, Single Nucleotide, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, GTP-Binding Proteins, Risk Factors, NOD2, medicine, Genetics, Humans, Genetic Predisposition to Disease, Colitis, ATG16L1, 030304 developmental biology, Homeodomain Proteins, 0303 health sciences, Crohn's disease, Extracellular Matrix Proteins, HLA-A Antigens, Interleukin-12 Subunit p40, Intracellular Signaling Peptides and Proteins, Receptors, Interleukin, medicine.disease, Ulcerative colitis, digestive system diseases, 3. Good health, Case-Control Studies, Immunology, IRGM, 030211 gastroenterology & hepatology, Colitis, Ulcerative, Carrier Proteins, Biomarkers
Abstract: We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously unknown susceptibility locus at ECM1. We also show that several risk loci are common to ulcerative colitis and Crohn's disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohn's disease. These data provide the first detailed illustration of the genetic relationship between these common inflammatory bowel diseases.
Published: 2007
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30. Molecular analysis of the VSX1 gene in familial keratoconus

Author: Petra, Liskova, Neil D, Ebenezer, Pirro G, Hysi, Rhian, Gwilliam, Mohamed F, El-Ashry, Lalitha C, Moodaley, Scott, Hau, Michael, Twa, Stephen J, Tuft, and Shomi S, Bhatacharya
Subjects: Adult, Homeodomain Proteins, Male, Aspartic Acid, Genetic Variation, Glutamic Acid, Middle Aged, Keratoconus, Polymorphism, Single Nucleotide, Article, Pedigree, Humans, Female, Eye Proteins
Abstract: To evaluate the role of the visual system homeobox gene 1 (VSX1) in the pathogenesis of familial keratoconus.Families with two or more individuals with keratoconus were recruited and their members examined. The coding region and intron-exon junctions of the VSX1 gene were sequenced in affected individuals. In cases where there were possible pathogenic changes, segregation within the pedigree was analyzed. Meta analysis of reports on an association of p.D144E change with keratoconus phenotype was performed.Probands from a panel of 85 apparently unrelated keratoconus families were included. Eleven sequence variants were observed, including the previously reported c.432CG (p.D144E) change and two novel intronic single nucleotide polymorphisms. However, these three changes did not cosegregate with the disease phenotype.We excluded the c.432CG sequence alteration as the direct cause of the disease. Lack of possibly pathogenic VSX1 sequence variants in the familial panel suggests that involvement of this gene in the pathogenesis of keratoconus is likely to be confined to a small number of pedigrees, at least in the population studied.
Published: 2007

31. A genotype calling algorithm for the Illumina BeadArray platform

Author: Yik Y. Teo, Taane G. Clark, Michael Inouye, Dominic P. Kwiatkowski, Panagiotis Deloukas, Rhian Gwilliam, and Kerrin S. Small
Subjects: Statistics and Probability, Genotype, Stability (learning theory), Biology, Polymorphism, Single Nucleotide, Biochemistry, Article, Software, Cluster Analysis, Molecular Biology, Genotyping, In Situ Hybridization, Fluorescence, Oligonucleotide Array Sequence Analysis, Training set, business.industry, Chromosome Mapping, Sequence Analysis, DNA, computer.file_format, Computer Science Applications, Computational Mathematics, ComputingMethodologies_PATTERNRECOGNITION, Computational Theory and Mathematics, Metric (mathematics), Affymetrix genechip, Executable, business, Algorithm, computer, Algorithms
Abstract: Motivation: Large-scale genotyping relies on the use of unsupervised automated calling algorithms to assign genotypes to hybridization data. A number of such calling algorithms have been recently established for the Affymetrix GeneChip genotyping technology. Here, we present a fast and accurate genotype calling algorithm for the Illumina BeadArray genotyping platforms. As the technology moves towards assaying millions of genetic polymorphisms simultaneously, there is a need for an integrated and easy-to-use software for calling genotypes. Results: We have introduced a model-based genotype calling algorithm which does not rely on having prior training data or require computationally intensive procedures. The algorithm can assign genotypes to hybridization data from thousands of individuals simultaneously and pools information across multiple individuals to improve the calling. The method can accommodate variations in hybridization intensities which result in dramatic shifts of the position of the genotype clouds by identifying the optimal coordinates to initialize the algorithm. By incorporating the process of perturbation analysis, we can obtain a quality metric measuring the stability of the assigned genotype calls. We show that this quality metric can be used to identify SNPs with low call rates and accuracy. Availability: The C++ executable for the algorithm described here is available by request from the authors. Contact: teo@well.ox.ac.uk or tgc@well.ox.ac.uk
Published: 2007

32. Posterior polymorphous corneal dystrophy in Czech families maps to chromosome 20 and excludes the VSX1 gene

Author: Shomi S. Bhattacharya, Alison J. Hardcastle, Katerina Jirsova, Neil D. Ebenezer, Catherine L. Stables, Rhian Gwilliam, Martin Filipec, Panos Deloukas, Stanislav Kmoch, Petra Liskova, and Elizabeth J. Huckle
Subjects: Genetic Markers, Male, Candidate gene, Quantitative Trait Loci, Chromosomes, Human, Pair 20, Locus (genetics), Biology, Genetic linkage, medicine, Humans, Allele, Eye Proteins, Descemet Membrane, Czech Republic, Genetics, Corneal Dystrophies, Hereditary, Homeodomain Proteins, Endothelium, Corneal, Chromosome Mapping, medicine.disease, Pedigree, Posterior polymorphous corneal dystrophy, Genetic marker, Female, Chromosome 20, Congenital hereditary endothelial dystrophy, Lod Score
Abstract: PURPOSE. Posterior polymorphous corneal dystrophy (PPCD) is an autosomal dominant disorder, affecting both the corneal endothelium and Descemet's membrane. In the Czech Republic, PPCD is one of the most prevalent corneal dystrophies. The purpose of this study was to determine the chromosomal locus of PPCD in two large Czech families, by using linkage analysis. METHODS. Linkage analysis was performed on 52 members of two Czech families with PPCD and polymorphic microsatellite markers and lod scores were calculated. The candidate gene VSX1 was also screened for mutations. RESULTS. Significant lod scores were obtained with microsatellite markers on chromosome 20. Linkage analysis delineated the Czech PPCD locus to a 2.7-cM locus on chromosome 20, region p11.2, between flanking markers D20S48 and D20S139, which excluded VSX1 as the disease-causing gene in both families. In addition, the exclusion of VSX1 was confirmed by sequence analysis. CONCLUSIONS. This study reports the localization of PPCD in patients of Czech origin to chromosome 20 at p11.2. Linkage data and sequence analysis exclude VSX1 as causative of PPCD in two Czech families. This refined locus for PPCD overlaps the congenital hereditary endothelial dystrophy (CHED1) disease interval, and it is possible that these corneal dystrophies are allelic.
Published: 2005

33. The mei3 region of the Schizosaccharomyces pombe genome

Author: Zheng Xiang, Carol Churcher, Cherryl Hunt, Barclay G. Barrell, M. Lyne, Jason Skelton, David Harris, Stephen J. Aves, Marie-Adèle Rajandream, Valerie Wood, Rhian Gwilliam, and Timothy Warren
Subjects: Transposable element, BAG domain, Molecular Sequence Data, Bioengineering, Biology, Applied Microbiology and Biotechnology, Biochemistry, SH3 domain, Fungal Proteins, Open Reading Frames, Schizosaccharomyces, Genetics, ORFS, Gene, Intron, biology.organism_classification, Cosmids, Molecular biology, Open reading frame, Meiosis, Schizosaccharomyces pombe, Schizosaccharomyces pombe Proteins, Genome, Fungal, Sequence Analysis, Biotechnology
Abstract: Expression of the mei3 gene is sufficient to induce meiosis in the fission yeast Schizosaccharomyces pombe. The mei3 gene is located 0.64 Mb from the telomere of the left arm of Sz. pombe chromosome II. We have sequenced and analysed 107 kb of DNA from the mei3 genomic region. The sequence includes 14 known genes (bag1-B, csh3, dps1, gpt1, mei3, mfm3, pac1, prp31, rpl38-1, rpn3, rti1, spa1, spm1 and ubc4) and 26 other open reading frames (ORFs) longer than 100 codons: a density of one protein-coding gene per 2.7 kb. Twenty-one of the 40 ORFs (53%) have introns. In addition there is one lone Tf1 transposon long terminal repeat (LTR), tRNATrp and tRNASer genes and a 5S rRNA gene. 14 of the novel ORFs show sequence similarities which suggest functions of their products, including a coatomer α-subunit, a catechol O-methyltransferase, protein kinase, asparagine synthetase, zinc metalloprotease, acetyltransferase, phosphatidylinositol 4-kinase, inositol polyphosphate phosphatase, GTPase-activating protein, permease, pre-mRNA splicing factor, 20S proteasome component and a thioredoxin-like protein. One predicted protein has similarity to the human Cockayne syndrome protein CSA and one with human GTPase XPA binding protein XAB1. Three ORFs are likely to code for proteins because they have sequence similarity with hypothetical proteins, three encode predicted coiled-coil proteins and four are sequence orphans. The sequence is derived from cosmid clones c4664, c119 and c557 and has been submitted to the EMBL database under Accession Nos AL591302, AL022117, AL110506 and AL023634 (part). Copyright © 2002 John Wiley & Sons, Ltd.
Published: 2002

34. The physical maps for sequencing human chromosomes 1, 6, 9, 10, 13, 20 and X

Author: Nigel P. Carter, Ian Dunham, A. L. Atkinson, Jaime Hughes, M. Izmajlowicz, Richard Durbin, Mark T. Ross, Soumi Joseph, Adam Butler, G. L. Harper, Louise McDonald, Rohan Taylor, W. D. Burrill, Graeme Bethel, S. R. Prathalingam, David R. Bentley, Theologia Sarafidou, Vassos Neocleous, John Sulston, F. L. Dearden, C. M. Rice, E. C. Sotheran, Carol A. Edwards, S. M. Clegg, N. Brady, T. E. Wilmer, B. L. Hopkins, G. L. Maslen, Simon G. Gregory, Owen T. McCann, Andrew J. Mungall, M.A. Leversha, Elisabeth Dawson, K. J. Phillips, R Evans, A. A. Thorpe, C M Clee, Cordelia Langford, E. J. Huckle, Helen E. Steingruber, Carol Scott, Y. H. Ramsey, John E. Collins, Gareth R. Howell, Adam Whittaker, M. E. Earthrowl, M. H. Lehvaslaiho, Pamela Whittaker, G. Laird, J. C. Brook, D. J. Scott, K. J. Ashcroft, S. H. Williams, Georgina Warry, Nicholas K. Moschonas, D. M. Pearson, K. S. Halls, C. L. Wright, R. W. Heathcott, C. Carder, Jane L. Holden, D. C. Burford, S. A. Ranby, P. J. Howard, K. Aubin, K. M. Porter, E. Holloway, R. A. Cooper, A. J. Coffey, David Beare, J. J. Catanese, C. A. Jones, J. S. Conquer, J. Ghori, E. J. Tinsley, Lisa French, Charlotte G. Cole, P. D. Dhami, K. M. Culley, Christopher J. Gillson, Sarah E. Hunt, Rhian Gwilliam, Panagiotis Deloukas, V. Cobley, Carol Soderlund, A. Taylor, G. J. Sharp, Luc J. Smink, S. Hammond, Andrew Dunham, L. J. Rogers, D. Mistry, Richard Wooster, P. J. De Jong, Jane Rogers, P. J. Hunt, L D Green, C. J. Shaw-Smith, Jennifer McDowall, C. Burrows, and Sean Humphray
Subjects: Genetics, Multidisciplinary, X Chromosome, Contig, Gene map, Chromosomes, Human, Pair 13, Chromosomes, Human, Pair 10, Genome, Human, Chromosomes, Human, Pair 20, food and beverages, Chromosome, Computational biology, Biology, Genome, Contig Mapping, Gene mapping, Chromosomes, Human, Pair 1, Humans, Chromosomes, Human, Pair 6, X chromosome, Genomic organization
Abstract: We constructed maps for eight chromosomes (1, 6, 9, 10, 13, 20, X and (previously) 22), representing one-third of the genome, by building landmark maps, isolating bacterial clones and assembling contigs. By this approach, we could establish the long-range organization of the maps early in the project, and all contig extension, gap closure and problem-solving was simplified by containment within local regions. The maps currently represent more than 94% of the euchromatic (gene-containing) regions of these chromosomes in 176 contigs, and contain 96% of the chromosome-specific markers in the human gene map. By measuring the remaining gaps, we can assess chromosome length and coverage in sequenced clones.
Published: 2001

35. The complete nucleotide sequence of chromosome 3 of Plasmodium falciparum

Author: K. Oliver, D. Brown, Sharon Moule, Jason Skelton, Sharen Bowman, Karen Mungall, J. McLean, Alister Craig, Daniel Lawson, S. Holroyd, D. Basham, S. Squares, Kay Jagels, S. Rutter, T. Hornsby, S Kyes, Paul Horrocks, Carol Churcher, Theresa Feltwell, Rob Squares, John Sulston, Lee Murphy, Robert L. Davies, Bart Barrell, N. Hamlin, S. Gentles, Rhian Gwilliam, David Harris, Tracey Chillingworth, Michael A. Quail, J. R. Woodward, Bijay Jassal, Chris I. Newbold, K. Devlin, Sally Whitehead, and Marie-Adèle Rajandream
Subjects: Genetics, Multidisciplinary, Base Sequence, Centromere, Molecular Sequence Data, Plasmodium falciparum, Protozoan Proteins, Chromosome Mapping, Sequence Analysis, DNA, Biology, DNA, Protozoan, Telomere, Chromosomes, Chromosome 17 (human), Chromosome 15, Chromosome 16, Chromosome 3, Chromosome 19, Animals, Chromosome 21, Chromosome 22, Genome, Protozoan, Chromosome 12
Abstract: Analysis of Plasmodium falciparum chromosome 3, and comparison with chromosome 2, highlights novel features of chromosome organization and gene structure. The sub-telomeric regions of chromosome 3 show a conserved order of features, including repetitive DNA sequences, members of multigene families involved in pathogenesis and antigenic variation, a number of conserved pseudogenes, and several genes of unknown function. A putative centromere has been identified that has a core region of about 2 kilobases with an extremely high (adenine + thymidine) composition and arrays of tandem repeats. We have predicted 215 protein-coding genes and two transfer RNA genes in the 1,060,106-base-pair chromosome sequence. The predicted protein-coding genes can be divided into three main classes: 52.6% are not spliced, 45.1% have a large exon with short additional 5' or 3' exons, and 2.3% have a multiple exon structure more typical of higher eukaryotes.
Published: 1999

36. Gamma-glutamyl carboxylase (GGCX) microsatellite and warfarin dosing

Author: Niclas Eriksson, David Bentley, Mia Wadelius, Panos Deloukas, Rhian Gwilliam, and Leslie Y. Chen
Subjects: Male, Severe bleeding, Genotype, medicine.drug_class, Immunology, Pharmacology, Biochemistry, Gamma-glutamyl carboxylase, Therapeutic index, Trinucleotide Repeats, Thromboembolism, medicine, Humans, Dosing, Alleles, Genome, Human, business.industry, Anticoagulant, Warfarin, Anticoagulants, Cell Biology, Hematology, Carbon-Carbon Ligases, Chromosomes, Human, Pair 2, Initial phase, Female, business, medicine.drug
Abstract: Warfarin is the most widely prescribed anticoagulant for thromboembolic therapy, despite a 20-fold interindividual difference in dose requirement and a narrow therapeutic range. Incorrect dosage, especially during the initial phase of treatment, carries a high risk of either severe bleeding or
Published: 2005
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37. Erratum: Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease

Author: A. David Smith, Nick C. Fox, Johannes Kornhuber, Carlos Cruchaga, Peter Paul De Deyn, Jens Wiltfang, Hugh Gurling, Wolfgang Maier, Clive Holmes, Bernadette McGuinness, Norman Klopp, Alison Goate, Isabella Heuser, Carol Brayne, Seth Love, Stephen Todd, Patrick G. Kehoe, Frank Jessen, John Hardy, Hendrik van den Bussche, Rita Guerreiro, Rhian Gwilliam, Julie Williams, Minerva M. Carrasquillo, Kevin Morgan, Susanne Moebus, Ammar Al-Chalabi, Michael HÃ¼ll, Paul Hollingworth, Michael John Owen, Karolien Bettens, Harald Hampel, Simon Mead, John S. K. Kauwe, Petra Nowotny, Angharad R. Morgan, Martin Dichgans, David Craig, Michelle K. Lupton, Denise Harold, Valentina Moskvina, Martin N. Rossor, V. Shane Pankratz, Lutz FrÃ¶lich, Amy L. Williams, Nicola Jones, Gill Livingston, Petroula Proitsi, John Collinge, Panagiotis Deloukas, Marian L. Hamshere, Andrew McQuillin, Kimberley Dowzell, Markus M NÃ¶then, Britta SchÃ¼rmann, Charlene Thomas, Michael Gill, David G. Mann, H-Erich Wichmann, Steven G. Younkin, John C. Morris, Reinhard Heun, Simon Lovestone, Michael OtextquotesingleDonovan, Andrew B. Singleton, Peter Passmore, Amy Gerrish, Kevin Mayo, Richard Abraham, Jaspreet Singh Pahwa, Magda Tsolaki, Dan Rujescu, Kristel Sleegers, Peter Holmans, David C. Rubinsztein, John Powell, Alexandra Stretton, Kristelle Brown, Aoibhinn Lynch, Nicholas Bass, Christine Van Broeckhoven, Sebastiaan Engelborghs, Thomas W MÃ¼hleisen, Brian A. Lawlor, Rebecca Sims, Christopher Shaw, and Karl-Heinz JÃ¶ckel
Subjects: Genetics, Medizin, Genome-wide association study, Disease, Biology, PICALM
Published: 2013
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38. Lumbar vertebral and femoral neck bone mineral density are higher in postmenopausal women with the alpha 2HS-glycoprotein 2 phenotype

Author: Rhian Gwilliam, S Murphy, Ian R. Dickson, Kay-Tee Khaw, Christopher Phillips, P. J. Lincoln, and Mary Arora
Subjects: medicine.medical_specialty, Bone density, alpha-2-HS-Glycoprotein, Osteoporosis, Lumbar vertebrae, Biochemistry, Bone remodeling, Endocrinology, Bone Density, Internal medicine, medicine, Humans, Risk factor, Femoral neck, Aged, Bone mineral, Lumbar Vertebrae, Estradiol, business.industry, Femur Neck, Blood Proteins, Middle Aged, medicine.disease, Postmenopause, medicine.anatomical_structure, Phenotype, Surgery, Female, business, Hormone
Abstract: alpha 2HS-glycoprotein (AHSG) is a plasma protein which becomes concentrated in the organic matrix of bone. The two most common alleles, AHSG*1 and AHSG*2, give rise to three common phenotypes. A recent report showed that a group of postmenopausal white North American women with different AHSG phenotypes differed significantly with respect to their oestrogen status. We have studied variations in bone mineral density, measured by DEXA, and levels of sex hormones and biochemical markers of bone metabolism in a group of 88 post-menopausal women unselected as to their health status. Lumbar vertebral and femoral neck bone mineral density (BMD), and the free oestradiol index were all significantly higher (P < 0.05) in women with the AHSG 2 phenotype. Values of these three parameters were lowest in the AHSG 1 phenotype and intermediate in the AHSG 2-1 phenotype. Because the differences in BMD between the AHSG 2 and 1 phenotypes represent at least a 40% difference in fracture risk, the AHSG phenotype may be of some clinical relevance as a risk factor for osteoporosis.
Published: 1994

39. Erratum: Corrigendum: Multiple common variants for celiac disease influencing immune gene expression

Author: Patrick Dubois, Mathieu Platteel, Kalle Kurppa, Chris J. J. Mulder, Miguel Fernández-Arquero, Alexandra Zhernakova, Jihane Romanos, Roel A. Ophoff, Szilvia Fiatal, Maria Cristina Mazzilli, Graham A. Heap, Jan H. Veldink, David A. van Heel, Veikko Salomaa, Bárbara Dema, Róza Ádány, Maria Pia Sperandeo, Cisca Wijmenga, Leena Peltonen, Bożena Cukrowska, Maria Teresa Bardella, Padraic MacMathuna, Gosia Trynka, Concepción Núñez, Joseph A. Murray, Susan L. Neuhausen, Katherine I. Morley, Joachim J. Schweizer, Roderick H. J. Houwen, Karen A. Hunt, Elvira Grandone, Elvira Oosterom, M. Luisa Mearin, Barbara Mora, Donatella Barisani, Victorien M. Wolters, Katri Kaukinen, Charles A. Mein, Nicholas A. Bockett, Dermot Kelleher, Ilma Rita Korponay-Szabó, Markku Maeki, Rhian Gwilliam, Graham Turner, Jeffrey C. Barrett, Lude Franke, Alessandra Curtotti, Sarah E. Hunt, Elena Urcelay, Emilio G. de la Concha, Rinse K. Weersma, Leonard H. van den Berg, Peter M. Green, Harry J.M. Groen, Anna Rybak, Luigi Greco, Ross McManus, Muddassar M. Mirza, Vanisha Mistry, Greetje J. Tack, Päivi Saavalainen, O. T. McCann, Isabel Polanco, Rudolf S N Fehrmann, Wieke H. M. Verbeek, Arpo Aromaa, and Panos Deloukas
Subjects: Genetics, Disease, Biology, Bioinformatics, Immune gene
Abstract: Nat. Genet.; doi:10.1038/ng.543; corrected online 12 March 2010 In the version of this article initially published online, the P value ranges in the second paragraph of the Results section under (iii) and (iv) were noted incorrectly. These errors have been corrected for the print, PDF and HTML versions of this article.
Published: 2010
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40. Erratum: Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease

Author: Michael Conlon O'Donovan, Markus M. Nöthen, D P De Deyn, Heinz Erich Wichmann, Michelle K. Lupton, Andrew McQuillin, Gill Livingston, Michael Hüll, Kauwe Jsk., Nick C. Fox, Carlos Cruchaga, Bernadette McGuinness, Norman Klopp, Sebastiaan Engelborghs, A. D. Smith, Jens Wiltfang, Panagiotis Deloukas, Richard Abraham, Karolien Bettens, Denise Harold, Martin Dichgans, Britta Schürmann, Valentina Moskvina, Frank Jessen, Amy Williams, Julie Williams, Lutz Frölich, Alison Goate, Kevin Morgan, Johannes Kornhuber, Carol Brayne, Susanne Moebus, John Hardy, J Singh Pahwa, John Collinge, M. J. Owen, Alexandra Stretton, Ammar Al-Chalabi, Aoibhinn Lynch, Seth Love, Nicola Jones, C. Van Broeckhoven, Rita Guerreiro, Kevin Mayo, Martin N. Rossor, Stephen Todd, Minerva M. Carrasquillo, Kristelle Brown, Wolfgang Maier, Karl-Heinz Jöckel, Michael Gill, Rebecca Sims, John C. Morris, Petra Nowotny, Angharad R. Morgan, Hugh Gurling, Dan Rujescu, Simon Lovestone, Peter Passmore, Peter Holmans, Harald Hampel, Steve Younkin, Simon Mead, H Van Den Bussche, Rhian Gwilliam, Petra Proitsi, AB Singleton, Kimberley Dowzell, Marian L. Hamshere, Charlene Thomas, V. Pankratz, Magda Tsolaki, David Craig, Christopher Shaw, Kristel Sleegers, Christopher Holmes, Brian A. Lawlor, N Bass, Isabella Heuser, John Powell, Patrick G. Kehoe, Amy Gerrish, D. M. A. Mann, David C. Rubinsztein, T W Mühleisen, and Paul Hollingworth
Subjects: Genetics, Genome-wide association study, Disease, Biology, PICALM
Published: 2009
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41. S1751 Copy Number Variant and Extended SNP Genome Wide Association Study in Celiac Disease

Author: Ross McManus, Cisca Wijmenga, Gosia Trynka, Patrick Dubois, Päivi Saavalainen, David A. van Heel, Panagiotis Deloukas, Lude Franke, Rhian Gwilliam, Graham A. Heap, and Karen A. Hunt
Subjects: Messenger RNA, Hepatology, medicine.medical_treatment, Gastroenterology, Biology, Molecular biology, Small hairpin RNA, Cytokine, In vivo, RNA interference, medicine, Gene silencing, human activities, Gene, Functional genomics
Abstract: Background and Aim: RNAi is a powerful biological tool whereby any specific genes of interest can be specifically targeted. However, application of RNAi for silencing genes of the GI tract has proven difficult. We recently described a bacteria-based RNAi technology (transkingdom RNAi, tkRNAi) to simultaneously produce and deliver RNAi to the GI tract (Xiang, Nat Biotech 2006, 697). The aim of this study was to examine whether tkRNAi can be used to silence the expression of IL-10, an anti-inflammatory cytokine, and induce a pro-inflammatory state In Vivo. Methods: After selection of themost powerful siRNA sequence, tkRNAi bacteria were created producing shRNA against mouse IL-10 (TRIP-sh7) and control (TRIP-scrambled). J774.A1 cells were incubated with TRIP-bearing bacteria for 2h at various MOIs, and then stimulated with LPS for 24h. IL-10 gene silencing was analyzed by quantitative RT-PCR and ELISA. To assess In Vivo gene silencing, 12 Balb/c mice were randomized into 3 groups: untreated (n=4); TRIP-sh7 (n=4); TRIP-scrambled (n=4). Following bacteria treatment for 2 weeks, colons were harvested and analyzed by qRT-PCR and IHC staining for IL-10 and γ-IFN. Results: treatment of J774.A1 cells with TRIP-sh7 reduced IL-10 mRNA and protein levels by >80% (p 70% (p < 0.05) compared to animals treated with TRIPscrambled control bacteria. IHC staining of colon tissue demonstrated a marked reduction of IL-10 protein expression in TRIP-sh7 treated mice compared to untreated or mice treated with control bacteria. Moreover, treatment with TRIP-sh7 was associated with increased colonic production of the TH1 cytokine γ-IFN. Treatment with TRIP-sh7 for two weeks was also associated with a significant loss of body weight compared to untreated or mice treated with control bacteria (p < 0.05 for both). Summary and Conclusion: bacteria expressing shRNA against IL-10 can mediate potent gene silencing in LPS-stimulated J774.A1 cells, and in colonic epithelial cells In Vivo. Furthermore colonic levels of γ-IFN were markedly increased following bacterial RNAi against IL-10. tkRNAi approach may be useful for In Vivo functional genomics studies in the GI tract, and for developing RNAi therapies for GI diseases. Since tkRNAi can be adapted to induce silencing in multiple animal species, this approach may be suited for development of animal models in rodents or non-rodent, for diseases such as IBD.
Published: 2009
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42. Investigation of Crohn's Disease Risk Loci in Ulcerative Colitis Further Defines Their Molecular Relationship

Author: Cathryn M. Lewis, Jeremy D. Sanderson, Miles Parkes, Dunecan Massey, Derek P. Jewell, Radhi Ravindrarajah, John C. Mansfield, Naomi Hammond, Elaine R. Nimmo, Panos Deloukas, Katarzyna Blaszczyk, David P. Strachan, Gregory Lewis, Heather Attlesey, Dhiraj Varma, Christopher G. Mathew, Clive M. Onnie, Jack Satsangi, Wendy L. McArdle, Mark Tremelling, Rhian Gwilliam, Alan J Lobo, Nicholas A. Watkins, Willem H. Ouwehand, Natalie J. Prescott, Jeffrey C. Barrett, Sarah E. Hunt, Catherine Hanson, Sheila A. Fisher, Jemima Jacob, Charlie W. Lees, Carl A. Anderson, and Hazel E. Drummond
Subjects: Adult, Male, STAT3 Transcription Factor, Genotype, Population, Genome-wide association study, Single-nucleotide polymorphism, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Inflammatory bowel disease, Crohn Disease, Risk Factors, medicine, Humans, Genetic Predisposition to Disease, education, CDKAL1, Genetics, Extracellular Matrix Proteins, tRNA Methyltransferases, education.field_of_study, Crohn's disease, Hepatology, Gastroenterology, Cyclin-Dependent Kinase 5, Janus Kinase 2, medicine.disease, TRNA Methyltransferases, Case-Control Studies, Immunology, Colitis, Ulcerative, Female
Abstract: Background & Aims: Identifying shared and disease-specific susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC) would help define the biologic relationship between the inflammatory bowel diseases. More than 30 CD susceptibility loci have been identified. These represent important candidate susceptibility loci for UC. Loci discovered by the index genome scans in CD have previously been tested for association with UC, but those identified in the recent meta-analysis await such investigation. Furthermore, the recently identified UC locus at ECM1 requires formal testing for association with CD. Methods: We analyzed 45 single nucleotide polymorphisms, tagging 29 of the loci recently associated with CD in 2527 UC cases and 4070 population controls. We also genotyped the UC-associated ECM1 variant rs11205387 in 1560 CD patients and 3028 controls. Results: Nine regions showed association with UC at a threshold corrected for the 29 loci tested (P < .0017). The strongest association (P = 4.13 x 10(-8); odds ratio = 1.27) was identified with a 170-kilobase region on chromosome 1q32 that contains 3 genes. We also found association with JAK2 and replicated a recently reported association with STAT3, further implicating the role of this signaling pathway in inflammatory bowel disease. Additional novel UC susceptibility genes were LYRM4 and CDKAL1. Twenty of the loci were not associated with UC, and several appear to be specific to CD. ECM1 variation was not associated with CD. Conclusions: Collectively, these data help define the genetic relationship between CD and UC and characterize common, as well as disease-specific mechanisms of pathogenesis.
Published: 2009
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43. Observational study on variability between biobanks in the estimation of DNA concentration

Author: Jay Brown, Päivi Laiho, Rhian Gwilliam, Gunnel Tybring, Helen Stevens, Charalampos Aslanidis, Wendy L. McArdle, K Dixon, Manuela Foedinger, H.-Erich Wichmann, Gerd Schmitz, William E R Ollier, Matthew Hardy, Dagni Krinka, Xiayi Ke, Pippa Bracegirdle, Simon Patton, David Lewis, Camilla Lagerberg, A. N. Donev, Martin Yuille, Susan M. Ring, and Thomas Illig
Subjects: Computer science, Short Report, lcsh:Medicine, Bioinformatics, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Consistency (statistics), Statistics, lcsh:Science (General), lcsh:QH301-705.5, Anecdotal evidence, Medicine(all), Estimation, 030219 obstetrics & reproductive medicine, Biochemistry, Genetics and Molecular Biology(all), lcsh:R, 0402 animal and dairy science, Dna concentration, 04 agricultural and veterinary sciences, General Medicine, 040201 dairy & animal science, Biobank, lcsh:Biology (General), Observational study, lcsh:Q1-390
Abstract: Background There is little confidence in the consistency of estimation of DNA concentrations when samples move between laboratories. Evidence on this consistency is largely anecdotal. Therefore there is a need first to measure this consistency among different laboratories and then identify and implement remedies. A pilot experiment to test logistics and provide initial data on consistency was therefore conceived. Methods DNA aliquots at nominal concentrations between 10 and 300 ng/μl were dispensed into the wells of 96-well plates by one participant - the coordinating centre. Participants estimated the concentration in each well and returned estimates to the coordinating centre. Results Considerable overall variability was observed among estimates. There were statistically significant differences between participants' measurements and between fluorescence emission and absorption spectroscopy. Conclusion Anecdotal evidence of variability in DNA concentration estimation has been substantiated. Reduction in variability between participants will require the identification of major sources of variation, specification of effective remedies and their implementation.
Published: 2009
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44. Novel mutations in theZEB1 gene identified in Czech and British patients with posterior polymorphous corneal dystrophy

Author: Neil D. Ebenezer, Katerina Jirsova, Rhian Gwilliam, Neil Sinclair, Shomi S. Bhattacharya, Marike Pretorius, Quincy Prescott, Alison J. Hardcastle, Radka Martincova, D.L. Boase, Stephen J. Tuft, Martin Filipec, Petra Liskova, Margaret J. Jeffrey, and Panos Deloukas
Subjects: Adult, Male, Adolescent, DNA Mutational Analysis, Locus (genetics), Collagen Type VIII, Biology, Article, Exon, Rare Diseases, Gene duplication, Genetics, Humans, Eye Proteins, Gene, Genetics (clinical), Aged, Czech Republic, Corneal Dystrophies, Hereditary, Homeodomain Proteins, Haplotype, Intron, Zinc Finger E-box-Binding Homeobox 1, Middle Aged, United Kingdom, Pedigree, Posterior polymorphous corneal dystrophy, Mutation, Eye disorder, Female, Transcription Factors
Abstract: We describe the search for mutations in six unrelated Czech and four unrelated British families with posterior polymorphous corneal dystrophy (PPCD); a relatively rare eye disorder. Coding exons and intron/exon boundaries of all three genes (VSX1, COL8A2, and ZEB1/TCF8) previously reported to be implicated in the pathogenesis of this disorder were screened by DNA sequencing. Four novel pathogenic mutations were identified in four families; two deletions, one nonsense, and one duplication within exon 7 in the ZEB1 gene located at 10p11.2. We also genotyped the Czech patients to test for a founder haplotype and lack of disease segregation with the 20p11.2 locus we previously described. Although a systematic clinical examination was not performed, our investigation does not support an association between ZEB1 changes and self reported non-ocular anomalies. In the remaining six families no disease causing mutations were identified thereby indicating that as yet unidentified gene(s) are likely to be responsible for PPCD.
Published: 2007
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