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1. Comparison of four methods to measure haemoglobin concentrations in whole blood donors (COMPARE): a diagnostic accuracy study

Author

Anna Ramond, Ryan Chung, Emanuele Di Angelantonio, Jennifer G. Sambrook, Susan Mehenny, Amy McMahon, Stephen Kaptoge, Jane Armitage, Carmel Moore, Steven Bell, Dave Roberts, Michael J. Sweeting, Angela M. Wood, Donna Cullen, John Danesh, Sarah Fahle, Gail Miflin, Thomas Bolton, Matthew G. Walker, and Willem H. Ouwehand

Subjects
Adult, Male, medicine.medical_specialty, non‐invasive haemoglobin measurement, Adolescent, Blood Donors, haemoglobin screening, Diagnostic accuracy, Test sensitivity, 030204 cardiovascular system & hematology, gravimetry, Sensitivity and Specificity, inappropriate bleeding, Donor Selection, Hemoglobins, Young Adult, 03 medical and health sciences, 0302 clinical medicine, HemoCue, medicine, Humans, Reference standards, Aged, Whole blood, Aged, 80 and over, Measurement method, Cross-Over Studies, inappropriate deferral, Obstetrics, business.industry, Anemia, Original Articles, Hematology, Middle Aged, Reference Standards, Blood donor, Spectrophotometry, whole blood donor, Hemoglobinometry, Whole blood donor, Female, Original Article, business, Biomarkers, 030215 immunology
Abstract

SUMMARYObjectiveTo compare four haemoglobin measurement methods in whole blood donors.BackgroundTo safeguard donors, blood services measure haemoglobin concentration in advance of each donation. NHS Blood and Transplant’s (NHSBT) usual method has been capillary gravimetry (copper sulphate), followed by venous HemoCue® (spectrophotometry) for donors failing gravimetry. However, gravimetry/venous HemoCue® results in 10% of donors being inappropriately bled (i.e., with haemoglobin values below the regulatory threshold).MethodsThe following were compared in 21,840 blood donors (aged ≥18 years) recruited from 10 mobile centres of NHSBT in England, with each method compared with the Sysmex XN-2000 haematology analyser, the reference standard: 1) gravimetry/venous HemoCue®; 2) “post donation” approach, i.e., estimating current haemoglobin concentration from that measured by a haematology analyser at a donor’s most recent prior donation; 3) capillary HemoCue®; and 4) non-invasive spectrometry (MBR Haemospect® or Orsense NMB200®). We assessed each method for sensitivity; specificity; proportion of donors who would have been inappropriately bled, or rejected from donation (“deferred”) incorrectly; and test preference.ResultsCompared with the reference standard, the methods ranged in test sensitivity from 17.0% (MBR Haemospect®) to 79.0% (HemoCue®) in men, and from 19.0% (MBR Haemospect®) to 82.8% (HemoCue®) in women. For specificity, the methods ranged from 87.2% (MBR Haemospect®) to 99.9% (gravimetry/venous HemoCue®) in men, and from 74.1% (Orsense NMB200®) to 99.8% (gravimetry/venous HemoCue®) in women. The proportion of donors who would have been inappropriately bled ranged from 2.2% in men for HemoCue® to 18.9% in women for MBR Haemospect®. The proportion of donors who would have been deferred incorrectly with haemoglobin concentration above the minimum threshold ranged from 0.1% in men for gravimetry/venous HemoCue® to 20.3% in women for OrSense®. Most donors preferred non-invasive spectrometry.ConclusionIn the largest study reporting head-to-head comparisons of four methods to measure haemoglobin prior to blood donation, our results support replacement of venous HemoCue® with the capillary HemoCue® when donors fail gravimetry. These results have had direct translational implications for NHS Blood and Transplant in England.

Published
2021

2. Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.

Author

Joshua C Randall, Thomas W Winkler, Zoltán Kutalik, Sonja I Berndt, Anne U Jackson, Keri L Monda, Tuomas O Kilpeläinen, Tõnu Esko, Reedik Mägi, Shengxu Li, Tsegaselassie Workalemahu, Mary F Feitosa, Damien C Croteau-Chonka, Felix R Day, Tove Fall, Teresa Ferreira, Stefan Gustafsson, Adam E Locke, Iain Mathieson, Andre Scherag, Sailaja Vedantam, Andrew R Wood, Liming Liang, Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Emmanouil T Dermitzakis, Antigone S Dimas, Fredrik Karpe, Josine L Min, George Nicholson, Deborah J Clegg, Thomas Person, Jon P Krohn, Sabrina Bauer, Christa Buechler, Kristina Eisinger, DIAGRAM Consortium, Amélie Bonnefond, Philippe Froguel, MAGIC Investigators, Jouke-Jan Hottenga, Inga Prokopenko, Lindsay L Waite, Tamara B Harris, Albert Vernon Smith, Alan R Shuldiner, Wendy L McArdle, Mark J Caulfield, Patricia B Munroe, Henrik Grönberg, Yii-Der Ida Chen, Guo Li, Jacques S Beckmann, Toby Johnson, Unnur Thorsteinsdottir, Maris Teder-Laving, Kay-Tee Khaw, Nicholas J Wareham, Jing Hua Zhao, Najaf Amin, Ben A Oostra, Aldi T Kraja, Michael A Province, L Adrienne Cupples, Nancy L Heard-Costa, Jaakko Kaprio, Samuli Ripatti, Ida Surakka, Francis S Collins, Jouko Saramies, Jaakko Tuomilehto, Antti Jula, Veikko Salomaa, Jeanette Erdmann, Christian Hengstenberg, Christina Loley, Heribert Schunkert, Claudia Lamina, H Erich Wichmann, Eva Albrecht, Christian Gieger, Andrew A Hicks, Asa Johansson, Peter P Pramstaller, Sekar Kathiresan, Elizabeth K Speliotes, Brenda Penninx, Anna-Liisa Hartikainen, Marjo-Riitta Jarvelin, Ulf Gyllensten, Dorret I Boomsma, Harry Campbell, James F Wilson, Stephen J Chanock, Martin Farrall, Anuj Goel, Carolina Medina-Gomez, Fernando Rivadeneira, Karol Estrada, André G Uitterlinden, Albert Hofman, M Carola Zillikens, Martin den Heijer, Lambertus A Kiemeney, Andrea Maschio, Per Hall, Jonathan Tyrer, Alexander Teumer, Henry Völzke, Peter Kovacs, Anke Tönjes, Massimo Mangino, Tim D Spector, Caroline Hayward, Igor Rudan, Alistair S Hall, Nilesh J Samani, Antony Paul Attwood, Jennifer G Sambrook, Joseph Hung, Lyle J Palmer, Marja-Liisa Lokki, Juha Sinisalo, Gabrielle Boucher, Heikki Huikuri, Mattias Lorentzon, Claes Ohlsson, Niina Eklund, Johan G Eriksson, Cristina Barlassina, Carlo Rivolta, Ilja M Nolte, Harold Snieder, Melanie M Van der Klauw, Jana V Van Vliet-Ostaptchouk, Pablo V Gejman, Jianxin Shi, Kevin B Jacobs, Zhaoming Wang, Stephan J L Bakker, Irene Mateo Leach, Gerjan Navis, Pim van der Harst, Nicholas G Martin, Sarah E Medland, Grant W Montgomery, Jian Yang, Daniel I Chasman, Paul M Ridker, Lynda M Rose, Terho Lehtimäki, Olli Raitakari, Devin Absher, Carlos Iribarren, Hanneke Basart, Kees G Hovingh, Elina Hyppönen, Chris Power, Denise Anderson, John P Beilby, Jennie Hui, Jennifer Jolley, Hendrik Sager, Stefan R Bornstein, Peter E H Schwarz, Kati Kristiansson, Markus Perola, Jaana Lindström, Amy J Swift, Matti Uusitupa, Mustafa Atalay, Timo A Lakka, Rainer Rauramaa, Jennifer L Bolton, Gerry Fowkes, Ross M Fraser, Jackie F Price, Krista Fischer, Kaarel Krjutå Kov, Andres Metspalu, Evelin Mihailov, Claudia Langenberg, Jian'an Luan, Ken K Ong, Peter S Chines, Sirkka M Keinanen-Kiukaanniemi, Timo E Saaristo, Sarah Edkins, Paul W Franks, Göran Hallmans, Dmitry Shungin, Andrew David Morris, Colin N A Palmer, Raimund Erbel, Susanne Moebus, Markus M Nöthen, Sonali Pechlivanis, Kristian Hveem, Narisu Narisu, Anders Hamsten, Steve E Humphries, Rona J Strawbridge, Elena Tremoli, Harald Grallert, Barbara Thorand, Thomas Illig, Wolfgang Koenig, Martina Müller-Nurasyid, Annette Peters, Bernhard O Boehm, Marcus E Kleber, Winfried März, Bernhard R Winkelmann, Johanna Kuusisto, Markku Laakso, Dominique Arveiler, Giancarlo Cesana, Kari Kuulasmaa, Jarmo Virtamo, John W G Yarnell, Diana Kuh, Andrew Wong, Lars Lind, Ulf de Faire, Bruna Gigante, Patrik K E Magnusson, Nancy L Pedersen, George Dedoussis, Maria Dimitriou, Genovefa Kolovou, Stavroula Kanoni, Kathleen Stirrups, Lori L Bonnycastle, Inger Njølstad, Tom Wilsgaard, Andrea Ganna, Emil Rehnberg, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Themistocles L Assimes, Inês Barroso, Michael Boehnke, Ingrid B Borecki, Panos Deloukas, Caroline S Fox, Timothy Frayling, Leif C Groop, Talin Haritunians, David Hunter, Erik Ingelsson, Robert Kaplan, Karen L Mohlke, Jeffrey R O'Connell, David Schlessinger, David P Strachan, Kari Stefansson, Cornelia M van Duijn, Gonçalo R Abecasis, Mark I McCarthy, Joel N Hirschhorn, Lu Qi, Ruth J F Loos, Cecilia M Lindgren, Kari E North, and Iris M Heid

Subjects
Genetics, QH426-470
Abstract

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR

Published
2013
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3. Genetic Analyses of Blood Cell Structure for Biological and Pharmacological Inference

Author

Stephen Kaptoge, Jeffrey M. Verboon, Jennifer G. Sambrook, Emanuele Di Angelantonio, Tao Jiang, William J. Astle, Louisa Mayer, Taco W. Kuijpers, Janine Collins, Vijay G. Sankaran, Michel Georges, Nicholas A. Watkins, Julian C. Knight, Kousik Kundu, Roman Kreuzhuber, Kate Downes, Adam S. Butterworth, Stephen Burgess, David J. Roberts, Luigi Grassi, Stuart Meacham, Dragana Vuckovic, Denis Seyres, Jose A. Guerrero, Parsa Akbari, Mattia Frontini, Nicole Soranzo, Willem H. Ouwehand, Klaudia Walter, Erik L. Bao, John Danesh, Oliver Stegle, and James E. Peters

Subjects
0303 health sciences, Cell type, education.field_of_study, Multiple sclerosis, Population, Genome-wide association study, Computational biology, Disease, Biology, medicine.disease, Phenotype, 3. Good health, Blood cell, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, medicine, Epigenetics, education, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

SUMMARYThousands of genetic associations with phenotypes of blood cells are known, but few are with phenotypes relevant to cell function. We performed GWAS of 63 flow-cytometry phenotypes, including measures of cell granularity, nucleic acid content, and reactivity, in 39,656 participants in the INTERVAL study, identifying 2,172 variant-trait associations. These include associations mediated by functional cellular structures such as secretory granules, implicated in vascular, thrombotic, inflammatory and neoplastic diseases. By integrating our results with epigenetic data and with signals from molecular abundance/disease GWAS, we infer the hematopoietic origins of population phenotypic variation and identify the transcription factor FOG2 as a regulator of plateletα-granularity. We show how flow cytometry genetics can suggest cell types mediating complex disease risk and suggest efficacious drug targets, presenting Daclizumab/Vedolizumab in autoimmune disease as positive controls. Finally, we add to existing evidence supporting IL7/IL7-R as drug targets for multiple sclerosis.

Published
2020
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4. Development and validation of a universal blood donor genotyping platform: A multinational prospective study

Author

Augusto Rendon, John M. Jongerius, Nicholas A. Watkins, Kim Brügger, Nicholas Gleadall, Daniel Duarte, Tiffany C. Timmer, Sara Trompeter, Matthew R. Walker, Jennifer G. Sambrook, David J. Roberts, Christopher J. Penkett, Carolin M. Sauer, Nieke van der Bolt, Barbera Veldhuisen, Shane Grimsley, Colin Brown, Adam S. Butterworth, Michael J. Sweeting, Salih Tuna, Emanuele Di Angelantonio, John Ord, Karyn Megy, Jessie S Luken, C. Ellen van der Schoot, Ilenia Simeoni, Gail Miflin, William J. Lane, Nicole Thornton, Ram Varma, William J. Astle, Connie M. Westhoff, Christopher S. Nelson, Katja van den Hurk, Jeremy Gollub, Kathleen Stirrups, Willem H. Ouwehand, Femmeke J. Prinsze, Alexander T. Dilthey, John Danesh, Public and occupational health, Graduate School, AII - Inflammatory diseases, APH - Methodology, and Landsteiner Laboratory

Subjects
medicine.medical_specialty, Blood transfusion, Genotype, medicine.medical_treatment, Concordance, Blood Donors, Human leukocyte antigen, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Isoantibodies, medicine, Humans, Blood Transfusion, Prospective Studies, Typing, Genotyping, biology, Transfusion Medicine, business.industry, Transfusion medicine, Hematology, Biobank, Immunology, biology.protein, Antibody, business, 030215 immunology
Abstract

Each year, blood transfusions save millions of lives. However, under current blood-matching practices, sensitization to non–self-antigens is an unavoidable adverse side effect of transfusion. We describe a universal donor typing platform that could be adopted by blood services worldwide to facilitate a universal extended blood-matching policy and reduce sensitization rates. This DNA-based test is capable of simultaneously typing most clinically relevant red blood cell (RBC), human platelet (HPA), and human leukocyte (HLA) antigens. Validation was performed, using samples from 7927 European, 27 South Asian, 21 East Asian, and 9 African blood donors enrolled in 2 national biobanks. We illustrated the usefulness of the platform by analyzing antibody data from patients sensitized with multiple RBC alloantibodies. Genotyping results demonstrated concordance of 99.91%, 99.97%, and 99.03% with RBC, HPA, and HLA clinically validated typing results in 89 371, 3016, and 9289 comparisons, respectively. Genotyping increased the total number of antigen typing results available from 110 980 to >1 200 000. Dense donor typing allowed identification of 2 to 6 times more compatible donors to serve 3146 patients with multiple RBC alloantibodies, providing at least 1 match for 176 individuals for whom previously no blood could be found among the same donors. This genotyping technology is already being used to type thousands of donors taking part in national genotyping studies. Extraction of dense antigen-typing data from these cohorts provides blood supply organizations with the opportunity to implement a policy of genomics-based precision matching of blood.

Published
2020

5. Powerful identification of cis-regulatory SNPs in human primary monocytes using allele-specific gene expression.

Author

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

Subjects
Medicine, Science
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
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6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. Characterisation of a gene cluster in Fugu rubripes containing the complement component C4 gene

Author

Jennifer G. Sambrook, Greg Elgar, and R. Duncan Campbell

Subjects
Sequence analysis, Molecular Sequence Data, Takifugu, Contig Mapping, Exon, Gene Order, MHC class I, Genetics, CSNK2B, Amino Acid Sequence, education, Gene, Phylogeny, education.field_of_study, Sequence Homology, Amino Acid, biology, Fugu, fungi, Complement C4, Tenascin, Complement C3, DNA, Sequence Analysis, DNA, General Medicine, biology.organism_classification, Multigene Family, Allograft inflammatory factor 1, biology.protein, Steroid 21-Hydroxylase, Sequence Alignment
Abstract

In this study, we describe the characterisation of the complement component C4 gene in Fugu rubripes. The Fugu C4 gene, orthologous to the tetrapod C4 gene, encompasses a genomic span of 9702 base pairs and contains 41 exons, encoding the typical C4 three-chain polypeptide. The gene encodes a protein containing 1703 amino acids. The Fugu C4 protein demonstrates the presence of 25 conserved cysteine residues, as well as conservation of the functionally important thioester site. Complete sequencing of one cosmid and sequence scans from a cluster of 18 overlapping BAC clones, centering around the C4 gene, have identified the short-range linkage with five orthologous human genes mapping to the Major Histocompatibility Complex (MHC) including: tenascin X (TNX); cytochrome P450, subfamily XXIA, polypeptide 2 (CYP21A2); allograft inflammatory factor 1 (AIF1) and casein kinase 2, beta polypeptide (CSNK2B), all found in the MHC class III region; and retinoid X receptor, beta (RXRB),which resides in the MHC extended class II region. To date, this syntenic association of the Fugu C4 and other MHC class III region genes has not been observed in other teleost fish. Data from the recent whole-genome shotgun assemblies reveal the Fugu MHC-related cluster of genes to be flanked predominantly by genes mapping to human chromosomes 7 and 19. All of the six identified Fugu MHC-related genes have been characterised at the genomic level.

Published
2003

16. The INTERVAL trial to determine whether intervals between blood donations can be safely and acceptably decreased to optimise blood supply: study protocol for a randomised controlled trial

Author

Jennifer G. Sambrook, David Allen, Willem H. Ouwehand, Carmel Moore, Stephen Kaptoge, Simon G. Thompson, Emanuele Di Angelantonio, David J. Roberts, Zoe Tolkien, John Danesh, Jonathan Mant, Susan Mehenny, Matthew G. Walker, Kaptoge, Stephen [0000-0002-1155-4872], Mant, Jonathan [0000-0002-9531-0268], Di Angelantonio, Emanuele [0000-0001-8776-6719], Thompson, Simon [0000-0002-5274-7814], Ouwehand, Willem [0000-0002-7744-1790], Danesh, John [0000-0003-1158-6791], and Apollo - University of Cambridge Repository

Subjects
Research design, Male, medicine.medical_specialty, Blood transfusion, Time Factors, medicine.medical_treatment, Health Status, Medicine (miscellaneous), Blood Donors, Risk Assessment, law.invention, Donor Selection, whole blood donation, Study Protocol, Randomized controlled trial, Quality of life, Clinical Protocols, law, Risk Factors, Surveys and Questionnaires, medicine, Humans, Blood Transfusion, Pharmacology (medical), Whole blood, Intention-to-treat analysis, Donor selection, business.industry, donor well-being, Middle Aged, blood supply, donation frequency, 3. Good health, Surgery, Intention to Treat Analysis, England, Research Design, Donation, Emergency medicine, Quality of Life, Female, Patient Safety, business, randomised controlled trial
Abstract

BACKGROUND: Ageing populations may demand more blood transfusions, but the blood supply could be limited by difficulties in attracting and retaining a decreasing pool of younger donors. One approach to increase blood supply is to collect blood more frequently from existing donors. If more donations could be safely collected in this manner at marginal cost, then it would be of considerable benefit to blood services. National Health Service (NHS) Blood and Transplant in England currently allows men to donate up to every 12 weeks and women to donate up to every 16 weeks. In contrast, some other European countries allow donations as frequently as every 8 weeks for men and every 10 weeks for women. The primary aim of the INTERVAL trial is to determine whether donation intervals can be safely and acceptably decreased to optimise blood supply whilst maintaining the health of donors. METHODS/DESIGN: INTERVAL is a randomised trial of whole blood donors enrolled from all 25 static centres of NHS Blood and Transplant. Recruitment of about 50,000 male and female donors started in June 2012 and was completed in June 2014. Men have been randomly assigned to standard 12-week versus 10-week versus 8-week inter-donation intervals, while women have been assigned to standard 16-week versus 14-week versus 12-week inter-donation intervals. Sex-specific comparisons will be made by intention-to-treat analysis of outcomes assessed after two years of intervention. The primary outcome is the number of blood donations made. A key secondary outcome is donor quality of life, assessed using the Short Form Health Survey. Additional secondary endpoints include the number of 'deferrals' due to low haemoglobin (and other factors), iron status, cognitive function, physical activity, and donor attitudes. A comprehensive health economic analysis will be undertaken. DISCUSSION: The INTERVAL trial should yield novel information about the effect of inter-donation intervals on blood supply, acceptability, and donors' physical and mental well-being. The study will generate scientific evidence to help formulate blood collection policies in England and elsewhere. TRIAL REGISTRATION: Current Controlled Trials ISRCTN24760606, 25 January 2012.

Published
2014

17. 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

18. Supplementary Material 1

Author

Henry Völzke, Tõnu Esko, Ken K. Ong, Aldi T. Kraja, Anne U. Jackson, Meena Kumari, Eva Albrecht, Rona J. Strawbridge, Antti Jula, Mark J. Caulfield, Alistair S. Hall, Karol Estrada, Jennifer L. Bolton, Teresa Ferreira, Inger Njølstad, Thomas W. Winkler, Ross M. Fraser, Daniel I. Chasman, Maris Teder-Laving, Yii-Der Ida Chen, Claudia Langenberg, Kevin B. Jacobs, Jennifer G. Sambrook, Evelin Mihailov, Peter Kovacs, Susanne Moebus, Jouke-Jan Hottenga, George Dedoussis, Gudmar Thorleifsson, Sirkka M. Keinanen Kiukaanniemi, Matti Uusitupa, Denise Anderson, Lindsay L. Waite, Johan G. Eriksson, Mustafa Atalay, Kari Stefansson, Amélie Bonnefond, Gerry Fowkes, Tove Fall, Dmitry Shungin, Stephan J. L. Bakker, Tamara B. Harris, Thomas Illig, Wolfgang Koenig, Heribert Schunkert, Caroline S. Fox, Gabrielle Boucher, Sonja I. Berndt, Timo Saaristo, Maria Dimitriou, Pim van der Harst, Christina Loley, John Yarnell, Rainer Rauramaa, Sarah Edkins, Jaakko Tuomilehto, Karen L. Mohlke, Damien C. Croteau Chonka, Reedik Mägi, Olli T. Raitakari, Kathleen Stirrups, Aroon D. Hingorani, Inga Prokopenko, Henrik Grönberg, Marcus E. Kleber, Massimo Mangino, Michael A. Province, Markus M. Nöthen, Patricia B. Munroe, Francis S. Collins, Jeanette Erdmann, Mattias Lorentzon, Lynda M. Rose, Jon P. Krohn, Paul M. Ridker, M. Carola Zillikens, Jouko Saramies, Andrew Wong, Anuj Goel, Christa Buechler, Chris Power, Iain Mathieson, Bernhard O. Boehm, Jonathan Tyrer, Fredrik Karpe, Lu Qi, Nicholas G. Martin, Kristian Hveem, Jackie F. Price, Martin Farrall, Albert V. Smith, Mary F. Feitosa, Caroline Hayward, Juha Sinisalo, Stavroula Kanoni, Elina Hyppönen, Christian Hengstenberg, Lori L. Bonnycastle, Ilja M. Nolte, Sonali Pechlivanis, Barbara Thorand, Patrik K. E. Magnusson, Cristina Barlassina, Andrew A. Hicks, Genovefa Kolovou, Melanie M. van der Klauw, Markus Perola, Tsegaselassie Workalemahu, Ida Surakka, Veikko Salomaa, Andrea Ganna, Timothy M. Frayling, Iris M. Heid, Brenda W.J.H. Penninx, Stephen J. Chanock, Jeffrey R. O'Connell, Tom Wilsgaard, Alan R. Shuldiner, David J. Hunter, Deborah J. Clegg, Toby Johnson, Cornelia M. van Duijn, Samuli Ripatti, David P. Strachan, Lyle J. Palmer, Alexander Teumer, Kari E. North, L. Adrienne Cupples, Carlos Iribarren, Anna-Liisa Hartikainen, Andrew R. Wood, Lambertus A. Kiemeney, Ulf Gyllensten, Jennie Hui, Tim D. Spector, Paul W. Franks, Andrew D. Morris, Ruth J. F. Loos, George Nicholson, Felix R. Day, Kati Kristiansson, Talin Haritunians, Martina Müller-Nurasyid, Sailaja Vedantam, Pablo V. Gejman, Martin den Heijer, Andrea Maschio, Anke Tönjes, Kari Kuulasmaa, Raimund Erbel, Markku Laakso, Devin Absher, Narisu Narisu, Zhaoming Wang, Jing Hua Zhao, Thomas N. Person, Irene Mateo Leach, Mark I. McCarthy, Albert Hofman, Joel N. Hirschhorn, H.-Erich Wichmann, Nicholas J. Wareham, André Scherag, Jarmo Virtamo, James F. Wilson, Gonçalo R. Abecasis, Winfried März, Nilesh J. Samani, Timo A. Lakka, Jacques S. Beckmann, Harold Snieder, Adam E. Locke, Hanneke Basart, Grant W. Montgomery, Robert C. Kaplan, Claudia Lamina, Sekar Kathiresan, Mika Kivimäki, Leif Groop, Emil Rehnberg, Jana V. Van Vliet Ostaptchouk, Ingrid B. Borecki, Sabrina Bauer, Terho Lehtimäki, Steve E. Humphries, Zoltán Kutalik, Kees Hovingh, Carolina Medina-Gomez, Panos Deloukas, Antony P. Attwood, Kay-Tee Khaw, Per Hall, Jaakko Kaprio, Jian Yang, Tuomas O. Kilpeläinen, Andres Metspalu, Igor Rudan, Michael Boehnke, Ben A. Oostra, Jaana Lindström, André G. Uitterlinden, Peter Schwarz, Keri L. Monda, John Beilby, Fernando Rivadeneira, Emmanouil T. Dermitzakis, Dominique Arveiler, Valgerdur Steinthorsdottir, Jian'an Luan, Cecilia M. Lindgren, Guo Li, Bruna Gigante, Göran Hallmans, Liming Liang, Peter S. Chines, Sarah E. Medland, Joseph Hung, Peter P. Pramstaller, Ulf de Faire, Joshua C. Randall, Nancy L. Pedersen, Wendy L. McArdle, Unnur Thorsteinsdottir, Bernhard R. Winkelmann, Kaarel KrjutÅ¡kov, Philippe Froguel, Harry Campbell, Dorret I. Boomsma, Harald Grallert, Nancy L. Heard Costa, Shengxu Li, Amy J. Swift, Diana Kuh, Gerjan Navis, Christian Gieger, Heikki V. Huikuri, Niina Eklund, Anders Hamsten, Elizabeth K. Speliotes, Josine L. Min, Hendrik B. Sager, Stefan Gustafsson, Antigone S. Dimas, Elena Tremoli, Carlo Rivolta, Jianxin Shi, Najaf Amin, Claes Ohlsson, Johanna Kuusisto, Giancarlo Cesana, Lars Lind, Stefan R. Bornstein, Erik Ingelsson, Colin N. A. Palmer, Marjo-Riitta Järvelin, Krista Fischer, Annette Peters, David Schlessinger, Themistocles L. Assimes, Inês Barroso, Kristina Eisinger, Marja-Liisa Lokki, Jennifer Jolley, and Åsa Johansson

Subjects
Cultural Studies, Archeology, History, Chemistry, Cystolith, medicine, Magnesium ammonium phosphate, Bladder stones, medicine.disease, Nuclear chemistry
Published
2013

19. 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

20. 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

21. 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

22. 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

23. 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

24. Multiple loci are associated with white blood cell phenotypes

Author

Jacqueline C.M. Witteman, Holger Prokisch, Nicole L. Glazer, Koichi Matsuda, André G. Uitterlinden, Christian Gieger, Vilmundur Gudnason, Neil A. Zakai, Kerri L. Wiggins, Ming-Huei Chen, Stephan Menzel, Eric Boerwinkle, Angela Döring, Toshiko Tanaka, Natalia Gouskova, Inga Prokopenko, Aravinda Chakravarti, Caroline S. Fox, Jing-Ping Lin, Nicole Soranzo, Henry Völzke, Matt Moore, Sean Chong, Gudny Eiriksdottir, Paolo Gasparini, Bruce M. Psaty, Uwe Völker, Christa Meisinger, Kushang V. Patel, Joshua C. Bis, Guillaume Lettre, Brigitte Kühnel, Ben A. Oostra, Vasiliki Lagou, Dena G. Hernandez, Albert V. Smith, Alexander Teumer, Janine F. Felix, Mike A. Nalls, Daniel Levy, Abbas Dehghan, Tamara B. Harris, Luigi Ferrucci, Andreas Greinacher, Alessandro Biffi, Jonathan Stephens, Michael Stumvoll, Daniela Toniolo, Toshihiro Tanaka, Massimo Mangino, Augusto Rendon, Willem H. Ouwehand, Santhi K. Ganesh, Anke Tönjes, Kazuhiko Yamamoto, Yusuke Nakamura, Tatsuhiko Tsunoda, Nicola Pirastu, Giorgio Pistis, Josef Coresh, Qiong Yang, Frank J. A. van Rooij, Jennifer G. Sambrook, Yoichiro Kamatani, James G. Wilson, Stefania Bandinelli, Kent D. Taylor, H.-Erich Wichmann, Dan L. Longo, Atsushi Takahashi, Michiaki Kubo, David Melzer, Thomas Lumley, David Couper, Yukinori Okada, Sampath Arepalli, Matthias Nauck, Thomas Illig, Aaron R. Folsom, Cornelia M. van Duijn, Stephen F. Garner, Albert Hofman, Andrew B. Singleton, Naoyuki Kamatani, Yongmei Liu, L. Adrienne Cupples, Christopher J. O'Donnell, Melissa E. Garcia, Alexander P. Reiner, Tim D. Spector, Andrew R. Wood, Swee Lay Thein, Timothy M. Frayling, Nalls, Ma, Couper, Dj, Tanaka, T, van Rooij, Fj, Chen, Mh, Smith, Av, Toniolo, D, Zakai, Na, Yang, Q, Greinacher, A, Wood, Ar, Garcia, M, Gasparini, Paolo, Liu, Y, Lumley, T, Folsom, Ar, Reiner, Ap, Gieger, C, Lagou, V, Felix, Jf, Völzke, H, Gouskova, Na, Biffi, A, Döring, A, Völker, U, Chong, S, Wiggins, Kl, Rendon, A, Dehghan, A, Moore, M, Taylor, K, Wilson, Jg, Lettre, G, Hofman, A, Bis, Jc, Pirastu, Nicola, Fox, C, Meisinger, C, Sambrook, J, Arepalli, S, Nauck, M, Prokisch, H, Stephens, J, Glazer, Nl, Cupples, La, Okada, Y, Takahashi, A, Kamatani, Y, Matsuda, K, Tsunoda, T, Kubo, M, Nakamura, Y, Yamamoto, K, Kamatani, N, Stumvoll, M, Tönjes, A, Prokopenko, I, Illig, T, Patel, Kv, Garner, Sf, Kuhnel, B, Mangino, M, Oostra, Ba, Thein, Sl, Coresh, J, Wichmann, He, Menzel, S, Lin, J, Pistis, G, Uitterlinden, Ag, Spector, Td, Teumer, A, Eiriksdottir, G, Gudnason, V, Bandinelli, S, Frayling, Tm, Chakravarti, A, van Duijn, Cm, Melzer, D, Ouwehand, Wh, Levy, D, Boerwinkle, E, Singleton, Ab, Hernandez, Dg, Longo, Dl, Soranzo, N, Witteman, Jc, Psaty, Bm, Ferrucci, L, Harris, Tb, O'Donnell, Cj, and Ganesh, Sk

Subjects
Cancer Research, medicine.medical_specialty, Genetics, White blood cell, Ubiquitin-Protein Ligases, Genome-wide association study, Human leukocyte antigen, Biology, QH426-470, Polymorphism, Single Nucleotide, 03 medical and health sciences, Leukocyte Count, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Genetic, Polymorphism (computer science), Molecular genetics, medicine, Leukocytes, Humans, ddc:610, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, 0303 health sciences, Molecular Epidemiology, 0604 Genetics, medicine.diagnostic_test, Complete blood count, Heritability, 3. Good health, medicine.anatomical_structure, Phenotype, Genetic Loci, Multigene Family, Immunology, Differential Leukocyte Count, 030217 neurology & neurosurgery, Genome-Wide Association Study, Developmental Biology
Abstract

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count-3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.

Published
2011

25. 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

26. 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

27. Evolutionary vignettes of natural killer cell receptors

Author

Jennifer G. Sambrook and Stephan Beck

Subjects
Innate immune system, Immunology, Histocompatibility Antigens Class I, Pattern recognition receptor, chemical and pharmacologic phenomena, Immune receptor, biochemical phenomena, metabolism, and nutrition, Biology, Acquired immune system, Immunological synapse, Natural killer cell, Evolution, Molecular, Killer Cells, Natural, Immune system, medicine.anatomical_structure, Receptors, KIR, medicine, bacteria, Immunology and Allergy, Animals, Humans, Receptors, Immunologic, Receptor
Abstract

The discovery of novel immune receptors has led to a recent renaissance of research into the innate immune system, following decades of intense research of the adaptive immune system. Of particular interest has been the discovery of the natural killer (NK) cell receptors which, depending on type, interact with classical or non-classical MHC class I antigens of the adaptive immune system, thus functioning at the interface of innate and adaptive immunity. Here, we review recent progress with respect to two such families of NK receptors, the killer immunoglobulin-like receptors (KIRs) and the killer cell lectin-like receptors (KLRs), and attempt to trace their evolution across vertebrates.

Published
2007

28. Correction: Corrigendum: Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

Author

Toshiko Tanaka, Clara Camaschella, Niek Verweij, Denise Anderson, Peter Vollenweider, Nicholas G. Martin, Stefania Bandinelli, Andres Metspalu, Peter P. Pramstaller, Dorine W. Swinkels, Maristella Steri, Ayse Demirkan, Serena Sanna, Jennifer Jolley, Irene Pichler, Pamela A. F. Madden, Gérard Waeber, Lambertus A. Kiemeney, Clara Podmore, Daniela Toniolo, Jennie Hui, Tõnu Esko, Thomas Meitinger, Jennifer G. Sambrook, Jiaåan Luan, Andrew A. Hicks, Joachim Thiery, Claudia Langenberg, Andrew Heath, Robert A. Scott, Aaron Isaacs, Peter van der Meer, Cornelia M. van Duijn, Juliane Winkelmann, Fudi Wang, Peter M. Visscher, Fred C.G.J. Sweep, Zoltán Kutalik, Annette Peters, Michela Traglia, Cinzia Sala, Manuela Uda, Augusto Rendon, Melanie Waldenberger, Christian Gieger, Lili Milani, John Beilby, Margaret J. Wright, Konrad Oexle, Christine Schwienbacher, Linda Broer, Grant W. Montgomery, Najaf Amin, Dale R. Nyholt, Martin Gögele, Pim van der Harst, Dena G. Hernandez, Janina S. Ried, Aparna Radhakrishnan, Nicholas J. Wareham, Sita H. Vermeulen, John Whitfield, Harm-Jan Westra, Beben Benyamin, Joseph E. Powell, Evelin Mihailov, Lude Franke, Jonas Hälldin, Willem H. Ouwehand, Benyamin, B, Esko, T, Ried, J, Radhakrishnan, A, Vermeulen, Sh, Traglia, M, Gögele, M, Anderson, D, Broer, L, Podmore, C, Luan, J, Kutalik, Z, Sanna, S, VAN DER MEER, P, Tanaka, T, Wang, F, Westra, Hj, Franke, L, Mihailov, E, Milani, L, Hälldin, J, Winkelmann, J, Meitinger, T, Thiery, J, Peters, A, Waldenberger, M, Rendon, A, Jolley, J, Sambrook, J, Kiemeney, La, Sweep, Fc, Sala, Cf, Schwienbacher, C, Pichler, I, Hui, J, Demirkan, A, Isaacs, A, Amin, N, Steri, M, Waeber, G, Verweij, N, Powell, Je, Nyholt, Dr, Heath, Ac, Madden, Pa, Visscher, Pm, Wright, Mj, Montgomery, Gw, Martin, Ng, Hernandez, D, Bandinelli, S, VAN DER HARST, P, Uda, M, Vollenweider, P, Scott, Ra, Langenberg, C, Wareham, Nj, VAN DUIJN, C, Beilby, J, Pramstaller, Pp, Hicks, Aa, Ouwehand, Wh, Oexle, K, Gieger, C, Metspalu, A, Camaschella, Clara, Toniolo, D, Swinkels, Dw, and Whitfield, Jb

Subjects
Genetics, Multidisciplinary, General Physics and Astronomy, General Chemistry, Biology, medicine.disease, General Biochemistry, Genetics and Molecular Biology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Iron homeostasis, 030220 oncology & carcinogenesis, medicine, 030217 neurology & neurosurgery, Hemochromatosis
Abstract

Corrigendum: Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

Published
2015

29. Identification of a single killer immunoglobulin-like receptor (KIR) gene in the porcine leukocyte receptor complex on chromosome 6q

Author

Penny Coggill, Jennifer G. Sambrook, Sophie Palmer, Haru-Hisa Takamatsu, Thomas Wileman, Sean Humphray, Sarah Sims, Alan Archibald, Stephan Beck, and Harminder Sehra

Subjects
Genetics, Receptor complex, Immunology, Molecular Sequence Data, Sus scrofa, chemical and pharmacologic phenomena, Immunoglobulin domain, Biology, Major histocompatibility complex, Chromosomes, KIR2DL1, Receptors, KIR, Receptors, KIR2DL1, biology.protein, Leukocytes, Gene family, Animals, Amino Acid Sequence, Receptors, Immunologic, Receptor, Gene, Phylogeny, Synteny
Abstract

Human killer immunoglobulin-like receptors (KIR) are expressed on natural killer (NK) cells and are involved in their immunoreactivity. While KIR with a long cytoplasmic tail deliver an inhibitory signal when bound to their respective major histocompatibility complex class I ligands, KIR with a short cytoplasmic tail can activate NK responses. The expansion of the KIR gene family originally appeared to be a phenomenon restricted to primates (human, apes, and monkeys) in comparison to rodents, which via convergent evolution have numerous C-type lectin-like Ly49 molecules that function analogously. Further studies have shown that multiple KIR are also present in cow and horse. In this study, we have identified by comparative genomics the first and possibly only KIR gene, named KIR2DL1, in the domesticated pig (Sus scrofa) allowing further evolutionary comparisons to be made. It encodes a protein with two extracellular immunoglobulin domains (D0 + D2), and a long cytoplasmic tail containing two inhibitory motifs. We have mapped the pig KIR2DL1 gene to chromosome 6q. Flanked by LILRa, LILRb, and LILRc, members of the leukocyte immunoglobulin-like receptor (LILR) family, on the centromeric end, and FCAR, NCR1, NALP7, NALP2, and GP6 on the telomeric end, pig demonstrates conservation of synteny with the human leukocyte receptor complex (LRC). Both the porcine KIR and LILR genes have diverged sufficiently to no longer be clearly orthologous with known human LRC family members.

Published
2006

30. A genome-wide survey of Major Histocompatibility Complex (MHC) genes and their paralogues in zebrafish

Author

Jennifer G. Sambrook, Felipe Figueroa, and Stephan Beck

Subjects
DNA, Complementary, lcsh:QH426-470, Genetic Linkage, lcsh:Biotechnology, Molecular Sequence Data, chemical and pharmacologic phenomena, Major histocompatibility complex, Genome, Major Histocompatibility Complex, 03 medical and health sciences, 0302 clinical medicine, Genetic linkage, lcsh:TP248.13-248.65, Chromosome 19, Gene Duplication, Genetics, Animals, Cluster Analysis, Humans, Zebrafish, Gene, 030304 developmental biology, 0303 health sciences, Models, Statistical, Polymorphism, Genetic, biology, Genome, Human, Chromosome Mapping, DNA, Genomics, biology.organism_classification, lcsh:Genetics, Haplotypes, Peptide transport, biology.protein, Human genome, Software, 030215 immunology, Biotechnology, Research Article
Abstract

BackgroundThe genomic organisation of the Major Histocompatibility Complex (MHC) varies greatly between different vertebrates. In mammals, the classical MHC consists of a large number of linked genes (e.g. greater than 200 in humans) with predominantly immune function. In some birds, it consists of only a small number of linked MHC core genes (e.g. smaller than 20 in chickens) forming a minimal essential MHC and, in fish, the MHC consists of a so far unknown number of genes including non-linked MHC core genes. Here we report a survey of MHC genes and their paralogues in the zebrafish genome.ResultsUsing sequence similarity searches against the zebrafish draft genome assembly (Zv4, September 2004), 149 putative MHC gene loci and their paralogues have been identified. Of these, 41 map to chromosome 19 while the remaining loci are spread across essentially all chromosomes. Despite the fragmentation, a set of MHC core genes involved in peptide transport, loading and presentation are still found in a single linkage group.ConclusionThe results extend the linkage information of MHC core genes on zebrafish chromosome 19 and show the distribution of the remaining MHC genes and their paralogues to be genome-wide. Although based on a draft genome assembly, this survey demonstrates an essentially fragmented MHC in zebrafish.

Published
2005

31. Single haplotype analysis demonstrates rapid evolution of the killer immunoglobulin-like receptor (KIR) loci in primates

Author

John Trowsdale, Sophie Palmer, Jennifer G. Sambrook, Stephan Beck, Mary Carrington, Laurent Abi-Rached, Peter Parham, Arman Bashirova, and Sarah Sims

Subjects
Most recent common ancestor, Genetic Markers, Primates, Receptor complex, Pan troglodytes, Sequence analysis, Molecular Sequence Data, chemical and pharmacologic phenomena, Biology, Evolution, Molecular, Receptors, KIR, Gene duplication, Genetics, otorhinolaryngologic diseases, Gene family, Animals, Humans, Amino Acid Sequence, Letters, Receptors, Immunologic, Gene, Genetics (clinical), Phylogeny, Repetitive Sequences, Nucleic Acid, Genome, Genome, Human, Haplotype, Genetic Variation, hemic and immune systems, Macaca mulatta, Killer Cells, Natural, Genes, Haplotypes, Human genome
Abstract

The human killer immunoglobulin-like receptors (KIR) are encoded within the Leukocyte Receptor Complex (LRC) on chromosome 19q13.4. Here we report the comparative genomic analysis of single KIR haplotypes in two other primates. In the common chimpanzee (Pan troglodytes), seven KIR genes (ptKIRnewI, ptKIRnewII, ptKIR2DL5, ptKIRnewIII, ptKIR3DP1, ptKIR2DL4, ptKIR3DL1/2) have been identified, and five KIR genes (mmKIRnewI, mmKIR1D, mmKIR2DL4, mmKIR3DL10, mmKIR3DL1) are present in the haplotype sequenced for the rhesus macaque (Macaca mulatta). Additional cDNA analysis confirms the genes predicted from the genomic sequence and reveals the presence of a fifth novel KIR gene (mmKIRnewII) in the second haplotype of the rhesus macaque. While all known human haplotypes contain both activating and inhibitory KIR genes, only inhibitory KIR genes (characterized by long cytoplasmic tails) were found by in silico and cDNA analyses in the two primate haplotypes studied here. Comparison of the two human and the two non-human primate haplotypes demonstrates rapid diversification of the KIR gene family members, many of which have diverged in a species-specific manner. An analysis of the intronic regions of the two non-human primates reveals the presence of ancient repeat elements, which are indicative of the duplication events that have taken place since the last common ancestor.

Published
2005

32. Fugu orthologues of human major histocompatibility complex genes: a genome survey

Author

Yagnesh Umrania, Melody S. Clark, Jennifer G. Sambrook, R. Duncan Campbell, Yvonne J. K. Edwards, Roslin Russell, and Greg Elgar

Subjects
Immunology, Genes, MHC Class II, Genes, MHC Class I, Locus (genetics), Biology, Major histocompatibility complex, Takifugu, Genome, Major Histocompatibility Complex, Antigen, Species Specificity, MHC class I, Genetics, Animals, Humans, Gene, Phylogeny, Zebrafish, Fugu, Chromosome Mapping, biology.organism_classification, Biological Evolution, biology.protein
Abstract

The major histocompatibility complex (MHC) region in fish has been subjected to piecemeal analysis centering on the in-depth characterization of single genes. The emphasis has been on those genes proven to be involved in the immune response such as the class I and class II antigen presenting genes and the complement genes. The Fugu genome data presents the opportunity to examine the short-range linkage of potentially all the human MHC orthologues and examine conserved synteny with the human and, to a more limited extent, zebrafish genomes. Analysis confirms the existence of a limited MHC locus in Fugu comprising the MHC class Ia genes and associated class II region genes involved in class I antigen presentation. Identification of additional human MHC orthologues indicates the completely dispersed nature of this region in fish, with a maximum of six MHC genes maintained within close proximity in any one contig. The majority of the other genes are present in the genome data as either singletons or pairs. Comparison with zebrafish substantiates previously observed linkages between class III region orthologues and hints at an ancient conserved class III region.

Published
2002

33. Association between Walking Speed and Age in Healthy, Free-Living Individuals Using Mobile Accelerometry—A Cross-Sectional Study

Author

Carmel Moore, Christian Lederer, Willem H. Ouwehand, Michaela Schimpl, Jennifer G. Sambrook, Martin Daumer, Anneke Neuhaus, and John Danesh

Subjects
Male, Aging, Anatomy and Physiology, Epidemiology, Cross-sectional study, Blood Pressure, Walking, Body Mass Index, 0302 clinical medicine, Interquartile range, 030212 general & internal medicine, Musculoskeletal System, Gait, Multidisciplinary, Epidemiology of Aging, Middle Aged, Databases as Topic, Health, Medicine, Female, Public Health, Algorithms, Research Article, Biotechnology, Adult, Drugs and Devices, medicine.medical_specialty, Adolescent, Science, Acceleration, Bioengineering, Context (language use), Biology, Medical Devices, Young Adult, 03 medical and health sciences, medicine, Humans, Sports and Exercise Medicine, Aged, Evolutionary Biology, Population Biology, Body Weight, Reproducibility of Results, Actigraphy, Body Height, Preferred walking speed, Cross-Sectional Studies, Gait analysis, Physical therapy, Exertion, Preventive Medicine, Physiological Processes, Organism Development, human activities, Body mass index, 030217 neurology & neurosurgery, Developmental Biology
Abstract

ContextWalking speed is a fundamental parameter of human motion and is increasingly considered as an important indicator of individuals' health status.ObjectiveTo evaluate the relationship of gait parameters, and demographic and physical characteristics in healthy men and women.Design, setting, and participantsRecruitment of a subsample (n = 358) of male and female blood donors taking part in the Cambridge CardioResource study. Collection of demographic data, measurement of physical characteristics (height, weight and blood pressure) and assessment of 7-day, free-living activity parameters using accelerometry and a novel algorithm to measure walking speed. Participants were a median (interquartile range[IQR]) age of 49 (16) years; 45% women; and had a median (IQR) BMI of 26 (5.4).Main outcome measureWalking speed.ResultsIn this study, the hypothesis that walking speed declines with age was generated using an initial 'open' dataset. This was subsequently validated in a separate 'closed' dataset that showed a decrease of walking speed of -0.0037 m/s per year. This is equivalent to a difference of 1.2 minutes, when walking a distance of 1 km aged 20 compared to 60 years. Associations between walking speed and other participant characteristics (i.e. gender, BMI and blood pressure) were non-significant. BMI was negatively correlated with the number of walking and running steps and longest non-stop distance.ConclusionThis is the first study using accelerometry which shows an association between walking speed and age in free-living, healthy individuals. Absolute values of gait speed are comparable to published normal ranges in clinical settings. This study highlights the potential use of mobile accelerometry to assess gait parameters which may be indicative of future health outcomes in healthy individuals.

Published
2011

34. Identification of the ancestral killer immunoglobulin-like receptor gene in primates

Author

Mike Piatak, J. D. Lifson, Jennifer G. Sambrook, Arman Bashirova, Stephan Beck, Penny Coggill, Mary Carrington, George S Vernikos, and Hanne Andersen

Subjects
Gene Expression, 0302 clinical medicine, Receptors, KIR, Gene cluster, Receptors, Immunologic, Cells, Cultured, Phylogeny, Genetics, 0303 health sciences, education.field_of_study, biology, Reverse Transcriptase Polymerase Chain Reaction, Chromosome Mapping, Killer Cells, Natural, Receptors, KIR2DL4, Common chimpanzee, Biotechnology, Research Article, Primates, Lineage (genetic), DNA, Complementary, lcsh:QH426-470, Pan troglodytes, lcsh:Biotechnology, Population, Molecular Sequence Data, chemical and pharmacologic phenomena, Human leukocyte antigen, KIR2DL4, Evolution, Molecular, 03 medical and health sciences, biology.animal, lcsh:TP248.13-248.65, otorhinolaryngologic diseases, Gene family, Animals, Humans, Amino Acid Sequence, RNA, Messenger, education, 030304 developmental biology, Gorilla gorilla, Sequence Homology, Amino Acid, Genome, Human, Sequence Analysis, DNA, Macaca mulatta, lcsh:Genetics, Human genome, Chromosomes, Human, Pair 19, 030215 immunology
Abstract

BackgroundKiller Immunoglobulin-like Receptors (KIR) are essential immuno-surveillance molecules. They are expressed on natural killer and T cells, and interact with human leukocyte antigens. KIR genes are highly polymorphic and contribute vital variability to our immune system. Numerous KIR genes, belonging to five distinct lineages, have been identified in all primates examined thus far and shown to be rapidly evolving. Since few KIR remain orthologous between species, with only one of them,KIR2DL4, shown to be common to human, apes and monkeys, the evolution of the KIR gene family in primates remains unclear.ResultsUsing comparative analyses, we have identified the ancestral KIR lineage (provisionally namedKIR3DL0) in primates. We showKIR3DL0to be highly conserved with the identification of orthologues in human (Homo sapiens), common chimpanzee (Pan troglodytes), gorilla (Gorilla gorilla), rhesus monkey (Macaca mulatta) and common marmoset (Callithrix jacchus). We predictKIR3DL0to encode a functional molecule in all primates by demonstrating expression in human, chimpanzee and rhesus monkey. Using the rhesus monkey as a model, we further show the expression profile to be typical of KIR by quantitative measurement ofKIR3DL0from an enriched population of natural killer cells.ConclusionOne reason whyKIR3DL0may have escaped discovery for so long is that, in human, it maps in between two related leukocyte immunoglobulin-like receptor clusters outside the known KIR gene cluster on Chromosome 19. Based on genomic, cDNA, expression and phylogenetic data, we report a novel lineage of immunoglobulin receptors belonging to the KIR family, which is highly conserved throughout 50 million years of primate evolution.

Published
2006

35. The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

Author

Suthesh Sivapalaratnam, Matthias Haimel, Stephen Kaptoge, Nilofar Sharifi, John J. Lambourne, Karyn Megy, Bing Ge, Jared O'Connell, William J. Astle, Luigi Grassi, Martijn van der Ent, Stuart Meacham, Stephen F. Garner, Eleanor Wheeler, John Danesh, Tony Kwan, Jennifer G. Sambrook, Tao Jiang, Louise C. Daugherty, Dirk S. Paul, Eva M. Janssen-Megens, Klaudia Walter, Stephen Watt, Alfonso Valencia, Joost H.A. Martens, Jonathan Marchini, S.M. Sheard, Mihir A Kamat, Ying Yang, Stephan Beck, Anita Kaan, Guillaume Bourque, Louella Vasquez, Jose A. Guerrero, Emanuele Di Angelantonio, Daniel Mead, David J. Roberts, Mattia Frontini, Nicole Soranzo, Myrto Kostadima, John Bradley, Heather Elding, Shuang-Yin Wang, Lu Chen, Salih Tuna, Kousik Kundu, Olivier Delaneau, Kathleen Freson, Diego Garrido-Martín, Dave Allen, David Bujold, Amit Mandoli, Lorenzo Bomba, Taco W. Kuijpers, Valentina Iotchkova, Alice L. Mann, James R Staley, Heleen J. Bouman, Kate Downes, Roderic Guigó, Carmel Moore, Kim Berentsen, Tomi Pastinen, Hendrik G. Stunnenberg, Willem H. Ouwehand, Fernando Riveros-Mckay, Romina Petersen, Enrique Carrillo-de-Santa-Pau, Steven P. Wilder, David Juan, Bowon Kim, Dace Ruklisa, Daniel Rico, Adam S. Butterworth, Vascular Medicine, Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Amsterdam institute for Infection and Immunity, Landsteiner Laboratory, and Other departments

Subjects
0301 basic medicine, COMPLEX DISEASES, Platelet disorder, Autoimmune diseases, Population, Genome-wide association study, Quantitative trait locus, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, blood, Mendelian randomization, autoimmune diseases, genetics, Allele, Complex disease, education, Mendelian randomisation, Molecular Biology, cardiovasular diseases, Genetic association, Genetics, education.field_of_study, epigenetics, hematology, Biochemistry, Genetics and Molecular Biology(all), complex disease, Hematology, hematopoiesis, cardiovascular diseases, 3. Good health, Hematopoiesis, 030104 developmental biology, Cardiovascular diseases, Epigenetics, Common disease-common variant
Abstract

Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (

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