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1. The Genetic Links to anxiety and depression (GLAD) study: online recruitment into the largest recontactable study of depression and anxiety

Author

Nigel R. Ovington, Jennifer Leng, Christopher Hübel, R. K. Price, Sofie Ashford, Megan Hammond Bennett, Le Roy C. Dowey, Henry C. Rogers, Allan H. Young, Anthony J. Cleare, Donald M. Lyall, Eddy L.A. Suarez, Jonathan R. I. Coleman, Charles Curtis, Ian Jones, David Veale, Anna Spaul, Shivani Parikh, Katie M White, Susannah C.B. Curzons, Ioana Beange, Carmine M. Pariante, Nathalie Kingston, Megan Skelton, Jennifer G. Sambrook, Janet Wingrove, Bethany D. Mason, Daniel J. Smith, Gursharan Kalsi, Alexei Moulton, Alicia J. Peel, Yoriko Hirose, James T.R. Walters, Kimberley Goldsmith, Andrew M. McIntosh, Victor A. Gault, Elisavet Palaiologou, Dina Monssen, Katrina A. S. Davis, Carola Kanz, Anamaria Brailean, John Bradley, Monika McAtarsney-Kovacs, Cherie Armour, Bronte L. Sykes, Evangelos Vassos, Molly R. Davies, Gerome Breen, Matthew Hotopf, Keith Thomas, Katharine A. Rimes, and Thalia C. Eley

Subjects
Male, 050103 clinical psychology, Anxiety, GLAD, Genetic Links to Anxiety and Depression, 0302 clinical medicine, MDD, Major depressive disorder, SURE, Service User Research Enterprise, Young adult, SOPs, standard operating procedures, Age of Onset, Program Development, Depression (differential diagnoses), Aged, 80 and over, GAD, Generalised anxiety disorder, Depression, Medical record, SLaM, South London and Maudsley, 05 social sciences, SNP, single nucleotide polymorphism, Middle Aged, 3. Good health, Psychiatry and Mental health, Clinical Psychology, Phenotype, Phobic Disorders, Psychiatric genetics, Female, medicine.symptom, Psychology, Clinical psychology, Adult, IAPT, Improving Access to Psychological Therapies, Adolescent, Genotype, Experimental and Cognitive Psychology, NHS, National Health Service, Article, Life events, 03 medical and health sciences, Young Adult, SDG 3 - Good Health and Well-being, medicine, GP, general practitioner, Humans, 0501 psychology and cognitive sciences, GWAS, genome-wide association study, Behavioural genetics, Aged, FAST-R, Feasibility and Acceptability Support Team for Researchers, PR, public relations, Internet, Patient Selection, Stressor, medicine.disease, Comorbidity, Mental health, NIHR, National Institute for Health Research, CCG, Clinical Commissioning Group, Behavior genetics, Data sharing, 030217 neurology & neurosurgery, CRN, Clinical Research Networks
Abstract

Background Anxiety and depression are common, debilitating and costly. These disorders are influenced by multiple risk factors, from genes to psychological vulnerabilities and environmental stressors, but research is hampered by a lack of sufficiently large comprehensive studies. We are recruiting 40,000 individuals with lifetime depression or anxiety and broad assessment of risks to facilitate future research. Methods The Genetic Links to Anxiety and Depression (GLAD) Study (www.gladstudy.org.uk) recruits individuals with depression or anxiety into the NIHR Mental Health BioResource. Participants invited to join the study (via media campaigns) provide demographic, environmental and genetic data, and consent for medical record linkage and recontact. Results Online recruitment was effective; 42,531 participants consented and 27,776 completed the questionnaire by end of July 2019. Participants’ questionnaire data identified very high rates of recurrent depression, severe anxiety, and comorbidity. Participants reported high rates of treatment receipt. The age profile of the sample is biased toward young adults, with higher recruitment of females and the more educated, especially at younger ages. Discussion This paper describes the study methodology and descriptive data for GLAD, which represents a large, recontactable resource that will enable future research into risks, outcomes, and treatment for anxiety and depression., Highlights • Online recruitment of 40,000 individuals with lifetime depression or anxiety. • Detailed online phenotyping combined with genetic and clinical data. • The study sample is severe, highly comorbid, with chronic psychopathology. • The study protocol enables recall of participants for future research and trials.

Published
2019

2. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease

Author

Christopher L. Bowlus, Sören Mucha, Piotr Milkiewicz, Jennifer G. Sambrook, Michael P. Manns, Peter R. Durie, Daniel J. Gaffney, Catalina Coltescu, Konstantinos N. Lazaridis, David Ellinghaus, Daniel Gotthardt, George F. Mells, Espen Melum, Joseph A. Odin, Mattias Laudes, Cisca Wijmenga, Kris V. Kowdley, Annarosa Floreani, Tejas S. Shah, Richard Sandford, Erik M. Schlicht, Kirsten Muri Boberg, Javier Gutierrez-Achury, Felix Braun, Martina Sterneck, Carl A. Anderson, Tom H. Karlsen, Andre Franke, Velimir A. Luketic, Brijesh Srivastava, Aliya Gulamhusein, Elizabeth C. Goode, Kelly Spiess, Gunnar Jacobs, Olivier Chazouillères, Wolfgang Lieb, Tobias Müller, Andreas Teufel, Trine Folseraas, Roger W. Chapman, Hanns-Ulrich Marschall, David J. Roberts, Christoph Schramm, Sun-Gou Ji, Albert Parés, Mariza de Andrade, Stefan Schreiber, Elizabeth J. Atkinson, Kimmo Kontula, Pietro Invernizzi, Simon M. Rushbrook, Luke Jostins, Carmel Moore, Naga Chalasani, Jimmy Z. Liu, Brian D. Juran, Willem H. Ouwehand, Graeme J.M. Alexander, John E. Eaton, Gideon M. Hirschfield, Natsuhiko Kumasaka, Martti Färkkilä, Annika Bergquist, Kapil B. Chopra, John Danesh, Bertus Eksteen, Tobias J. Weismüller, Rinse K. Weersma, Ulrich Beuers, Severine Vermeire, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Ji, S, Juran, B, Mucha, S, Folseraas, T, Jostins, L, Melum, E, Kumasaka, N, Atkinson, E, Schlicht, E, Liu, J, Shah, T, Gutierrez Achury, J, Boberg, K, Bergquist, A, Vermeire, S, Eksteen, B, Durie, P, Farkkila, M, Müller, T, Schramm, C, Sterneck, M, Weismüller, T, Gotthardt, D, Ellinghaus, D, Braun, F, Teufel, A, Laudes, M, Lieb, W, Jacobs, G, Beuers, U, Weersma, R, Wijmenga, C, Marschall, H, Milkiewicz, P, Pares, A, Kontula, K, Chazouillères, O, Invernizzi, P, Goode, E, Spiess, K, Moore, C, Sambrook, J, Ouwehand, W, Roberts, D, Danesh, J, Floreani, A, Gulamhusein, A, Eaton, J, Schreiber, S, Coltescu, C, Bowlus, C, Luketic, V, Odin, J, Chopra, K, Kowdley, K, Chalasani, N, Manns, M, Srivastava, B, Mells, G, Sandford, R, Alexander, G, Gaffney, D, Chapman, R, Hirschfield, G, de Andrade, M, Rushbrook, S, Franke, A, Karlsen, T, Lazaridis, K, Anderson, C, and Universitat de Barcelona

Subjects
0301 basic medicine, Genome-wide association study, VARIANTS, Bioinformatics, Gastroenterology, Inflammatory bowel disease, 0302 clinical medicine, Risk Factors, Gastroenterologia, education.field_of_study, digestive, oral, and skin physiology, REGIONS, Ulcerative colitis, Inflamació, 3. Good health, Malalties inflamatòries intestinals, ULCERATIVE-COLITIS, 030211 gastroenterology & hepatology, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Population, Cholangitis, Sclerosing, Locus (genetics), Biology, Inflammatory bowel diseases, digestive system, Polymorphism, Single Nucleotide, Article, Primary sclerosing cholangitis, 03 medical and health sciences, Internal medicine, REVEALS, Genetics, medicine, SNP, Humans, RNA, Messenger, Allele, TRANSCRIPTOME, education, METAANALYSIS, Alleles, Adaptor Proteins, Signal Transducing, Inflammation, medicine.disease, Inflammatory Bowel Diseases, digestive system diseases, 030104 developmental biology, PSORIATIC-ARTHRITIS, Colitis, Ulcerative, Genome-Wide Association Study
Abstract

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; similar to 75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (r(G)) between PSC and ulcerative colitis (UC) (r(G) = 0.29) was significantly greater than that between PSC and Crohn's disease (CD) (r(G) = 0.04) (P = 2.55 x 10(-15)). UC and CD were genetically more similar to each other (r(G) = 0.56) than either was to PSC (P

Published
2016

3. 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

4. Common genetic variants do not associate with CAD in familial hypercholesterolemia

Author

Marcel Levi, Mieke D. Trip, Nicole Soranzo, Suthesh Sivapalaratnam, Jennifer G. Sambrook, Erik P A Van Iperen, John J.P. Kastelein, S. Matthijs Boekholdt, Aeilko H. Zwinderman, Michael W.T. Tanck, Stephanie Maiwald, Willem H. Ouwehand, Jonathan Stephens, G. Kees Hovingh, Amsterdam Public Health, Epidemiology and Data Science, Graduate School, Vascular Medicine, Amsterdam Cardiovascular Sciences, Cardiology, and Other departments

Subjects
Male, Oncology, medicine.medical_specialty, Genotype, Single-nucleotide polymorphism, Locus (genetics), Coronary Artery Disease, Familial hypercholesterolemia, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Risk Assessment, Disease-Free Survival, Article, Hyperlipoproteinemia Type II, Gene Frequency, Risk Factors, Internal medicine, Genetics, medicine, Humans, SNP, Genetic Predisposition to Disease, cardiovascular diseases, Allele frequency, Genetics (clinical), Aged, Proportional Hazards Models, Proportional hazards model, Hazard ratio, DNA Helicases, Nuclear Proteins, Middle Aged, medicine.disease, Cohort, Female, Transcription Factors
Abstract

In recent years, multiple loci dispersed on the genome have been shown to be associated with coronary artery disease (CAD). We investigated whether these common genetic variants also hold value for CAD prediction in a large cohort of patients with familial hypercholesterolemia (FH). We genotyped a total of 41 single-nucleotide polymorphisms (SNPs) in 1701 FH patients, of whom 482 patients (28.3%) had at least one coronary event during an average follow up of 66 years. The association of each SNP with event-free survival time was calculated with a Cox proportional hazard model. In the cardiovascular disease risk factor adjusted analysis, the most significant SNP was rs1122608:G>T in the SMARCA4 gene near the LDL-receptor (LDLR) gene, with a hazard ratio for CAD risk of 0.74 (95% CI 0.49–0.99; P-value 0.021). However, none of the SNPs reached the Bonferroni threshold. Of all the known CAD loci analyzed, the SMARCA4 locus near the LDLR had the strongest negative association with CAD in this high-risk FH cohort. The effect is contrary to what was expected. None of the other loci showed association with CAD.

Published
2014

5. SMIM1 underlies the Vel blood group and influences red blood cell traits

Author

Dorine W. Swinkels, Heather Lloyd-Jones, Hendrik G. Stunnenberg, Graham Kiddle, Hindrik H. D. Kerstens, Gregory E. Jordan, Lonneke Haer-Wigman, Rudolf S N Fehrmann, Juha Karjalainen, Herman H W Silljé, Peter A. Smethurst, Cornelis A. Albers, Harm-Jan Westra, Hein Schepers, Jonathan Stephens, J. Poole, Willem H. Ouwehand, Mattia Frontini, Derek L. Stemple, Nicole Soranzo, Nicholas A. Watkins, Niek Verweij, Samantha Farrow, Augusto Rendon, Emile van den Akker, Vincent G. Haver, Alan Gray, C. Ellen van der Schoot, Ana Cvejic, Jennifer G. Sambrook, Myrto Kostadima, Nick Goldman, Ewa Bielczyk-Maczyńska, Botond Sipos, Malcolm Needs, Asif U. Tamuri, Aicha Ait Soussan, Lude Franke, Klaus Rieneck, Paul Bertone, Pim van der Harst, Masja de Haas, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Landsteiner Laboratory, and Clinical Haematology

Subjects
Erythrocytes, Molecular Sequence Data, Quantitative Trait Loci, Iron metabolism Pathogenesis and modulation of inflammation [IGMD 7], GENOMES, Electrophoretic Mobility Shift Assay, 030204 cardiovascular system & hematology, Biology, VARIANTS, Article, Frameshift mutation, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], 03 medical and health sciences, 0302 clinical medicine, Isoantibodies, Pregnancy, Gene expression, Genetics, medicine, Animals, Humans, Exome, Gene Regulatory Networks, Allele, Gene, Molecular Biology, Alleles, Zebrafish, 030304 developmental biology, Oligonucleotide Array Sequence Analysis, GENE-EXPRESSION, 0303 health sciences, Gene knockdown, Gene Expression Profiling, Erythrocyte Membrane, Homozygote, Membrane Proteins, Molecular biology, 3. Good health, Gene expression profiling, Red blood cell, ALIGNMENT, medicine.anatomical_structure, biology.protein, Blood Group Antigens, Female, Antibody, Biomarkers, Gene Deletion
Abstract

The blood group Vel was discovered 60 years ago(1), but the underlying gene is unknown. Individuals negative for the Vel antigen are rare and are required for the safe transfusion of patients with antibodies to Vel(2). To identify the responsible gene, we sequenced the exomes of five individuals negative for the Vel antigen and found that four were homozygous and one was heterozygous for a low-frequency 17-nucleotide frameshift deletion in the gene encoding the 78-amino-acid transmembrane protein SMIM1. A follow-up study showing that 59 of 64 Vel-negative individuals were homozygous for the same deletion and expression of the Vel antigen on SMIM1-transfected cells confirm SMIM1 as the gene underlying the Vel blood group. An expression quantitative trait locus (eQTL), the common SNP rs1175550 contributes to variable expression of the Vel antigen (P = 0.003) and influences the mean hemoglobin concentration of red blood cells (RBCs; P = 8.6 x 10(-15))(3). In vivo, zebrafish with smim1 knockdown showed a mild reduction in the number of RBCs, identifying SMIM1 as a new regulator of RBC formation. Our findings are of immediate relevance, as the homozygous presence of the deletion allows the unequivocal identification of Vel-negative blood donors.

Published
2013

6. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

Author

Elena Prigmore, Christopher Thornborough, Judith A. Goodship, Koenraad Devriendt, Matthew E. Hurles, Siddharth Banka, Hashim Abdul-Khaliq, Carmel Moore, Denise Williams, Seham Osman Omer, Soo-Mi Park, Diana Rajan, Okan Toka, Ganesh J. Swaminathan, Jeffrey C. Barrett, Martin O. Pollard, Frances A. Bu'Lock, Allan Daly, Anne-Karin Kahlert, Tessa Homfray, Shoumo Bhattacharya, Catherine Cosgrove, Irina-Gabriela Colgiu, Tarjinder Singh, Ingo Daehnert, Karen P. McCarthy, Michael Parker, Brigitte Stiller, Jeroen Breckpot, U.M.M. Bauer, Anna Wilsdon, Kay Metcalfe, Dorin Manase, Ami Ketley, David R. FitzPatrick, Bernard Thienpont, Katherine Lachlan, Jeremy F. McRae, Kirstin Hoff, Helen V. Firth, Marc Gewillig, Sabine Klaassen, Seema Mital, Alan Fryer, Jennifer G. Sambrook, Kerry Setchfield, Willem H. Ouwehand, Hans-Heiner Kramer, Michael Wright, Saeed Al Turki, Jacoba Louw, Bernard Keavney, AK Lampe, Hugh Watkins, Natalie Canham, Jamie Bentham, Riyadh M. Abu-Sulaiman, Ashok Kumar Manickara, Thomas Pickardt, Alejandro Sifrim, David J. Roberts, J. David Brook, Ruth Newbury-Ecob, John Danesh, Caroline F. Wright, Leema Robert, Marc-Phillip Hitz, Felix Berger, Piers E.F. Daubeney, Emma Hobson, Tomas W Fitzgerald, and Helen Cox

Subjects
0301 basic medicine, Proband, Male, Protein Conformation, Disease, Bioinformatics, Autoantigens, DISEASE, FAMILIES, 0302 clinical medicine, Genotype, Exome, Exome sequencing, Protein Kinase C, Sequence Deletion, Genetics & Heredity, Genetics, 11 Medical And Health Sciences, Syndrome, Deciphering Developmental Disorders Study, Penetrance, GENOTYPE, Medical genetics, Female, Life Sciences & Biomedicine, Mi-2 Nucleosome Remodeling and Deacetylase Complex, INTERVAL Study, Heart Defects, Congenital, medicine.medical_specialty, Biology, Article, 03 medical and health sciences, CDC2 Protein Kinase, Journal Article, medicine, UK10K Consortium, Humans, cardiovascular diseases, Sibling, RECURRENCE, Science & Technology, 06 Biological Sciences, FRAMEWORK, Clinical Genetics, Congenital Heart Defects, Genetics Research, 030104 developmental biology, DE-NOVO MUTATIONS, DISCOVERY, Mutation, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Congenital heart defects (CHDs) have a neonatal incidence of 0.8–1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (~2.7%)3, suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance4, 5. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations6, 7. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings8. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.

Published
2016

7. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Author

Morris J. Brown, Sanjeev S. Bhaskar, Alison J. Coffey, Suzanne Rafelt, Kirsten McLay, John Bowes, Francesca Bredin, Alastair Compston, John C. Mansfield, Elaine R. Nimmo, Kate Downes, Peter McGuffin, Neil Walker, Anthony J. Balmforth, Philip Howard, Detelina Grozeva, Helen Stevens, Kate L. Lee, Richard D. Pearson, Gerome Breen, T. Daniel Andrews, Sheila Seal, Anna Elliot, Beverley M. Shields, Andrew T. Hattersley, Sarah Edkins, Ann E. Morgan, Gil McVean, Julian Maller, Millicent A. Stone, Adam Auton, Carol Scott, Michael R. Stratton, Matthew Woodburn, John R. B. Perry, Michael Conlon O'Donovan, Nigel P. Carter, Vincent Plagnol, Stephen Sawcer, Sarah Hines, Mahim Jain, Allan H. Young, Steve Eyre, Elilan Somaskantharajah, Alexander J. Mentzer, Niall Cardin, Eleanor Howard, Inês Barroso, Stephen C. L. Gough, Toby Johnson, Deborah P M Symmons, Christopher Holmes, David St Clair, Patricia B. Munroe, Sue Shaw-Hawkins, Emma Gray, Stephen W. Scherer, Tariq Ahmad, Jaswinder Bull, Debbie Hughes, E. Russell, Timothy M. Frayling, Chris Clee, I. Nicol Ferrier, James Lee, Dominic P. Kwiatkowski, Husam Hebaishi, Anne Hinks, Simon Myers, Gareth Evans, Eleftheria Zeggini, Katarina Spanova, Michael L. Mimmack, David M. Reid, Amanda J. Bennett, Richard T. Scott, Armand Valsesia, Derek P. Jewell, Andrew P. Morris, Peter Donnelly, Mark J. Caulfield, Jake K. Byrnes, Lars Feuk, Pile Harrison, Anna F. Dominiczak, Cathryn Edwards, Andrew Dunham, Dalila Pinto, Inga Prokopenko, Ian Jones, Craig Mowat, Nigel R. Ovington, Willem H. Ouwehand, Edward Flynn, Jason D. Cooper, Louise V. Wain, Alistair Forbes, Bernadette Ebbs, Jennifer Jolley, Jonathan Marchini, Peter S. Braund, Ifejinelo Onyiah, Mark Walker, Adrian V. S. Hill, Cordelia Langford, Anne M. Phillips, George Kirov, David P. Strachan, Oliver S. Burren, Martin D. Tobin, Anthony G. Wilson, Ian N. Bruce, Hana Lango-Allen, Alistair S. Hall, Natalie J. Prescott, Charles Lee, Clare Turnbull, Cecilia M. Lindgren, John D. Isaacs, Jack Satsangi, Liz Forty, John M. C. Connell, Neelam Hassanali, Hazel E. Drummond, Matthew A. Brown, John A. Todd, Joanna M. M. Howson, Jennifer G. Sambrook, Graham A. Hitman, Michael N. Weedon, Christopher Yau, Abiodun Onipinla, Kathy Stirrups, Chris Tyler-Smith, Darshna Dudakia, G. Mark Lathrop, Katherine Gordon-Smith, Nazneen Rahman, Christopher J. Groves, William G. Newman, Kirstie Parnell, Stephen G. Ball, Tomas W Fitzgerald, Paul Gilbert, Kevin Lewis, Charlie W. Lees, Polly Gibbs, Rachel M. Freathy, Aarno Palotie, Katarzyna Blaszczyk, Matthew E. Hurles, Jonathan Stephens, Lynne J. Hocking, Nicholas A. Watkins, Christopher G. Mathew, Helen Schuilenburg, David Pernet, Eleni Giannoulatou, Kimmo Palin, Nigel W. Rayner, Donald F. Conrad, Susan M. Ring, John R. Thompson, Debbie J. Smyth, Wendy L. McArdle, B. Paul Wordsworth, David M. Evans, Dunecan Massey, Naomi Hammond, Diana Eccles, Panos Deloukas, Sian Caesar, Chris P. Barnes, Sophia Steer, Anthony Attwood, Chris Wallace, Richard Redon, Paul Burton, Anne Barton, Marcus Pembrey, Michael John Owen, Jane Worthington, Mary E. Travers, Jeremy D. Sanderson, Meeta Maisuria-Armer, Elaine K. Green, Michael A. Quail, Oliver J. Brand, Anne Farmer, Matthew J. Simmonds, Neil Robertson, Nicholas John Craddock, Zhan Su, Jan Aerts, Martin Farrall, Hazel Arbury, Damjan Vukcevic, Paul Emery, Omer Gokumen, A Hall, Wendy Thomson, Jeffrey C. Barrett, Margaret Warren-Perry, Rhian Gwilliam, Sarah E. Hunt, Samuel Robson, Paul Martin, Audrey Duncanson, Anthony Renwick, John Webster, Lisa Jones, Mark I. McCarthy, Nilesh J. Samani, Matthew Hardy, Miles Parkes, John Burton, Jayne A. Franklyn, Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Statistics [Oxford], University of Oxford, The Wellcome Trust Centre for Human Genetics [Oxford], The Wellcome Trust Case Control Consortium, Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Oxford [Oxford], and Medical Research Council (MRC)

Subjects
endocrine system diseases, [SDV]Life Sciences [q-bio], Genome-wide association study, Pilot Projects, CCL3L1, SUSCEPTIBILITY, Arthritis, Rheumatoid, Diabetes mellitus genetics, 0302 clinical medicine, Crohn Disease, Gene Frequency, DUPLICATIONS, SCHIZOPHRENIA, Disease, Copy-number variation, Oligonucleotide Array Sequence Analysis, Genetics, 0303 health sciences, Multidisciplinary, PSORIASIS, HERITABILITY, LARGE-SCALE, Nucleic Acid Hybridization, Science & Technology - Other Topics, Wellcome Trust Case Control Consortium, Quality Control, DNA Copy Number Variations, General Science & Technology, Single-nucleotide polymorphism, COPY-NUMBER VARIATION, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, MD Multidisciplinary, mental disorders, Genetic predisposition, Diabetes Mellitus, SNP, Humans, Genetic Predisposition to Disease, Allele frequency, POLYMORPHISMS, 030304 developmental biology, Genetic association, Science & Technology, MULTIDISCIPLINARY SCIENCES, DELETION, C431 Medical Genetics, Case-Control Studies, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with diseaseIRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetesalthough in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. © 2010 Macmillan Publishers Limited. All rights reserved.

Published
2016

8. Hundreds of variants clustered in genomic loci and biological pathways affect human height

Author

Vilmundur Gudnason, Robert J. Weyant, Robert C. Kaplan, Jeffrey R. O'Connell, Panos Deloukas, Barbara McKnight, Alessandro De Grandi, Gert-Jan B. van Ommen, Eric Boerwinkle, Liming Liang, Douglas F. Levinson, Richard B. Hayes, Mark I. McCarthy, Andrew P. Morris, Joel N. Hirschhorn, Jaakko Kaprio, Nilesh J. Samani, Inke R. König, Frank B. Hu, Nicholas J. Wareham, Ozren Polasek, Michael C. Turchin, Daniel F. Gudbjartsson, Wilmar Igl, Vincent Mooser, Aki S. Havulinna, Themistocles L. Assimes, Cameron D. Palmer, Lachlan J. M. Coin, Eva Albrecht, Hana Lango Allen, Inês Barroso, Eco J. C. de Geus, H.-Erich Wichmann, Michael A. Province, Sarah H. Wild, Patricia B. Munroe, Jeanette Erdmann, Mattias Lorentzon, Michael Preuss, Nelson B. Freimer, Mika Kähönen, Tushar Bhangale, Nicole L. Glazer, Markku S. Nieminen, Andrew A. Hicks, Jonathan Tyrer, Grant W. Montgomery, Ruth J. F. Loos, Shaun Purcell, Manfred Kayser, Marjo-Riitta Järvelin, Guillaume Paré, Terho Lehtimäki, Irene Pichler, Ida Surakka, Tõnu Esko, Peter Kraft, Talin Haritunians, Juha Sinisalo, Mari Nelis, Veronique Vitart, Alan R. Sanders, Alistair S. Hall, Carlos Iribarren, Mark E. Cooper, André G. Uitterlinden, Peter Kovacs, David Schlessinger, Florian Ernst, Marja-Liisa Lokki, M. Juhani Junttila, Martin Ridderstråle, Jorma Viikari, Inga Prokopenko, Christopher J. O'Donnell, Jennie Hui, Aila Rissanen, Gonçalo R. Abecasis, Jouke-Jan Hottenga, Tomi Pastinen, Kevin B. Jacobs, Jan Smit, Kristin G. Ardlie, Niina Pellikka, Neil R. Robertson, Martina Müller, John F. Peden, Mary F. Feitosa, Thomas W. Winkler, Kari Stefansson, Jianjun Liu, Jaana Laitinen, Shen Haiqing, Martin Farrall, Nilanjan Chatterjee, Eleanor Wheeler, Tamara B. Harris, Åsa Johansson, Anders Hamsten, Elizabeth K. Speliotes, Larry D. Atwood, Valgerdur Steinthorsdottir, Elin Grundberg, Nicole Soranzo, Anna-Liisa Hartikainen, Devin Absher, Cecilia M. Lindgren, Rany M. Salem, Lorena Citterio, Karol Estrada, Sven Bergmann, Tony Kwan, Thomas Meitinger, Alan F. Wright, Richard N. Bergman, Sailaja Vedantam, Kirsi H. Pietiläinen, Lina Zgaga, Anne U. Jackson, Stefan Schreiber, Ju-Hyun Park, Nicola Glorioso, Jianxin Shi, Najaf Amin, Dale R. Nyholt, Lenore J. Launer, Heribert Schunkert, Thomas Quertermous, Mari Liis Tammesoo, Dorret I. Boomsma, Harry Campbell, Albert V. Smith, Andrew R. Wood, Caroline S. Fox, Paavo Zitting, Gabrielle Boucher, Alex N. Parker, Jennifer G. Sambrook, Joyce B. J. van Meurs, Heather M. Stringham, Marjolein J. Peters, Sekar Kathiresan, Elisabeth Widen, Caroline Hayward, Tim D. Spector, Dawn M. Waterworth, Carlo Rivolta, Antti Jula, Albert Hofman, Hugh Watkins, Wendy L. McArdle, Roberto Elosua, Markku Koiranen, Paul M. Ridker, Iris M. Heid, Lee M. Kaplan, Brenda W.J.H. Penninx, Peter M. Visscher, Claes Ohlsson, Per Hall, Benjamin F. Voight, Ben A. Oostra, Anna F. Dominiczak, Martin den Heijer, Andrea Maschio, Quince Gibson, Peter P. Pramstaller, Nigel W. Rayner, Carsten Oliver Schmidt, Toby Johnson, Henrik Grönberg, M. Carola Zillikens, Alan R. Shuldiner, Cornelia M. van Duijn, Samuli Ripatti, Erik Ingelsson, John R. Thompson, Stephen J. Chanock, Johannes Kettunen, David J. Hunter, Lyle J. Palmer, Ulf Gyllensten, Jianfeng Xu, Astrid Petersmann, Johan G. Eriksson, Guillaume Lettre, Teresa Ferreira, Fredrik Wiklund, Andreas Ziegler, Andres Metspalu, Jerome I. Rotter, Suzanne Rafelt, Julius S. Ngwa, Francis S. Collins, Michael N. Weedon, Thomas Illig, Wolfgang Hoffman, Nancy L. Heard-Costa, Anke Tönjes, Daniel I. Chasman, Alice M. Arnold, Olli T. Raitakari, Anna L. Dixon, Lu Qi, Michael E. Goddard, Anneli Pouta, Mark J. Caulfield, Liesbeth Vandenput, Christian Gieger, L. Adrienne Cupples, Veikko Salomaa, Elizabeth L. Altmaier, Nicholas G. Martin, Thomas D. Kocher, Jubao Duan, David S. Siscovick, Heikki V. Huikuri, Willem H. Ouwehand, Kari E. North, Christian Hengstenberg, Jacques S. Beckmann, Constance Chen, John Perry, Ana Marušić, Olle Melander, John D. Rioux, Erika Salvi, Andrew T. Hattersley, Paul Elliott, Leif Groop, Cristen J. Willer, Manuela Uda, Gudmar Thorleifsson, Eric E. Schadt, Charles C. White, Pablo V. Gejman, Serena Sanna, Ulla Sovio, Robert W. Lawrence, Unnur Thorsteinsdottir, Ayellet V. Segrè, Daniele Cusi, G. Bragi Walters, Ken Sin Lo, Ivana Kolcic, Igor Rudan, Sonja I. Berndt, Keri L. Monda, Soumya Raychaudhuri, Jian'an Luan, Joshua C. Randall, Anthony J. Balmforth, Yurii S. Aulchenko, Peter Almgren, Karen L. Mohlke, Timothy M. Frayling, Shamika Ketkar, Thomas H. Mosley, Markus Perola, Henry Völzke, Laura Zagato, Leena Peltonen, Seppo Koskinen, Massimo Mangino, Ke Hao, Tsegaselassie Workalemahu, Lambertus A. Kiemeney, Helene Alavere, Jaakko Tuomilehto, Reedik Mägi, James F. Wilson, Ingrid B. Borecki, Zoltán Kutalik, Michael Stumvoll, Dominique J. Verlaan, Arthur W. Musk, Eero Kajantie, Jian Yang, Joshua W. Knowles, Tuomas O. Kilpeläinen, Michael Boehnke, G. Mark Lathrop, John Beilby, Fernando Rivadeneira, Gudny Eiriksdottir, Gonneke Willemsen, Andrew C. Heath, Antonella Mulas, Katja K.H. Aben, David P. Strachan, Thor Aspelund, Jing Hua Zhao, Psychiatry, NCA - Anxiety & Depression, EMGO - Mental health, Internal Medicine, Epidemiology, Intensive Care, Clinical Genetics, Genetic Identification, Medical Research Council (MRC), Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Genetics of Complex Traits, University of Exeter, Department of Epidemiology, Erasmus Medical Centre, Netherlands Genomics Initiative (NGI), Netherlands Genomics Initiative, Department of Medicine, Montreal, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Department of Biostatistics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, deCODE Genetics, deCODE genetics [Reykjavik], Divisions of Genetics and Endocrinology and Program in Genomics, Boston Children's Hospital, Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Institut de Génomique d'Evry (IG), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, the Genetic Investigation of ANthropocentric Traits (GIANT) Consortium, Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
Netherlands Twin Register (NTR), Multifactorial Inheritance, [SDV]Life Sciences [q-bio], Genome-wide association study, Aetiology, screening and detection [ONCOL 5], 0302 clinical medicine, POPULATION, SNPS, Genetics, 0303 health sciences, Multidisciplinary, HERITABILITY, COMMON VARIANTS, Phenotype, DISEASES, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Science & Technology - Other Topics, GROWTH, Allelic heterogeneity, Chromosomes, Human, Pair 3, Metabolic Networks and Pathways, TRAITS, Common disease-common variant, General Science & Technology, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, SDG 3 - Good Health and Well-being, ADULT, STRATIFICATION, MD Multidisciplinary, Humans, Genetic Predisposition to Disease, Genetic variability, 030304 developmental biology, Science & Technology, MULTIDISCIPLINARY SCIENCES, Genome, Human, Hormonal regulation [IGMD 6], Body Height, Genetic architecture, wide association analysis common variants heritability population adult stratification diseases traits growth snps, WIDE ASSOCIATION ANALYSIS, Genetic Loci, Evaluation of complex medical interventions [NCEBP 2], Polygene, Expression quantitative trait loci, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits1, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait2,3. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways ( P=0.016) and that underlie skeletal growth defects ( P

Published
2010

9. Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium

Author

Jerome I. Rotter, Abbas Dehghan, Gang Zheng, Willem H. Ouwehand, Caroline S. Fox, Jack M. Guralnik, Tamara B. Harris, Toshiko Tanaka, Andrew E. Jaffe, Albert Hofman, Andrew B. Singleton, Jing-Ping Lin, Joshua C. Bis, Santhi K. Ganesh, Christian Gieger, Christa Meisinger, Jaap Jan Zwaginga, Mary Cushman, Matthias Nauck, Aravinda Chakravarti, Gudny Eiriksdottir, Daniel Levy, Kenneth Rice, Swee Lay Thein, Augusto Rendon, Vilmundur Gudnason, Luigi Ferrucci, Frank J. A. van Rooij, Jennifer G. Sambrook, Andreas Greinacher, Dena G. Hernandez, Jacqueline C.M. Witteman, Lenore J. Launer, Qiong Yang, Thor Aspelund, Panos Deloukas, Eric Boerwinkle, Ben A. Oostra, Germaine C. Verwoert, Cornelia M. van Duijn, Albert V. Smith, Thomas Lumley, Anna Köttgen, Nicole L. Glazer, André G. Uitterlinden, Janine M. Vangils, Ming-Huei Chen, Georg Ehret, Janine F. Felix, Mike A. Nalls, Kushang V. Patel, Alexander Teumer, L. Adrienne Cupples, Susan L. Furth, Christopher J. O'Donnell, Josef Coresh, Tim D. Spector, Brigitte Kühnel, Stefania Bandinelli, Neil A. Zakai, Nicole Soranzo, Bruce M. Psaty, Ehret, Georg Benedikt, Epidemiology, Internal Medicine, and Clinical Genetics

Subjects
Quantitative Trait Loci, Gene Expression, Mean corpuscular hemoglobin, Genome-wide association study, Endothelial Cells/metabolism, Biology, Quantitative trait locus, Hematocrit, Polymorphism, Single Nucleotide, Article, Cell Line, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Genome-Wide Association Study, Erythrocytes/metabolism, Mean corpuscular volume, 030304 developmental biology, Genetic association, ddc:616, 0303 health sciences, medicine.diagnostic_test, Mean corpuscular hemoglobin concentration, Genome, Human, 3. Good health, Blood Pressure/*genetics, Phenotype, 030220 oncology & carcinogenesis, Hypertension/*genetics, Hemoglobin
Abstract

Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.

Published
2009

10. The LRC haplotype project: a resource for killer immunoglobulin-like receptor-linked association studies

Author

Jennifer G. Sambrook, Rosemary Ward, Jen Harrow, Sarah Sims, Sophie Palmer, Jane Rogers, James A. Traherne, Harminder Sehra, Stephan Beck, Penny Coggill, Mary Carrington, John Trowsdale, Roger Horton, and Marcos Mateo Miretti

Subjects
Genetic Research, Receptor complex, Immunology, Human leukocyte antigen, Major histocompatibility complex, Biochemistry, Article, Receptors, KIR, Databases, Genetic, Genetic variation, Genetics, Humans, Immunology and Allergy, Receptors, Immunologic, Gene, Genetic association, Internet, biology, Haplotype, Chromosome Mapping, Genetic Variation, General Medicine, Haplotypes, biology.protein, Epistasis
Abstract

There is increasing evidence for epistatic interactions between gene products (e.g. KIR) encoded within the Leukocyte Receptor Complex (LRC) with those (e.g. HLA) of the Major Histocompatibility Complex (MHC), resulting in susceptibility to disease. Identification of such associations at the DNA level requires comprehensive knowledge of the genetic variation and haplotype structure of the underlying loci. The LRC haplotype project aims to provide this knowledge by sequencing common LRC haplotypes.

Published
2006

11. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture

Author

Zhaoming Wang, André Scherag, James F. Wilson, Nancy L. Heard-Costa, Ingrid B. Borecki, Sang Hong Lee, Veronique Vitart, Zoltán Kutalik, Jeffrey R. O'Connell, Mieke D. Trip, Lu Qi, Peter Vollenweider, Jennifer L. Bragg-Gresham, Davide Gentilini, Kees Hovingh, Lynda M. Rose, Carolin Pütter, Martin Farrall, Albert V. Smith, Nicholas G. Martin, Tõnu Esko, David J. Hunter, Georg Homuth, Liming Liang, Yudi Pawitan, Winfried März, George Dedoussis, Irene Mateo Leach, Nicholas J. Wareham, Lars Lind, Thomas Illig, Andrew P. Morris, Daniele Cusi, Jouke-Jan Hottenga, Tove Fall, Themistocles L. Assimes, Massimo Mangino, Dmitry Shungin, Kari Stefansson, Anne U. Jackson, Inês Barroso, Sarah E. Medland, Lude Franke, Karen L. Mohlke, Folkert W. Asselbergs, Sarah E. Hunt, Gudmar Thorleifsson, Pablo V. Gejman, Serena Sanna, Mark I. McCarthy, David M. Evans, Joel N. Hirschhorn, Alan F. Wright, Sarah H. Wild, Patricia B. Munroe, Marcel Bruinenberg, Gonneke Willemsen, Ulf de Faire, Markku Laakso, Marja-Liisa Lokki, Andrew C. Heath, Jing Hua Zhao, Lavinia Paternoster, Jana V. van Vliet-Ostaptchouk, Sailaja Vedantam, Danyu Lin, Eric E. Schadt, Stefano Signorini, Harald Grallert, Tsegaselassie Workalemahu, Jonathan Tyrer, Albert Hofman, George Nicholson, Patrik K. E. Magnusson, Arthur W. Musk, Jian Yang, Vilmundur Gudnason, Robert C. Kaplan, Panos Deloukas, Nilesh J. Samani, Inke R. König, Frank B. Hu, Paul M. Ridker, Tamara B. Harris, Bruce H. R. Wolffenbuttel, Ellen A. Nohr, Sarah Edkins, Lambertus A. Kiemeney, Anke Hinney, Eric Boerwinkle, Klaus Stark, Ben A. Oostra, Barbara Thorand, Unnur Thorsteinsdottir, Meena Kumari, Evelin Mihailov, Caroline S. Fox, Michael Boehnke, Aroon D. Hingorani, Jonathan Stephens, Kathleen Stirrups, Inga Prokopenko, Anke Tönjes, Lili Milani, John Beilby, Carlos Iribarren, Kari E. North, Cécile Lecoeur, So-Youn Shin, Marjo-Riitta Järvelin, Matti Uusitupa, Åsa Johansson, Nancy L. Pedersen, Krista Fischer, Fernando Rivadeneira, Wolfgang Koenig, Fredrik Karpe, Antti Jula, Lindsay L. Waite, Gérard Waeber, Mustafa Atalay, Heribert Schunkert, Narisu Narisu, Sita H. Vermeulen, Bernhard R. Winkelmann, Guo Li, Anders Hamsten, Elizabeth K. Speliotes, Ivonne Jarick, Sirkka Keinänen-Kiukaanniemi, L. Adrienne Cupples, Ruth J. F. Loos, Martina Müller-Nurasyid, David-Alexandre Trégouët, Claudia Langenberg, Willem H. Ouwehand, Julius S. Ngwa, Jennifer E. Huffman, H-Erich Wichmann, Amy J. Swift, Marco M Ferrario, Leif Groop, Henrik Grönberg, Peter M. Visscher, Claes Ohlsson, Markku S. Nieminen, Aparna Radhakrishnan, Harold Snieder, Devin Absher, Albertine J. Oldehinkel, Erik Ingelsson, Anna Maria Di Blasio, M. Carola Zillikens, Veikko Salomaa, Colin N. A. Palmer, Lori L. Bonnycastle, Teresa Ferreira, Ronald P. Stolk, Annette Peters, Philippe Froguel, Michael Stumvoll, David Schlessinger, Maria Dimitriou, Timo Saaristo, Cristen J. Willer, Jarmo Virtamo, Jorma Viikari, Alena Stančáková, Mika Kivimäki, Paolo Brambilla, Jaakko Tuomilehto, Dorret I. Boomsma, Harry Campbell, Jianjun Liu, Daniel I. Chasman, Gonçalo R. Abecasis, Ilja M. Nolte, Karl-Heinz Jöckel, Reedik Mägi, Pamela A. F. Madden, Jaana Laitinen, Sonja I. Berndt, Frank Kee, Marcus E. Kleber, Jacqueline C.M. Witteman, Jouko Saramies, Francis S. Collins, Johan G. Eriksson, Melanie M. van der Klauw, Yi-Juan Hu, John F. Peden, Markus Perola, Henri Wallaschofski, Jean Ferrières, Elena Tremoli, Marjolein J. Peters, Olli T. Raitakari, Claudia Lamina, Sekar Kathiresan, Mary F. Feitosa, Diana Kuh, Tim D. Spector, Paul W. Franks, Gerjan Navis, Martin den Heijer, Christian Gieger, Kevin B. Jacobs, Andrea Ganna, Timothy M. Frayling, Iris M. Heid, Bernhard O. Boehm, Eleanor Wheeler, Sonali Pechlivanis, Miriam F. Moffatt, Brenda W.J.H. Penninx, Anna-Liisa Hartikainen, Augusto Rendon, Stefan Schreiber, Stephen J. Chanock, Andrew R. Wood, Jianxin Shi, Najaf Amin, Lenore J. Launer, Michael A. Province, Jeanette Erdmann, Mattias Lorentzon, Hugh Watkins, Johanna Kuusisto, John-Olov Jansson, David P. Strachan, Anne E. Justice, Toby Johnson, Cornelia M. van Duijn, Niina Eklund, Samuli Ripatti, Aarno Palotie, Aldi T. Kraja, Michael Preuss, Rona J. Strawbridge, Ozren Polasek, Elisabeth Widen, Barbara McKnight, Mariano Dei, Vincent Mooser, Josine L. Min, Caroline Hayward, Mika Kähönen, Peter P. Pramstaller, Femmie de Vegt, Rainer Rauramaa, Douglas F. Levinson, Diana Marek, Antonio Liuzzi, Stefan Gustafsson, Andrew A. Hicks, Gemma Cadby, Damien C. Croteau-Chonka, Mark J. Caulfield, Boris Skrobek, Lyle J. Palmer, Alexander Teumer, Ken K. Ong, Ulf Gyllensten, Anneli Pouta, Anuj Goel, Eva Albrecht, Kristian Hveem, Inger Njølstad, David Meyre, Ida Surakka, Francesca Frau, Paolo Manunta, Sabine Schipf, Carolina Medina-Gomez, Kay-Tee Khaw, Alan R. Sanders, Thorkild I. A. Sørensen, André G. Uitterlinden, Alistair S. Hall, Felix R. Day, Karol Estrada, Jennifer G. Sambrook, Eirini V. Theodoraki, Valgerdur Steinthorsdottir, Cecilia M. Lindgren, Talin Haritunian, Benjamin M. Neale, Juha Sinisalo, Kati Kristiansson, Thomas W. Winkler, Pim van der Harst, Peter S. Chines, Joyce B. J. van Meurs, Wendy L. McArdle, Andrew Wong, Grant W. Montgomery, Terho Lehtimäki, Igor Rudan, Keri L. Monda, John M. C. Connell, Jian'an Luan, Per Hall, Joshua C. Randall, Anthony J. Balmforth, Chris Power, Philippe Amouyel, Andres Metspalu, Johannes Hebebrand, Andrew D. Morris, Jaana Lindström, Liesbeth Vandenput, William O.C.M. Cookson, Hanneke Basart, Stavroula Kanoni, Elina Hyppönen, Christian Hengstenberg, Thomas W. Mühleisen, Kari Kuulasmaa, Timo A. Lakka, Nicole Soranzo, Bruce M. Psaty, Antony P. Attwood, Epidemiology, Clinical Genetics, Surgery, Erasmus School of Social and Behavioural Sciences, Public Health, Internal Medicine, Immunology, Child and Adolescent Psychiatry / Psychology, Internal medicine, Psychiatry, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Lifestyle, overweight and diabetes, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Other departments, Vascular Medicine, Biological Psychology, Cognitive Psychology, AIMMS, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Berndt, S, Gustafsson, S, Mägi, R, Ganna, A, Wheeler, E, Feitosa, M, Justice, A, Monda, K, Croteau Chonka, D, Day, F, Esko, T, Fall, T, Ferreira, T, Gentilini, D, Jackson, A, Luan, J, Randall, J, Vedantam, S, Willer, C, Winkler, T, Wood, A, Workalemahu, T, Hu, Y, Lee, S, Liang, L, Lin, D, Min, J, Neale, B, Thorleifsson, G, Yang, J, Albrecht, E, Amin, N, Bragg Gresham, J, Cadby, G, den Heijer, M, Eklund, N, Fischer, K, Goel, A, Hottenga, J, Huffman, J, Jarick, I, Johansson, Å, Johnson, T, Kanoni, S, Kleber, M, König, I, Kristiansson, K, Kutalik, Z, Lamina, C, Lecoeur, C, Li, G, Mangino, M, Mcardle, W, Medina Gomez, C, Müller Nurasyid, M, Ngwa, J, Nolte, I, Paternoster, L, Pechlivanis, S, Perola, M, Peters, M, Preuss, M, Rose, L, Shi, J, Shungin, D, Smith, A, Strawbridge, R, Surakka, I, Teumer, A, Trip, M, Tyrer, J, Van Vliet Ostaptchouk, J, Vandenput, L, Waite, L, Zhao, J, Absher, D, Asselbergs, F, Atalay, M, Attwood, A, Balmforth, A, Basart, H, Beilby, J, Bonnycastle, L, Brambilla, P, Bruinenberg, M, Campbell, H, Chasman, D, Chines, P, Collins, F, Connell, J, Cookson, W, De, F, U, D, Vegt, F, Dei, M, Dimitriou, M, Edkins, S, Estrada, K, Evans, D, Farrall, M, Ferrario, M, Ferrières, J, Franke, L, Frau, F, Gejman, P, Grallert, H, Grönberg, H, Gudnason, V, Hall, A, Hall, P, Hartikainen, A, Hayward, C, Heard Costa, N, Heath, A, Hebebrand, J, Homuth, G, Hu, F, Hunt, S, Hyppönen, E, Iribarren, C, Jacobs, K, Jansson, J, Jula, A, Kähönen, M, Kathiresan, S, Kee, F, Khaw, K, Kivimäki, M, Koenig, W, Kraja, A, Kumari, M, Kuulasmaa, K, Kuusisto, J, Laitinen, J, Lakka, T, Langenberg, C, Launer, L, Lind, L, Lindström, J, Liu, J, Liuzzi, A, Lokki, M, Lorentzon, M, Madden, P, Magnusson, P, Manunta, P, Marek, D, März, W, Mateo Leach, I, Mcknight, B, Medland, S, Mihailov, E, Milani, L, Montgomery, G, Mooser, V, Mühleisen, T, Munroe, P, Musk, A, Narisu, N, Navis, G, Nicholson, G, Nohr, E, Ong, K, Oostra, B, Palmer, C, Palotie, A, Peden, J, Pedersen, N, Peters, A, Polasek, O, Pouta, A, Pramstaller, P, Prokopenko, I, Pütter, C, Radhakrishnan, A, Raitakari, O, Rendon, A, Rivadeneira, F, Rudan, I, Saaristo, T, Sambrook, J, Sanders, A, Sanna, S, Saramies, J, Schipf, S, Schreiber, S, Schunkert, H, Shin, S, Signorini, S, Sinisalo, J, Skrobek, B, Soranzo, N, Stančáková, A, Stark, K, Stephens, J, Stirrups, K, Stolk, R, Stumvoll, M, Swift, A, Theodoraki, E, Thorand, B, Tregouet, D, Tremoli, E, Van der Klauw, M, van Meurs, J, Vermeulen, S, Viikari, J, Virtamo, J, Vitart, V, Waeber, G, Wang, Z, Widén, E, Wild, S, Willemsen, G, Winkelmann, B, Witteman, J, Wolffenbuttel, B, Wong, A, Wright, A, Zillikens, M, Amouyel, P, Boehm, B, Boerwinkle, E, Boomsma, D, Caulfield, M, Chanock, S, Cupples, L, Cusi, D, Dedoussis, G, Erdmann, J, Eriksson, J, Franks, P, Froguel, P, Gieger, C, Gyllensten, U, Hamsten, A, Harris, T, Hengstenberg, C, Hicks, A, Hingorani, A, Hinney, A, Hofman, A, Hovingh, K, Hveem, K, Illig, T, Jarvelin, M, Jöckel, K, Keinanen Kiukaanniemi, S, Kiemeney, L, Kuh, D, Laakso, M, Lehtimäki, T, Levinson, D, Martin, N, Metspalu, A, Morris, A, Nieminen, M, Njølstad, I, Ohlsson, C, Oldehinkel, A, Ouwehand, W, Palmer, L, Penninx, B, Power, C, Province, M, Psaty, B, Qi, L, Rauramaa, R, Ridker, P, Ripatti, S, Salomaa, V, Samani, N, Snieder, H, Sørensen, T, Spector, T, Stefansson, K, Tönjes, A, Tuomilehto, J, Uitterlinden, A, Uusitupa, M, van der Harst, P, Vollenweider, P, Wallaschofski, H, Wareham, N, Watkins, H, Wichmann, H, Wilson, J, Abecasis, G, Assimes, T, Barroso, I, Boehnke, M, Borecki, I, Deloukas, P, Fox, C, Frayling, T, Groop, L, Haritunian, T, Heid, I, Hunter, D, Kaplan, R, Karpe, F, Moffatt, M, Mohlke, K, O'Connell, J, Pawitan, Y, Schadt, E, Schlessinger, D, Steinthorsdottir, V, Strachan, D, Thorsteinsdottir, U, Van, D, Cm, Visscher, P, Di Blasio, A, Hirschhorn, J, Lindgren, C, Meyre, D, Scherag, A, Mccarthy, M, Speliotes, E, North, K, Loos, R, Ingelsson, E, Life Course Epidemiology (LCE), Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Cardiovascular Centre (CVC), Medical Research Council (MRC), Berndt, Sonja I, Gustafsson, Stefan, Mägi, Reedik, Ganna, Andrea, Lee, Sang Hong, Hyppönen, Elina Tuulikki, Ingelsson, Erik, Berndt, Si, Feitosa, Mf, Justice, Ae, Monda, Kl, CROTEAU CHONKA, Dc, Day, Fr, Jackson, Au, Randall, Jc, Willer, Cj, Winkler, Tw, Wood, Ar, Hu, Yj, Lee, Sh, Lin, Dy, Min, Jl, Neale, Bm, BRAGG GRESHAM, Jl, DEN HEIJER, M, Hottenga, Jj, Huffman, Je, Johansson, A, Kleber, Me, König, Ir, Mcardle, Wl, MEDINA GOMEZ, C, MÜLLER NURASYID, M, Nolte, Im, Peters, Mj, Rose, Lm, Smith, Av, Strawbridge, Rj, Trip, Md, VAN VLIET OSTAPTCHOUK, Jv, Waite, Ll, Zhao, Jh, Asselbergs, Fw, Attwood, Ap, Balmforth, Aj, Bonnycastle, Ll, Chasman, Di, Connell, Jm, Cookson, Wo, DE FAIRE, U, DE VEGT, F, Evans, Dm, Ferrario, Mm, Gejman, Pv, Hartikainen, Al, HEARD COSTA, Nl, Heath, Ac, Hu, Fb, Hunt, Se, Jacobs, Kb, Jansson, Jo, Khaw, Kt, Kraja, At, Laitinen, Jh, Lakka, Ta, Launer, Lj, Lokki, Ml, Madden, Pa, Magnusson, Pk, Manunta, Paolo, MATEO LEACH, I, Medland, Se, Montgomery, Gw, Mühleisen, Tw, Munroe, Pb, Musk, Aw, Nohr, Ea, Ong, Kk, Oostra, Ba, Palmer, Cn, Peden, Jf, Pramstaller, Pp, Saaristo, Te, Sambrook, Jg, Sanders, Ar, Shin, Sy, Stephens, Jc, Stolk, Rp, Swift, Aj, Theodoraki, Ev, Tregouet, Da, VAN DER KLAUW, Mm, VAN MEURS, Jb, Vermeulen, Sh, Wild, Sh, Winkelmann, Br, Witteman, Jc, Wolffenbuttel, Bh, Wright, Af, Zillikens, Mc, Boehm, Bo, Boomsma, Di, Caulfield, Mj, Chanock, Sj, Cupples, La, Dedoussis, Gv, Eriksson, Jg, Franks, Pw, Harris, Tb, Hicks, Aa, Hovingh, Kg, Jarvelin, Mr, Jöckel, Kh, KEINANEN KIUKAANNIEMI, Sm, Kiemeney, La, Levinson, Df, Martin, Ng, Morris, Ad, Oldehinkel, Aj, Ouwehand, Wh, Palmer, Lj, Province, Ma, Psaty, Bm, Ridker, Pm, Samani, Nj, Sørensen, Ti, Spector, Td, Uitterlinden, Ag, VAN DER HARST, P, Wareham, Nj, Wichmann, He, Wilson, Jf, Abecasis, Gr, Assimes, Tl, Borecki, Ib, Groop, Lc, Heid, Im, Kaplan, Rc, Moffatt, Mf, Mohlke, Kl, O'Connell, Jr, Schadt, Ee, Strachan, Dp, VAN DUIJN, Cm, Visscher, Pm, DI BLASIO, Am, Hirschhorn, Jn, Lindgren, Cm, Morris, Ap, Mccarthy, Mi, Speliotes, Ek, North, Ke, Loos, Rj, and Ingelsson, E.

Subjects
Netherlands Twin Register (NTR), Linkage disequilibrium, SORTILIN, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Medizin, Genome-wide association study, Aetiology, screening and detection [ONCOL 5], polymorphism, Body Mass Index, 0302 clinical medicine, Missing heritability problem, MISSING HERITABILITY, EXTREME OBESITY, CONFER RISK, POPULATION, Genetics & Heredity, 2. Zero hunger, Genetics, Medical And Health Sciences, 0303 health sciences, education.field_of_study, Anthropometry, COMMON VARIANTS, Single Nucleotide, ASSOCIATION, Biological Sciences, Anthropometry, Body Height, genetics, Body Mass Index, Case-Control Studies, European Continental Ancestry Group, genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Obesity, genetics, Phenotype, Polymorphism, genetics, Quantitative Trait Loci, Waist-Hip Ratio, Phenotype, Life Sciences & Biomedicine, EXPRESSION, Genotype, Missing heritabillity, Population, European Continental Ancestry Group, Quantitative Trait Loci, EARLY-ONSET, Genomics, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, White People, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Meta-Analysis as Topic, SDG 3 - Good Health and Well-being, Humans, Genetic Predisposition to Disease, Obesity, body height/genetics, Polymorphism, Allele, Genetik, education, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], 030304 developmental biology, Science & Technology, Waist-Hip Ratio, BMI, height, WHR, obesity, GWS, ta3121, Genetic architecture, Body Height, BODY-MASS INDEX, Case-Control Studies, gene, stature, height, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups. © 2013 Nature America, Inc. All rights reserved.

Published
2013

12. Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome

Author

K Smith, Chantal Thys, Najet Debili, Paul Bertone, Paquita Nurden, Gabriele Strauss, Kathleen Freson, Rémi Favier, Jennifer Jolley, Cornelis A. Albers, Jennifer G. Sambrook, Dirk S. Paul, Myrto Kostadima, Ingrid P.C. Krapels, Matthew E. Hurles, Graham Kiddle, Derek L. Stemple, Jonathan Stephens, Catherine M. Hobbs, Ana Cvejic, Janine Fiedler, Willem H. Ouwehand, Christel Van Geet, Cedric Ghevaert, Claudia A. L. Ruivenkamp, Panos Deloukas, Martijn H. Breuning, Ni Huang, Ruth Newbury-Ecob, Peter A. Smethurst, Harald Schulze, MUMC+: DA KG Polikliniek (9), Genetica & Celbiologie, and RS: GROW - School for Oncology and Reproduction

Subjects
Adult, Male, Adolescent, Protein subunit, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, Frameshift mutation, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], Young Adult, 03 medical and health sciences, 0302 clinical medicine, Transcription (biology), Genetics, medicine, Animals, Congenital Bone Marrow Failure Syndromes, Humans, Genetic Predisposition to Disease, Amino Acid Sequence, Upper Extremity Deformities, Congenital, Child, Zebrafish, 030304 developmental biology, 0303 health sciences, Base Sequence, Platelet Count, TAR syndrome, Infant, Newborn, Genetic Variation, Infant, RNA-Binding Proteins, Sequence Analysis, DNA, medicine.disease, Thrombocytopenia, Molecular biology, Null allele, Radius, Regulatory sequence, Child, Preschool, 030220 oncology & carcinogenesis, Mutation, Exon junction complex, Female, 5' Untranslated Regions, Sequence Alignment
Abstract

Item does not contain fulltext The exon-junction complex (EJC) performs essential RNA processing tasks. Here, we describe the first human disorder, thrombocytopenia with absent radii (TAR), caused by deficiency in one of the four EJC subunits. Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR. We found that this inheritance mechanism explained 53 of 55 cases (P < 5 x 10(-228)) of the rare congenital malformation syndrome. Of the 53 cases with this inheritance pattern, 51 carried a submicroscopic deletion of 1q21.1 that has previously been associated with TAR, and two carried a truncation or frameshift null mutation in RBM8A. We show that the two regulatory SNPs result in diminished RBM8A transcription in vitro and that Y14 expression is reduced in platelets from individuals with TAR. Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR syndrome.

Published
2012

13. Powerful Identification of Cis-regulatory SNPs in Human Primary Monocytes Using Allele-Specific Gene Expression

Author

Per Lundmark, Abigail Crisp-Hihn, Seraya Maouche, Tiphaine Godefroy, Harald H H Göring, Nilesh J. Samani, Anders Lundmark, Carole Proust, Jonathan Stephens, François Cambien, Jessy Brocheton, Bing Ge, Nicola S. Foad, Heribert Schunkert, Ulrika Liljedahl, Tomi Pastinen, Panos Deloukas, Camilla Enström, Jennifer Jolley, Rhian Gwilliam, Heather Lloyd-Jones, Ann-Christine Syvänen, Alison H. Goodall, Jonas Carlsson Almlöf, Jeanette Erdmann, Willem H. Ouwehand, Jennifer G. Sambrook, Catherine M. Rice, and Christian Hengstenberg

Subjects
Medicin och hälsovetenskap, genetic association, Microarrays, genotype, lcsh:Medicine, Gene Expression, Genome-wide association study, genotyping expression analysis, genetic analysis, Regulatory Sequences, Nucleic Acid, Medical and Health Sciences, Monocytes, 0302 clinical medicine, Gene Frequency, single nucleotide polymorphism, lcsh:Science, Genetics, 0303 health sciences, Multidisciplinary, messenger RNA, article, Chromosome Mapping, Genomics, sample size, Functional Genomics, quantitative trait locus mapping, monocyte, allele specific gene expression analysis, Research Article, Genetic Markers, Genotype, Quantitative Trait Loci, DNA flanking region, Single-nucleotide polymorphism, Biology, gene frequency, Polymorphism, Single Nucleotide, 03 medical and health sciences, Gene mapping, Genome Analysis Tools, Genetic Mutation, Genome-Wide Association Studies, Humans, RNA, Messenger, human, Allele, blood donor, intermethod comparison, Allele frequency, Genetic Association Studies, Alleles, 030304 developmental biology, Gene Expression Profiling, human cell, lcsh:R, Computational Biology, Human Genetics, gene mapping, Gene expression profiling, Minor allele frequency, Gene Expression Regulation, Expression quantitative trait loci, Genetic Polymorphism, gene expression, lcsh:Q, Genome Expression Analysis, Population Genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

A large number of genome-wide association studies have been performed during the past five years to identify associations between SNPs and human complex diseases and traits. The assignment of a functional role for the identified disease-associated SNP is not straight-forward. Genome-wide expression quantitative trait locus (eQTL) analysis is frequently used as the initial step to define a function while allele-specific gene expression (ASE) analysis has not yet gained a wide-spread use in disease mapping studies. We compared the power to identify cis-acting regulatory SNPs (cis-rSNPs) by genome-wide allele-specific gene expression (ASE) analysis with that of traditional expression quantitative trait locus (eQTL) mapping. Our study included 395 healthy blood donors for whom global gene expression profiles in circulating monocytes were determined by Illumina BeadArrays. ASE was assessed in a subset of these monocytes from 188 donors by quantitative genotyping of mRNA using a genome-wide panel of SNP markers. The performance of the two methods for detecting cis-rSNPs was evaluated by comparing associations between SNP genotypes and gene expression levels in sample sets of varying size. We found that up to 8-fold more samples are required for eQTL mapping to reach the same statistical power as that obtained by ASE analysis for the same rSNPs. The performance of ASE is insensitive to SNPs with low minor allele frequencies and detects a larger number of significantly associated rSNPs using the same sample size as eQTL mapping. An unequivocal conclusion from our comparison is that ASE analysis is more sensitive for detecting cis-rSNPs than standard eQTL mapping. Our study shows the potential of ASE mapping in tissue samples and primary cells which are difficult to obtain in large numbers.

Published
2012

14. Seventy-five genetic loci influencing the human red blood cell

Author

Teresa Nutile, Anna-Liisa Hartikainen, Stavroula Kanoni, Johannes H. Smit, Harm-Jan Westra, Beben Benyamin, Gonneke Willemsen, Clara S. Tang, Maria Dimitriou, Peter Vollenweider, Olle Melander, Inga Prokopenko, W.H. Wilson Tang, John P. Kemp, Tim D. Spector, Evelin Mihailov, Paul F. O'Reilly, Eleonora Porcu, Marcus E. Kleber, Sheila Ulivi, George Dedoussis, Manuela Uda, Matthias Nauck, Brenda W.J.H. Penninx, Daniela Ruggiero, Xinzhong Li, Dirk S. Paul, Niek Verweij, Bernd Genser, Harold Snieder, Willem H. Ouwehand, Ido P. Kema, Miriam F. Moffatt, Carmel Moore, Hilma Holm, Nicola Pirastu, Adamo Pio D'Adamo, Michael Stumvoll, Rossella Sorice, Kay-Tee Khaw, Heather Lloyd-Jones, Federico Murgia, Stephen F. Garner, Jing Hua Zhao, Laura Portas, Abdel Abdellaoui, Ursula Puc, Andres Metspalu, Marleen H. M. de Moor, Isleifur Olafsson, Ruth J. F. Loos, Andres Salumets, François Bastardot, James Scott, Jian Yang, Braxton D. Mitchell, Debora Parracciani, Maria Novatchkova, Panos Deloukas, William O.C.M. Cookson, Lorna M. Lopez, Andrew A. Hicks, Aude Saint-Pierre, Daniel F. Gudbjartsson, Vinicius Tragante, Mario Pirastu, Jacques S. Beckmann, L. Joost van Pelt, Winfried Maerz, Hooman Allayee, Jouke-Jan Hottenga, Kari Stefansson, Debashish Das, Weihua Zhang, Anke Tönjes, Michela Traglia, Stuart Meacham, Antonio Piga, Cornelis A. Albers, Nicholas G. Martin, John C. Chambers, Christa Meisinger, Leo-Pekka Lyytikäinen, Nicole Soranzo, Mika Kähönen, Katrin Voss, Micha Hersch, Claudia Langenberg, Sian Tsung Tan, Sandosh Padmanabhan, Christian X. Weichenberger, J. Gustav Smith, Antony P. Attwood, Claire E. Hastie, Gunnar Engström, Janina S. Ried, Carsten Oliver Schmidt, Pall T. Onundarson, Kathy Miller, Francisco S. Domingues, Stefania Bandinelli, Ulrich Elling, Augusto Rendon, Paul Elliott, Quince Gibson, Tõnu Esko, Robert Sladek, Marina Ciullo, Gerald Wirnsberger, Franco Anni, Antonietta Robino, Serena Sanna, Hein Schepers, Jonathan Stephens, Joban Sehmi, Beverley Balkau, Jennifer G. Sambrook, Lucia Perseu, Ilja M. Nolte, Herman H W Silljé, John M. Starr, Cinzia Sala, Peter P. Pramstaller, David M. Evans, Renzo Galanello, Uwe Völker, Philippe Froguel, Dorret I. Boomsma, Vasiliki Lagou, Gerjan Navis, Christian Gieger, Susan M. Ring, Alexander Teumer, Angela Döring, Ale Algra, Toshiko Tanaka, Bo Hedblad, Anneli Pouta, Unnur Thorsteinsdottir, Bernhard R. Winkelmann, Liming Liang, John Danesh, Paolo Gasparini, Sarah E. Medland, Ian J. Deary, Martin Gögele, Pim van der Harst, Giorgia Girotto, Josef M. Penninger, Jaspal S. Kooner, Patrick Sulem, Thomas Illig, Yasin Memari, Sarah E. Harris, Wiek H. van Gilst, Francesco Cucca, Dirk J. van Veldhuisen, So-Youn Shin, Giorgio Pistis, Olli T. Raitakari, Lude Franke, Folkert W. Asselbergs, Abtehale Al-Hussani, Stanley L. Hazen, Manuel A. R. Ferreira, Aimo Ruokonen, Christian Dina, Aparna Radhakrishnan, Irene Mateo Leach, Nicholas J. Wareham, George Davey Smith, Eric E. Schadt, Alan R. Shuldiner, John Whitfield, Gudmundur I. Eyjolfsson, Eco J. C. de Geus, Grant W. Montgomery, Afshin Parsa, Terho Lehtimäki, Paolo Fortina, Luigi Ferrucci, Andreas Greinacher, Marjo-Riitta Järvelin, Krista Fischer, Fabrice Danjou, Rudolf A. de Boer, Paul I.W. de Bakker, Peter M. Visscher, Anna F. Dominiczak, Ramiro Ramirez-Solis, Jennifer Jolley, Bruce H. R. Wolffenbuttel, Jaana Hartiala, Daniela Toniolo, Bernhard O. Boehm, van der Harst, P, Zhang, W, Mateo Leach, I, Rendon, A, Verweij, N, Sehmi, J, Paul, D, Elling, U, Allayee, H, Li, X, Radhakrishnan, A, Tan, St, Voss, K, Weichenberger, Cx, Albers, Ca, Al Hussani, A, Asselbergs, Fw, Ciullo, M, Danjou, F, Dina, C, Esko, T, Evans, Dm, Franke, L, Gögele, M, Hartiala, J, Hersch, M, Holm, H, Hottenga, Jj, Kanoni, S, Kleber, Me, Lagou, V, Langenberg, C, Lopez, Lm, Lyytikäinen, Lp, Melander, O, Murgia, F, Nolte, Im, O'Reilly, Pf, Padmanabhan, S, Parsa, A, Pirastu, Nicola, Porcu, E, Portas, L, Prokopenko, I, Ried, J, Shin, Sy, Tang, C, Teumer, A, Traglia, Michela, Ulivi, S, Westra, Hj, Yang, J, Zhao, Jh, Anni, F, Abdellaoui, A, Attwood, A, Balkau, B, Bandinelli, S, Bastardot, F, Benyamin, B, Boehm, Bo, Cookson, Wo, Das, D, de Bakker, Pi, de Boer, Ra, de Geus, Ej, de Moor, Mh, Dimitriou, M, Domingues, F, Döring, A, Engström, G, Eyjolfsson, Gi, Ferrucci, L, Fischer, K, Galanello, R, Garner, Sf, Genser, B, Gibson, Qd, Girotto, Giorgia, Gudbjartsson, Df, Harris, Se, Hartikainen, Al, Hastie, Ce, Hedblad, B, Illig, T, Jolley, J, Kähönen, M, Kema, Ip, Kemp, Jp, Liang, L, Lloyd Jones, H, Loos, Rj, Meacham, S, Medland, Se, Meisinger, C, Memari, Y, Mihailov, E, Miller, K, Moffatt, Mf, Nauck, M, Novatchkova, M, Nutile, T, Olafsson, I, Onundarson, Pt, Parracciani, D, Penninx, Bw, Perseu, L, Piga, A, Pistis, G, Pouta, A, Puc, U, Raitakari, O, Ring, Sm, Robino, Antonietta, Ruggiero, D, Ruokonen, A, Saint Pierre, A, Sala, C, Salumets, A, Sambrook, J, Schepers, H, Schmidt, Co, Silljé, Hh, Sladek, R, Smit, Jh, Starr, Jm, Stephens, J, Sulem, P, Tanaka, T, Thorsteinsdottir, U, Tragante, V, van Gilst, Wh, van Pelt, Lj, van Veldhuisen, Dj, Völker, U, Whitfield, Jb, Willemsen, G, Winkelmann, Br, Wirnsberger, G, Algra, A, Cucca, F, D'Adamo, ADAMO PIO, Danesh, J, Deary, Ij, Dominiczak, Af, Elliott, P, Fortina, P, Froguel, P, Gasparini, Paolo, Greinacher, A, Hazen, Sl, Jarvelin, Mr, Khaw, Kt, Lehtimäki, T, Maerz, W, Martin, Ng, Metspalu, A, Mitchell, Bd, Montgomery, Gw, Moore, C, Navis, G, Pirastu, M, Pramstaller, Pp, Ramirez Solis, R, Schadt, E, Scott, J, Shuldiner, Ar, Smith, Gd, Smith, Jg, Snieder, H, Sorice, R, Spector, Td, Stefansson, K, Stumvoll, M, Tang, Wh, Toniolo, D, Tönjes, A, Visscher, Pm, Vollenweider, P, Wareham, Nj, Wolffenbuttel, Bh, Boomsma, Di, Beckmann, J, Dedoussis, Gv, Deloukas, P, Ferreira, Ma, Sanna, S, Uda, M, Hicks, Aa, Penninger, Jm, Gieger, C, Kooner, J, Ouwehand, Wh, Soranzo, N, Chambers, J. C., Psychiatry, EMGO - Mental health, NCA - Anxiety & Depression, Biological Psychology, Neuroscience Campus Amsterdam - Anxiety & Depression, EMGO+ - Mental Health, Van Der Harst, Pim, Zhang, Weihua, Mateo Leach, Irene, Rendon, Augusto, Benyamin, Beben, Chambers, John C, Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Lifestyle Medicine (LM), Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), and Center for Liver, Digestive and Metabolic Diseases (CLDM)

Subjects
Male, Netherlands Twin Register (NTR), Candidate gene, Erythrocytes, PROTEIN, Genome-wide association study, DISEASE, Hemoglobins, Mice, 0302 clinical medicine, Genetics, Genomics, blood, 0303 health sciences, Multidisciplinary, biology, Cell Cycle, COMMON VARIANTS, Genomics, Phenotype, anemia, 3. Good health, Haematopoiesis, DROSOPHILA, Drosophila melanogaster, medicine.anatomical_structure, HEMOGLOBIN LEVELS, Organ Specificity, 030220 oncology & carcinogenesis, Cytokines, Female, RNA Interference, TRAITS, Signal Transduction, EXPRESSION, Polymorphism, Single Nucleotide, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic, blood, medicine, Animals, Humans, GENOME-WIDE ASSOCIATION, 030304 developmental biology, RECEPTOR, CONSORTIUM, ta3121, hemoglobin, biology.organism_classification, Hematopoiesis, meta-analysis, Red blood cell, Gene Expression Regulation, Genetic Loci, Expression quantitative trait loci, genome-wide association studies, Genome-Wide Association Study
Abstract

Item does not contain fulltext Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.

Published
2012

15. Blood Pressure Loci Identified with a Gene-Centric Array

Author

Meena Kumari, Claire E. Hastie, Jonathan Stephens, Patricia B. Munroe, Christopher P. Nelson, John M. C. Connell, Martin D. Tobin, Hani Neuvrith, Jean Tichet, Paul Burton, Gudrun Veldre, Daniele Cusi, Anna Levinsson, Paul Elliott, Elin Org, Erika Salvi, Tina Shah, Nabila Devos, Harm-Jan Westra, Juan-Pablo Casas, Olle Melander, Jan A. Staessen, Nilesh J. Samani, Jackie A. Cooper, Peter S. Braund, Neil R Poulter, Alive V. Stanton, Abiodun Onipinla, Marcel G. M. Wolfs, Steve E. Humphries, Philippa J. Talmud, Rebecca Hardy, Fotios Drenos, Maris Laan, Mark J. Caulfield, Richard Dobson, Willem H. Ouwehand, Yun Zhang, Li Chen, SG Wannamethee, Sue Shaw-Hawkins, Christopher Newton-Cheh, Eoin O'Brien, Simon A. McG. Thom, Maria Grazia Franzosi, Charles A. Mein, Mika Kivimäki, Tom R. Gaunt, Jennifer G. Sambrook, Andrea Stucchi, Annika Rosengren, Sonia Shah, Thomas Hedner, George A. Wells, Dag S. Thelle, Debbie A Lawlor, Pierre-François Plouin, Fredrik Nyberg, Richard W Morris, Ian N M Day, Vesela Gateva, Lude Franke, Peter S. Sever, Morris J. Brown, Margus Putku, Sandosh Padmanabhan, John F. Peden, Pim van der Harst, Jutta Palmen, Ioanna Tzoulaki, Alexandre F.R. Stewart, Andrew Wong, Peeter Juhanson, Marciej Tomaszewski, Alison H. Goodall, Martin Farrall, Wai K. Lee, Nicola Glorioso, Hugh Watkins, Xavier Jeunemaitre, Anders Hamsten, Robert Clarke, Anna F. Dominiczak, Mark Lathrop, Stephen Newhouse, Margus Viigimaa, George Davey Smith, Robert Roberts, John C. Whittaker, Michael V. Holmes, Toby Johnson, F. Gerald R. Fowkes, Aroon D. Hingorani, Udo Seedorf, Siim Sõber, Denis C. Shields, Diana Kuh, Chris Wallace, Philip Howard, Peter H. Whincup, Gonçalo R. Abecasis, Anuj Goel, Christian Delles, Björn Wahlstrand, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Cardiovascular Centre (CVC), Stem Cell Aging Leukemia and Lymphoma (SALL), Cardiogenics Consortium, Global BPgen Consortium, Newton-Cheh, C., Johnson, T., Gateva, V., Tobin, M.D., Bochud, M., Coin, L., Najjar, S.S., Hua, J., Heath, S.C., Eyheramendy, S., Papadakis, K., Voight, B.F., Scott, L.J., Zhang, F., Farrall, M., Tanaka, T., Wallace, C., Chambers, J.C., Khaw, K.T., Nilsson, P., van der Harst, P., Polidoro, S., Grobbee, D.E., Onland-Moret, N.C., Bots, M.L., Wain, L.V., Elliott, K.S., Teumer, A., Luan, J., Lucas, G., Kuusisto, J., Burton, P.R., Hadley, D., McArdle, W.L., Wellcome Trust Case Control Consortium, X, Brown, M., Dominiczak, A., Newhouse, S.J., Samani, N.J., Webster, J., Zeggini, E., Beckmann, J.S., Bergmann, S., Lim, N., Song, K., Vollenweider, P., Waeber, G., Waterworth, D.M., Yuan, X., Groop, L., Orho, M., Allione, A., Di Gregorio, A., Guarrera, S., Panico, S., Ricceri, F., Romanazzi, V., Sacerdote, C., Vineis, P., Barroso, I., Sandhu, M.S., Luben, R.N., Crawford, G.J., Jousilahti, P., Perola, M., Boehnke, M., Bonnycastle, L.L., Collins, F.S., Jackson, A.U., Mohlke, K.L., Stringham, H.M., Valle, T.T., Willer, C.J., Bergman, R.N., Morken, M.A., Döring, A., Gieger, C., Illig, T., Meitinger, T., Org, E., Pfeufer, A., Wichmann, H.E., Kathiresan, S., Marrugat, J., O'Donnell, C.J., Schwartz, S.M., Siscovick, D.S., Subirana, I., Freimer, N.B., Hartikainen, A.L., McCarthy, M.I., OReilly, P.F., Peltonen, L., Pouta, A., de Jong, P.E., Snieder, H., van Gilst, W.H., Clarke, R., Goel, A., Hamsten, A., Peden, J.F., Seedorf, U., Syv, C., Tognoni, G., Lakatta, E.G., Sanna, S., Scheet, P., Schlessinger, D., Scuteri, A., Dörr, M., Ernst, F., Felix, S.B., Homuth, G., Lorbeer, R., Reffelmann, T., Rettig, R., Völker, U., Galan, P., Gut, I.G., Hercberg, S., Lathrop, G.M., Zeleneka, D., Deloukas, P., Soranzo, N., Williams, F.M., Zhai, G., Salomaa, V., Laakso, M., Elosua, R., Forouhi, N.G., Völzke, H., Uiterwaal, C.S., van der Schouw, Y.T., Numans, M.E., Matullo, G., Navis, G., Berglund, G., Bingham, S.A., Kooner, J.S., Paterson, A.D., Connell, J.M., Bandinelli, S., Ferrucci, L., Watkins, H., Spector, T.D., Tuomilehto, J., Altshuler, D., Strachan, D.P., Laan, M., Meneton, P., Wareham, N.J., Uda, M., Jarvelin, M.R., Mooser, V., Melander, O., Loos, R.J., Elliott, P., Abecasis, G.R., Caulfield, M., Munroe, P.B., Attwood, T., Belz, S., Braund, P., Brocheton, J., Cambien, F., Cooper, J., Crisp-Hihn, A., Diemert, P., Eardman, J., Foad, N., Godefroy, T., Goodall, A.H., Gracey, J., Gray, E., Gwilliams, R., Heimer, S., Hengstenberg, C., Jolley, J., Krishnan, U., Lloyd-Jones, H., Liljedahl, U., Lugauer, I., Lundmark, P., Maouche, S., Moore, J.S., Montalescot, G., Muir, D., Murray, E., Nelson, C.P., Neudert, J., Niblett, D., O'Leary, K., Ouwehand, W.H., Pollard, H., Proust, C., Rankin, A., Rendon, A., Rice, C.M., Sager, H.B., Sambrook, J., Schmitz, G., Scholz, M., Schroeder, L., Schunkert, H., Stephens, J., Syvannen, A.C., and Tennstedt, S.

Subjects
Male, Linkage disequilibrium, Methylenetetrahydrofolate Reductase (NADPH2)/genetics, cardiovascular-disease, population, Genome-wide association study, Genetic Loci, Blood Pressure, ANGIOTENSINOGEN, 030204 cardiovascular system & hematology, Linkage Disequilibrium, 0302 clinical medicine, Gene Frequency, Receptors, common variants, Genetics(clinical), ESSENTIAL-HYPERTENSION, Genetics (clinical), POPULATION, Oligonucleotide Array Sequence Analysis, Genetics, 0303 health sciences, education.field_of_study, Adult, Aged, Blood Pressure/genetics, Case-Control Studies, Female, Gene Expression Profiling, Genome-Wide Association Study, Haplotypes, Humans, Hypertension/genetics, Middle Aged, Plasma Membrane Calcium-Transporting ATPases/genetics, Polymorphism, Single Nucleotide, Receptors, Atrial Natriuretic Factor/genetics, Sequence Analysis, DNA, COMMON VARIANTS, Single Nucleotide, 3. Good health, SNP genotyping, CARDIOVASCULAR-DISEASE, Hypertension, Sequence Analysis, Atrial Natriuretic Factor, QUANTITATIVE-TRAIT LOCI, metaanalysis, essential-hypertension, SUSCEPTIBILITY LOCI, Population, Single-nucleotide polymorphism, Biology, Article, 03 medical and health sciences, Plasma Membrane Calcium-Transporting ATPases, Polymorphism, GENOME-WIDE ASSOCIATION, education, Genotyping, Allele frequency, METAANALYSIS, Methylenetetrahydrofolate Reductase (NADPH2), 030304 developmental biology, quantitative-trait loci, Haplotype, Receptors, Atrial Natriuretic Factor, DNA, susceptibility loci, angiotensinogen, Hypertension/*genetics, genome-wide association, linkage disequilibrium
Abstract

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 x 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery, and follow-up data identified SNPs significantly associated with BP at p < 8.56 x 10(-7) at four further loci (NPR3, FIFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies. ispartof: American Journal of Human Genetics vol:89 issue:6 pages:688-700 ispartof: location:United States status: published

Published
2011

16. The serotonin transporter gene polymorphism and the effect of baseline on amygdala response to emotional faces

Author

Andrew J. Calder, Jennifer G. Sambrook, Luca Passamonti, Sarah Nutland, and Elisabeth A. H. von dem Hagen

Subjects
Male, Emotions, Tonic (physiology), Behavioral Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Mental Processes, Reference Values, Neurotransmitter, Evoked Potentials, Serotonin transporter, Serotonin Plasma Membrane Transport Proteins, 0303 health sciences, biology, Homozygote, fMRI, Amygdala, Magnetic Resonance Imaging, Facial expressions, Facial Expression, medicine.anatomical_structure, behavior and behavior mechanisms, Female, Analysis of variance, Psychology, psychological phenomena and processes, Adult, medicine.medical_specialty, Heterozygote, Serotonin, Cognitive Neuroscience, Experimental and Cognitive Psychology, Article, 03 medical and health sciences, Young Adult, Internal medicine, mental disorders, medicine, Humans, 030304 developmental biology, Facial expression, Analysis of Variance, Polymorphism, Genetic, Functional imaging, Endocrinology, chemistry, nervous system, biology.protein, Neuroscience, 030217 neurology & neurosurgery
Abstract

Research highlights ▶ 5-HTTLPR short allele carriers have greater amygdala response to emotional stimuli. ▶ Increased amygdala activity in s-carriers is consistent regardless of baseline. ▶ The results support a largely phasic model of 5-HTTLPR-mediated amygdala modulation., Previous research has found that a common polymorphism in the serotonin transporter gene (5-HTTLPR) is an important mediator of individual differences in brain responses associated with emotional behaviour. In particular, relative to individuals homozygous for the l-allele, carriers of the s-allele display heightened amygdala activation to emotional compared to non-emotional stimuli. However, there is some debate as to whether this difference is driven by increased activation to emotional stimuli, resting baseline differences between the groups, or decreased activation to neutral stimuli. We performed functional imaging during an implicit facial expression processing task in which participants viewed angry, sad and neutral faces. In addition to neutral faces, we included two further baseline conditions, houses and fixation. We found increased amygdala activation in s-allele carriers relative to l-homozygotes in response to angry faces compared to neutral faces, houses and fixation. When comparing neutral faces to houses or fixation, we found no significant difference in amygdala response between the two groups. In addition, there was no significant difference between the groups in response to fixation when compared with a houses baseline. Overall, these results suggest that the increased amygdala response observed in s-allele carriers to emotional faces is primarily driven by an increased response to emotional faces rather than a decreased response to neutral faces or an increased resting baseline. The results are discussed in relation to the tonic and phasic hypotheses of 5-HTTLPR-mediated modulation of amygdala activity.

Published
2010

17. A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium

Author

Nilesh J. Samani, Inke R. König, Mohammed J. R. Ghori, Alistair S. Hall, Christopher J. O'Donnell, Tim D. Spector, Jennifer G. Sambrook, Augusto Rendon, Christian Hengstenberg, Stefan Schreiber, Olle Melander, Jonathan Stephens, Philippa Burns, Simon C. Potter, Joseph M. Devaney, Suzannah Bumpstead, John R. Thompson, Markku S. Nieminen, Alexander Teumer, Mingyao Li, Nicole Soranzo, Heribert Schunkert, Angela Döring, Chris Tyler-Smith, Henry Völzke, Stephen E. Epstein, Leena Peltonen, Muredach P. Reilly, Klaus Stark, Yali Xue, Markus Perola, Swee Lay Thein, Brigitte Kühnel, Alexandre F.R. Stewart, Li Chen, David Altshuler, Alison H. Goodall, Veikko Salomaa, Hakon Hakonarson, Naomi Hammond, Uwe Völker, John Bradley, Perttu Salo, Mario Falchi, Robert Roberts, Mary-Susan Burnett, Christa Meisinger, Nicholas A. Watkins, David S. Siscovick, George A. Wells, Jovana Serbanovic-Canic, Holger Prokisch, Panos Deloukas, Stephan Menzel, Rhian Gwilliam, David A. van Heel, Roberto Elosua, Christian Gieger, Matthias Nauck, Juha Sinisalo, Wendy N. Erber, Thomas Illig, Benjamin J. Wright, Andreas Greinacher, Roman A. Laskowski, Christina Willenborg, H-Erich Wichmann, Catherine M. Rice, Stephen M. Schwartz, Willem H. Ouwehand, Christopher W. Knouff, Ida Surakka, Ruth McPherson, Benjamin F. Voight, Sekar Kathiresan, Jeanette Erdmann, Daniel J. Rader, Stephen F. Garner, Vincent Mooser, and Massimo Mangino

Subjects
Genetic Markers, medicine.medical_specialty, Genome-wide association study, Coronary Artery Disease, Disease, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, Article, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, White blood cell, Genetic variation, Genetics, medicine, Humans, Selection, Genetic, 030304 developmental biology, 0303 health sciences, Blood Cells, Chromosomes, Human, Pair 12, Hematology, Genome, Human, Haplotype, medicine.disease, Blood Cell Count, 3. Good health, medicine.anatomical_structure, Immunology, Selective sweep, Genome-Wide Association Study
Abstract

The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.

Published
2009

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