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1. Blood eosinophil count and airway epithelial transcriptome relationships in COPD versus asthma

Author: Matthew Richardson, Bertrand De-Meulder, John H. Riley, Anne Boland, Gian Andri Thun, Charles Auffray, Stewart Bates, Anna Esteve-Codina, María Soler Artigas, Wim Timens, Timothy S. C. Hinks, David G. Parr, Maarten van den Berge, Ivo Gut, Per Venge, Dave Singh, Christopher E. Brightling, Martin D. Tobin, Ratko Djukanovic, Leena George, Timm Greulich, Kian Fan Chung, Jens M. Hohlfeld, Antje Prasse, Stelios Pavlidis, Sally E. Wenzel, Ian M. Adcock, Scott Wagers, Piera Boschetto, Pieter S. Hiemstra, Loems Ziegler-Heitbrock, Lindsay M. Edwards, Adam Nowinski, Sven Erik-Dahlen, Simon Heath, Peter J. Sterk, Salman Siddiqui, Adam Taylor, Imre Barta, National Institute for Health Research, Groningen Research Institute for Asthma and COPD (GRIAC), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Pulmonology, and Publica
Subjects: Male, U-BIOPRED and the EvA study teams, 0301 basic medicine, Allergy, Respiratory Medicine and Allergy, Transcriptome, Leukocyte Count, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, T2-immunity, Immunology and Allergy, Prospective Studies, RNA-Seq, Lungmedicin och allergi, COPD, POST-HOC ANALYSIS, Middle Aged, Asthma, Chronic Obstructive Pulmonary Disease, Eosinophil, Gene Expression, respiratory system, 3. Good health, medicine.anatomical_structure, 1107 Immunology, Original Article, Female, medicine.symptom, Life Sciences & Biomedicine, medicine.drug, PHASE, Immunology, Eosinòfils, Respiratory Mucosa, Asthma and Lower Airway Disease, OBSTRUCTIVE PULMONARY-DISEASE, NO, chronic obstructive pulmonary disease, 03 medical and health sciences, T2‐immunity, Th2 Cells, SPUTUM, medicine, Humans, eosinophil, Asma, Aged, Science & Technology, Lung, MEPOLIZUMAB, business.industry, Pulmons -- Malalties, Immunoglobulin E, asthma, medicine.disease, Expressió gènica, SECONDARY ANALYSIS, respiratory tract diseases, Eosinophils, EXACERBATIONS, Immunitat, 030104 developmental biology, 030228 respiratory system, asthma, chronic obstructive pulmonary disease, eosinophil, gene expression, T2-immunity, gene expression, Sputum, ORIGINAL ARTICLES, business, Mepolizumab, Biomarkers, LUNG
Abstract: Background Whether the clinical or pathophysiologic significance of the “treatable trait” high blood eosinophil count in COPD is the same as for asthma remains controversial. We sought to determine the relationship between the blood eosinophil count, clinical characteristics and gene expression from bronchial brushings in COPD and asthma. Methods Subjects were recruited into a COPD (emphysema versus airway disease [EvA]) or asthma cohort (Unbiased BIOmarkers in PREDiction of respiratory disease outcomes, U‐BIOPRED). We determined gene expression using RNAseq in EvA (n = 283) and Affymetrix microarrays in U‐BIOPRED (n = 85). We ran linear regression analysis of the bronchial brushings transcriptional signal versus blood eosinophil counts as well as differential expression using a blood eosinophil > 200 cells/μL as a cut‐off. The false discovery rate was controlled at 1% (with continuous values) and 5% (with dichotomized values). Results There were no differences in age, gender, lung function, exercise capacity and quantitative computed tomography between eosinophilic versus noneosinophilic COPD cases. Total serum IgE was increased in eosinophilic asthma and COPD. In EvA, there were 12 genes with a statistically significant positive association with the linear blood eosinophil count, whereas in U‐BIOPRED, 1197 genes showed significant associations (266 positive and 931 negative). The transcriptome showed little overlap between genes and pathways associated with blood eosinophil counts in asthma versus COPD. Only CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts. Conclusion Despite shared “treatable traits” between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different., In a chronic obstructive pulmonary disease (COPD) cohort (EvA, n = 283), 12 genes, whereas in asthma cohort (UBIOPRED, n = 85), 1197 genes in bronchial epithelial brushes were correlated with a blood eosinophil count. The gene CST1 was common to eosinophilic asthma and COPD and was replicated in independent cohorts. Despite shared “treatable traits” between asthma and COPD, the molecular mechanisms underlying these clinical entities are predominately different.
Published: 2019
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2. DeepMP: a deep learning tool to detect DNA base modifications on Nanopore sequencing data

Author: Marc Dabad, Jens Lagergren, Jose Bonet, Simon Heath, Abel Gonzalez-Perez, Mandi Chen, and Nuria Lopez-Bigas
Subjects: Statistics and Probability, Computer science, Computational biology, Biochemistry, Convolutional neural network, Nanopores, 03 medical and health sciences, chemistry.chemical_compound, Deep Learning, 0302 clinical medicine, Escherichia coli, Humans, Molecular Biology, 030304 developmental biology, Supplementary data, 0303 health sciences, business.industry, Deep learning, Informàtica -- Programaris, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, DNA, Methylation, ADN -- Metilació, Base (topology), Computer Science Applications, Computational Mathematics, Genòmica, Nanopore Sequencing, Nanopore, Computational Theory and Mathematics, chemistry, DNA methylation, Nanopore sequencing, Artificial intelligence, business, Genètica, Software, 030217 neurology & neurosurgery
Abstract: Motivation DNA methylation plays a key role in a variety of biological processes. Recently, Nanopore long-read sequencing has enabled direct detection of these modifications. As a consequence, a range of computational methods have been developed to exploit Nanopore data for methylation detection. However, current approaches rely on a human-defined threshold to detect the methylation status of a genomic position and are not optimized to detect sites methylated at low frequency. Furthermore, most methods use either the Nanopore signals or the basecalling errors as the model input and do not take advantage of their combination. Results Here, we present DeepMP, a convolutional neural network-based model that takes information from Nanopore signals and basecalling errors to detect whether a given motif in a read is methylated or not. Besides, DeepMP introduces a threshold-free position modification calling model sensitive to sites methylated at low frequency across cells. We comprehensively benchmarked DeepMP against state-of-the-art methods on Escherichia coli, human and pUC19 datasets. DeepMP outperforms current approaches at read-based and position-based methylation detection across sites methylated at different frequencies in the three datasets. Availability and implementation DeepMP is implemented and freely available under MIT license at https://github.com/pepebonet/DeepMP. Supplementary information Supplementary data are available at Bioinformatics online.
Published: 2021
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3. Gender specific airway gene expression in COPD sub-phenotypes supports a role of mitochondria and of different types of leukocytes

Author: Timm Greulich, Simon Heath, Wolfgang Gesierich, Winfried Moeller, David Endesfelder, María Soler Artigas, Thasso Griebel, Andreas Rembert Koczulla, Anna Esteve-Codina, Jens M. Hohlfeld, Umme Kolsum, Robert Olaso, Balazs Dome, Ivo Gut, Mariarita Stendardo, Tobias Welte, János Strausz, Christopher E. Brightling, Deepak Subramanian, Marcos Fernandez-Callejo, Marion S Heiss-Neumann, Antje Prasse, Sunil Gupta, Marie-Thérèse Bihoreau, Dorothe Burggraf, Dave Singh, Marc Dabad, Piera Boschetto, Jean-François Deleuze, Imre Barta, Damian Korzybski, Joachim Müller-Quernheim, Per Venge, Thomas Fuehner, Kathrin Renner, Pieter S. Hiemstra, Loems Ziegler-Heitbrock, Thomas Höfer, Lukas Jerrentrup, Marco Piattella, Otmar Schmid, David G. Parr, Dorota Górecka, Elfriede Noessner, Wolfgang zu Castell, Anne Boland, Adam Nowinski, Vandana Gupta, Publica, Esteve-Codina, Anna, Soler Artigas, María, Dabad, Marc, Fernández Callejo, Marcos, Griebel, Thasso, Heath, Simon, Gut, Ivo Glynne, and Ziegler-Heitbrock, Loems
Subjects: Male, 0301 basic medicine, CPA3, Molecular biology, Science, Respiratory Medicine and Allergy, Immunology, Gene Expression, Socio-culturale, Respiratory Mucosa, Biology, Article, Transcriptome, Kruppel-Like Factor 4, Pulmonary Disease, Chronic Obstructive, 03 medical and health sciences, Medical research, Sex Factors, 0302 clinical medicine, Gene expression, Leukocytes, medicine, Humans, Gene, Molecular medicine, Lungmedicin och allergi, COPD, Multidisciplinary, Gene Expression Profiling, MNDA, Computational Biology, medicine.disease, Phenotype, Mitochondria, 3. Good health, ddc, respiratory tract diseases, CXCL1, 030104 developmental biology, 030228 respiratory system, Medicine, Female, Disease Susceptibility, Biomarkers
Abstract: Chronic obstructive pulmonary disease (COPD) is a destructive inflammatory disease and the genes expressed within the lung are crucial to its pathophysiology. We have determined the RNAseq transcriptome of bronchial brush cells from 312 stringently defined ex-smoker patients. Compared to healthy controls there were for males 40 differentially expressed genes (DEGs) and 73 DEGs for females with only 26 genes shared. The gene ontology (GO) term "response to bacterium" was shared, with several different DEGs contributing in males and females. Strongly upregulated genes TCN1 and CYP1B1 were unique to males and females, respectively. For male emphysema (E)-dominant and airway disease (A)-dominant COPD (defined by computed tomography) the term "response to stress" was found for both sub-phenotypes, but this included distinct up-regulated genes for the E-sub-phenotype (neutrophil-related CSF3R, CXCL1, MNDA) and for the A-sub-phenotype (macrophage-related KLF4, F3, CD36). In E-dominant disease, a cluster of mitochondria-encoded (MT) genes forms a signature, able to identify patients with emphysema features in a confirmation cohort. The MT-CO2 gene is upregulated transcriptionally in bronchial epithelial cells with the copy number essentially unchanged. Both MT-CO2 and the neutrophil chemoattractant CXCL1 are induced by reactive oxygen in bronchial epithelial cells. Of the female DEGs unique for E- and A-dominant COPD, 88% were detected in females only. In E-dominant disease we found a pronounced expression of mast cell-associated DEGs TPSB2, TPSAB1 and CPA3. The differential genes discovered in this study point towards involvement of different types of leukocytes in the E- and A-dominant COPD sub-phenotypes in males and females. This work was supported by the European Union, FP7 project # 200506. We acknowledge the helpful discussions with Emanuele Raineri, Barcelona, Spain and with Wilfried Karmaus, Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, Tennessee, USA. CNAG-CRG lab is a member of the Spanish National Bioinformatics Institute (INB), PRB2-ISCIII and is supported by grant PT13/0001 of the PE I+D+i 2013-2016, funded by ISCIII and FEDER. Work by CB at Leicester and by LZH at Munich was also supported the European Union FP7 project # 270194.
Published: 2021

4. Impact of DNA methylation on 3D genome structure

Author: Diana Buitrago, Anna Esteve-Codina, Isabelle Brun Heath, Mireia Labrador, Juan Pablo Arcon, Ivo Gut, Rafael Lema, Simon Heath, Pablo D. Dans, Marta Gut, Oscar Flores, Julie Blanc, Modesto Orozco, David Bellido, and Núria Villegas
Subjects: 0301 basic medicine, Methyltransferase, Intravital Microscopy, General Physics and Astronomy, DNA Methyltransferase 3A, Epigenesis, Genetic, Histones, chemistry.chemical_compound, 0302 clinical medicine, Computational models, DNA (Cytosine-5-)-Methyltransferases, RNA-Seq, 0303 health sciences, Multidisciplinary, DNA methylation, Methylation, Chromatin, Recombinant Proteins, Cell biology, Nucleosomes, Genome, Fungal, DNA (Cytosine-5-)-Methyltransferase 1, Saccharomyces cerevisiae Proteins, Science, Centromere, Chromatin remodelling, Saccharomyces cerevisiae, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Nucleosome, Epigenetics, Gene, 030304 developmental biology, Nuclear organization, Whole Genome Sequencing, General Chemistry, Chromatin Assembly and Disassembly, Repressor Proteins, 030104 developmental biology, chemistry, Mutation, Mutagenesis, Site-Directed, 5' Untranslated Regions, 030217 neurology & neurosurgery, DNA
Abstract: Determining the effect of DNA methylation on chromatin structure and function in higher organisms is challenging due to the extreme complexity of epigenetic regulation. We studied a simpler model system, budding yeast, that lacks DNA methylation machinery making it a perfect model system to study the intrinsic role of DNA methylation in chromatin structure and function. We expressed the murine DNA methyltransferases in Saccharomyces cerevisiae and analyzed the correlation between DNA methylation, nucleosome positioning, gene expression and 3D genome organization. Despite lacking the machinery for positioning and reading methylation marks, induced DNA methylation follows a conserved pattern with low methylation levels at the 5’ end of the gene increasing gradually toward the 3’ end, with concentration of methylated DNA in linkers and nucleosome free regions, and with actively expressed genes showing low and high levels of methylation at transcription start and terminating sites respectively, mimicking the patterns seen in mammals. We also see that DNA methylation increases chromatin condensation in peri-centromeric regions, decreases overall DNA flexibility, and favors the heterochromatin state. Taken together, these results demonstrate that methylation intrinsically modulates chromatin structure and function even in the absence of cellular machinery evolved to recognize and process the methylation signal., Multi-layered epigenetic regulation in higher eukaryotes makes it challenging to disentangle the individual effects of modifications on chromatin structure and function. Here, the authors expressed mammalian DNA methyltransferases in yeast, which have no DNA methylation, to show that methylation has intrinsic effects on chromatin structure.
Published: 2021

5. Lung microbiome composition and bronchial epithelial gene expression in patients with COPD versus healthy individuals: a bacterial 16S rRNA gene sequencing and host transcriptomic analysis

Author: Balazs Dome, Matthew Richardson, Dave Singh, Christopher E. Brightling, Adam Nowinski, Koirobi Haldar, Julie A. Morrissey, Joachim Müller-Quernheim, Michael R. Barer, Ivo Gut, Anna Esteve-Codina, Antje Prasse, Mohammadali Yavari Ramsheh, Loems Ziegler-Heitbrock, Imre Barta, Mariarita Stendardo, David G. Parr, Jens M. Hohlfeld, Simon Heath, Damian Korzybski, Tobias Welte, Lillie Faye Purser, Piera Boschetto, Timm Greulich, and Publica
Subjects: Microbiology (medical), Spirometry, Lung microbiome, Medicine (General), Prevotella, Socio-culturale, 030204 cardiovascular system & hematology, Microbiology, 03 medical and health sciences, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, R5-920, Adrenal Cortex Hormones, Virology, RNA, Ribosomal, 16S, medicine, Humans, Moraxella, 030212 general & internal medicine, Microbiome, Lung, 2. Zero hunger, COPD, biology, medicine.diagnostic_test, Bacteria, business.industry, Microbiota, Sputum, Genes, rRNA, medicine.disease, biology.organism_classification, QR1-502, 3. Good health, respiratory tract diseases, Infectious Diseases, medicine.anatomical_structure, Immunology, business, Transcriptome, Dysbiosis
Abstract: Background: Chronic obstructive pulmonary disease (COPD) is associated with airway inflammation and bacterial dysbiosis. The relationship between the airway microbiome and bronchial gene expression in COPD is poorly understood. We aimed to identify differences in the airway microbiome from bronchial brushings in patients with COPD and healthy individuals and to investigate whether any distinguishing bacteria are related to bronchial gene expression. Methods: For this 16S rRNA gene sequencing and host transcriptomic analysis, individuals aged 45–75 years with mild-to-moderate COPD either receiving or not receiving inhaled corticosteroids and healthy individuals in the same age group were recruited as part of the Emphysema versus Airways Disease (EvA) consortium from nine centres in the UK, Germany, Italy, Poland, and Hungary. Individuals underwent clinical characterisation, spirometry, CT scans, and bronchoscopy. From bronchoscopic bronchial brush samples, we obtained the microbial profiles using 16S rRNA gene sequencing and gene expression using the RNA-Seq technique. We analysed bacterial genera relative abundance and the associations between genus abundance and clinical characteristics or between genus abundance and host lung transcriptional signals in patients with COPD versus healthy individuals, and in patients with COPD with versus without inhaled corticosteroids treatment. Findings Between February, 2009, and March, 2012, we obtained brush samples from 574 individuals. We used 546 of 574 samples for analysis, including 207 from healthy individuals and 339 from patients with COPD (192 with inhaled corticosteroids and 147 without). The bacterial genera that most strongly distinguished patients with COPD from healthy individuals were Prevotella (median relative abundance 33·5%, IQR 14·5–49·4, in patients with COPD vs 47·7%, 31·1–60·7, in healthy individuals; p
Published: 2021

6. Dyslipidaemia and cardiovascular risk

Author: Simon Heath, Aidan Ryan, and Paul Cook
Subjects: Adult, Male, medicine.medical_specialty, medicine.medical_treatment, Psychotic depression, Disease, 030204 cardiovascular system & hematology, Cardiovascular System, Risk Assessment, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, Risk Factors, Internal medicine, medicine, Humans, 030212 general & internal medicine, Family history, Antipsychotic, Creatine Kinase, Triglycerides, Dyslipidemias, Risperidone, business.industry, Depression, General Medicine, medicine.disease, Patient Outcome Assessment, Cholesterol, chemistry, Cardiovascular Diseases, lipids (amino acids, peptides, and proteins), Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, Risk assessment, Lipoproteins, HDL, Risk Reduction Behavior, Kidney disease, medicine.drug, Antipsychotic Agents
Abstract: What you need to know A 40 year old man visits his general practitioner for annual antipsychotic monitoring. He is taking risperidone and sertraline for a previous diagnosis of psychotic depression. Recent blood tests showed a total cholesterol of 6.0, low density lipoprotein (calculated) (LDLc) 3.8, high density lipoprotein (HDL) 0.8, non-HDL 5.2, and triglyceride of 3.0 mmol/L; other blood tests were within the reference range. Patients may require consideration of dyslipidaemia and cardiovascular risk for a number of reasons, including pre-existing physical health conditions such as chronic kidney disease; medications such as antipsychotics; family history such as hypercholesterolaemia or ischaemic heart disease; or due to age thresholds, such as cardiovascular disease (CVD) screening in over-40s. This article provides a framework for diagnosing and managing dyslipidaemia, with the aim of reducing patients’ CVD risk. History Ask about Fig 1 Approach to diagnosis and management of hypercholesterolaemia (based on guidance from the National Institute of Health and Care Excellence) The patient advice leaflet, included as a supplementary file with this …
Published: 2019

7. Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage

Author: Anke K. Bergmann, Núria Verdaguer-Dot, José I. Martín-Subero, Christiane Pott, Hendrik G. Stunnenberg, Eva Giné, Wolfram Klapper, Itziar Salaverria, Roser Vilarrasa-Blasi, Joost H.A. Martens, Ivo Gut, Paul Flicek, Avik Datta, Giancarlo Castellano, Ana C. Queirós, Marta Kulis, Alba Navarro, Wyndham H. Wilson, María José Calasanz, Reiner Siebert, Armando López-Guillermo, Nuria Russiñol, Pedro Jares, Elias Campo, Anna Enjuanes, Emanuele Raineri, Renée Beekman, Angelika Merkel, Guillem Clot, Inga Vater, Harmen J.G. van de Werken, Simon Heath, Sílvia Beà, Romina Royo, Martí Duran-Ferrer, Cell biology, and Urology
Subjects: Epigenomics, 0301 basic medicine, Cancer Research, mantle cell lymphoma, lymphoma, Lymphoma, Mantle-Cell, Biology, Article, Epigenesis, Genetic, SOXC Transcription Factors, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, hemic and lymphatic diseases, SOX11, Humans, Cell Lineage, Computer Simulation, Epigenetics, DNA looping, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), RNA-Directed DNA Methylation, Molecular Biology, B-Lymphocytes, High-Throughput Nucleotide Sequencing, Methylation, Cell Biology, DNA Methylation, Molecular biology, Chromatin, ChIP-seq, Gene Expression Regulation, Neoplastic, Enhancer Elements, Genetic, 030104 developmental biology, Differentially methylated regions, Oncology, 030220 oncology & carcinogenesis, DNA methylation, Disease Progression, chromatin, Illumina Methylation Assay, enhancer, whole-genome bisulfite sequencing
Abstract: SummaryWe analyzed the in silico purified DNA methylation signatures of 82 mantle cell lymphomas (MCL) in comparison with cell subpopulations spanning the entire B cell lineage. We identified two MCL subgroups, respectively carrying epigenetic imprints of germinal-center-inexperienced and germinal-center-experienced B cells, and we found that DNA methylation profiles during lymphomagenesis are largely influenced by the methylation dynamics in normal B cells. An integrative epigenomic approach revealed 10,504 differentially methylated regions in regulatory elements marked by H3K27ac in MCL primary cases, including a distant enhancer showing de novo looping to the MCL oncogene SOX11. Finally, we observed that the magnitude of DNA methylation changes per case is highly variable and serves as an independent prognostic factor for MCL outcome.
Published: 2016
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8. Differential expression of long non-coding RNAs are related to proliferation and histological diversity in follicular lymphomas

Author: Philippe Salembier, Simon Heath, Alba Navarro, Andreas Rosenwald, Elias Campo, Marta Gut, Pau Bellot, Alejandro Roisman, José I. Martín-Subero, Patricia Pérez-Galán, Heike Horn, Laura Magnano, Anna Esteve-Codina, Blanca Gonzalez-Farre, Giancarlo Castellano, Mattia Bosio, Marta Aymerich, German Ott, Pedro Jares, Luis Hernández, Irma Slavutsky, Albert Oliveras, Marc Dabad, Armando López-Guillermo, Universitat Politècnica de Catalunya. Departament de Teoria del Senyal i Comunicacions, Barcelona Supercomputing Center, and Universitat Politècnica de Catalunya. GPI - Grup de Processament d'Imatge i Vídeo
Subjects: Male, Limfomes, CIENCIAS MÉDICAS Y DE LA SALUD, Proliferation index, Ciències de la salut::Medicina [Àrees temàtiques de la UPC], Cell, Follicular lymphoma, Genética Humana, Biology, 03 medical and health sciences, 0302 clinical medicine, Gene expression, medicine, Humans, Gene silencing, RNA, Neoplasm, Lymphoma, Follicular, Gene, Hematologia, Cell proliferation, Proliferació cel·lular, Cell growth, Hematology, Cell cycle, medicine.disease, G1 Phase Cell Cycle Checkpoints, LncRNA, Gene Expression Regulation, Neoplastic, Medicina Básica, medicine.anatomical_structure, 030220 oncology & carcinogenesis, S Phase Cell Cycle Checkpoints, Cancer research, RNA, Female, RNA, Long Noncoding, Lymphomas, RNA-seq, 030215 immunology
Abstract: Long non‐coding RNA s (lncRNA s) comprise a family of non‐coding transcripts that are emerging as relevant gene expression regulators of different processes, including tumour development. To determine the possible contribution of lncRNA to the pathogenesis of follicular lymphoma (FL ) we performed RNA ‐sequencing at high depth sequencing in primary FL samples ranging from grade 1‐3A to aggressive grade 3B variants using unpurified (n = 16) and purified (n = 12) tumour cell suspensions from nodal samples. FL grade 3B had a significantly higher number of differentially expressed lncRNA s (dif‐lncRNA s) with potential target coding genes related to cell cycle regulation. Nine out of the 18 selected dif‐lncRNA s were validated by quantitative real time polymerase chain reaction in an independent series (n = 43) of FL . RP 4‐694A7.2 was identified as the top deregulated lncRNA potentially involved in cell proliferation. RP 4‐694A7.2 silencing in the WSU ‐FSCCL FL cell line reduced cell proliferation due to a block in the G1/S phase. The relationship between RP 4‐694A7.2 and proliferation was confirmed in primary samples as its expression levels positively related to the Ki‐67 proliferation index. In summary, lncRNA s are differentially expressed across the clinico‐biological spectrum of FL and a subset of them, related to cell cycle, may participate in cell proliferation regulation in these tumours. Fil: Roisman, Alejandro. Lymphoid Neoplasm Programme, Institut d'Investigacions Biomèdiques August Pi i Sunyer; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Castellano, Giancarlo. Universidad de Barcelona; España Fil: Navarro, Alba. Centro de Investigación Biomédica en Red de Cáncer; España. Lymphoid Neoplasm Programme, Institut d'Investigacions Biomèdiques August Pi i Sunyer; España Fil: Gonzalez Farre, Blanca. Lymphoid Neoplasm Programme, Institut d'Investigacions Biomèdiques August Pi i Sunyer; España. Universidad de Barcelona; España Fil: Pérez Galan, Patricia. Lymphoid Neoplasm Programme, Institut d'Investigacions Biomèdiques August Pi i Sunyer; España Fil: Esteve Codina, Anna. Universitat Pompeu Fabra; España. Barcelona Institute Of Science And Technology.; España Fil: Dabad, Marc. Barcelona Institute Of Science And Technology.; España. Universitat Pompeu Fabra; España Fil: Heath, Simon. Universitat Pompeu Fabra; España. Barcelona Institute Of Science And Technology.; España Fil: Gut, Marta. Universitat Pompeu Fabra; España. Barcelona Institute Of Science And Technology.; España Fil: Bosio, Mattia. Barcelona Supercomputing Center - Centro Nacional de Supercomputacion; España Fil: Bellot, Pau. Barcelona Institute Of Science And Technology. Institut Català D'investigació Química.; España Fil: Salembier, Philippe. Universidad Politécnica de Catalunya; España Fil: Oliveras, Albert. Universidad Politécnica de Catalunya; España Fil: Slavutsky, Irma Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Magnano, Andrea Laura. Hospital Clínico de Barcelona; España. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Horn, Heike. Eberhard Karls Universität Tübingen.; Alemania Fil: Rosenwald, Andreas. University of Würzburg; Alemania Fil: Ott, German. Department of Clinical Pathology; Alemania Fil: Aymerich, Marta. Lymphoid Neoplasm Programme, Institut d'Investigacions Biomèdiques August Pi i Sunyer; España Fil: López Guillermo, Armando. Hospital Clínico de Barcelona; España Fil: Jares, Pedro. Universidad de Barcelona; España. Lymphoid Neoplasm Programme, Institut d'Investigacions Biomèdiques August Pi i Sunyer; España Fil: Martín Subero, José I.. Centro de Investigación Biomédica en Red de Cáncer; España. Lymphoid Neoplasm Programme, Institut d'Investigacions Biomèdiques August Pi i Sunyer; España Fil: Campo, Elías. Centro de Investigación Biomédica en Red de Cáncer; España. Lymphoid Neoplasm Programme, Institut d'Investigacions Biomèdiques August Pi i Sunyer; España. Hospital Clínico de Barcelona; España Fil: Hernández, Luis. Lymphoid Neoplasm Programme, Institut d'Investigacions Biomèdiques August Pi i Sunyer; España. Centro de Investigación Biomédica en Red de Cáncer; España
Published: 2019

9. Whole-genome DNA hyper-methylation in iPSC-derived dopaminergic neurons from Parkinson's disease patients

Author: Simon Heath, Angelika Merkel, Mario Ezquerra, Angel Raya, Antonella Consiglio, Giancarlo Castellano, María-José Martí, Rubén Fernández-Santiago, and Eduard Tolosa
Subjects: 0301 basic medicine, Male, Parkinson's disease, Bisulfite sequencing, ADN, Genome, Epigenesis, Genetic, 0302 clinical medicine, Malaltia de Parkinson, DMCpGs, DNA methylation, Differentially methylated CpGs, Parkinson disease (PD), Whole-genome bisulfite sequencing (WGBS), iPSC-derived DAn, Genetics (clinical), Cells, Cultured, Genetics, Cultured, DNA methylation, Parkinson Disease, Methylation, Middle Aged, 3. Good health, CpG site, 030220 oncology & carcinogenesis, Female, Metilació, Adult, Cells, Induced Pluripotent Stem Cells, Short Report, Biology, 03 medical and health sciences, Parkinson disease (PD), Genetic, DMCpGs, Humans, Epigenetics, Molecular Biology, Gene, Differentially methylated CpGs, iPSC-derived DAn, Whole-genome bisulfite sequencing (WGBS), CpG Islands, Dopaminergic Neurons, Whole Genome Sequencing, DNA Methylation, DNA, Human genetics, 030104 developmental biology, Developmental Biology, Epigenesis
Abstract: Background: Parkinson’s disease (PD) is characterized by the loss of midbrain dopaminergic neurons (DAn). Previously, we described the presence of DNA hyper- and hypo-methylation alterations in induced pluripotent stem cells (iPSC)-derived DAn from PD patients using the Illumina 450K array which prominently covers gene regulatory regions. Methods: To expand and contextualize previous findings, we performed the first whole-genome DNA bisulfite sequencing (WGBS) using iPSC-derived DAn from representative PD subjects: one sporadic PD (sPD) patient, one monogenic LRRK2-associated PD patient (L2PD), and one control. Results: At the whole-genome level, we detected global DNA hyper-methylation in the PD which was similarly spread across the genome in both sPD and L2PD and mostly affected intergenic regions. Conclusion: This study implements previous epigenetic knowledge in PD at a whole genome level providing the first comprehensive and unbiased CpG DNA methylation data using iPSC-derived DAn from PD patients. Our results indicate that DAn from monogenic or sporadic PD exhibit global DNA hyper-methylation changes. Findings from this exploratory study are to be validated in further studies analyzing other PD cell models and patient tissues. This work was supported by the Fondo de Investigaciones Sanitarias of the Instituto de Salud Carlos III (ISCIII) to M.E. (grant # PI14/00426), the Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) to the Movement Disorders Unit of the Neurology Service from the Hospital Clínic de Barcelona to E.T., M.-J.M., R.F.-S., and M.E. (grant # PRI-16-2017). R.F.S. was supported by a Jóvenes Investigadores grant (#SAF2015-73508-JIN) through the Programa Estatal de Investigación, Desarrollo e Innovación Orientada a los Retos de la Sociedad (Plan Estatal de I+D+I 2013–2016) of the Spanish Ministry of Economy and Competitiveness (MINECO), and the Agencia Estatal de Investigación (AEI), which is cofunded by FEDER (AEI/FEDER/UE). Other funding included the grants BFU2013-49157-P, BFU2016-80870-P, and the European Research Council (ERC) 2012-StG (311736- PD-HUMMODEL) to A.C; ISCIII/FEDER (RD16/0011/0024) and Generalitat de Catalunya (iPS4BioMed SGR 2017–2019) to A.R.; and ISCIII/FEDER (PIE14/00061) to A.R.
Published: 2019

10. PD-1 signaling affects cristae morphology and leads to mitochondrial dysfunction in human CD8+ T lymphocytes

Author: Jesús Ogando, Cristina Nuevo-Tapioles, Antonio González-Pérez, Marta Gut, Anna Esteve-Codina, Santos Mañes, Simon Heath, José M. Cuezva, Rosa Ana Lacalle, Javier Santos, María Eugenia Sáez, UAM. Departamento de Biología Molecular, Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Fundación Merck Salud, European Commission, Instituto de Salud Carlos III, and Comunidad de Madrid
Subjects: 0301 basic medicine, Cancer Research, Mitochondrial DNA, T cell, Immunology, Oxidative phosphorylation, Mitochondrion, lcsh:RC254-282, Cristae, 03 medical and health sciences, 0302 clinical medicine, PD-1, medicine, Immunology and Allergy, Receptor, Pharmacology, Chemistry, CD28, CD8, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Biología y Biomedicina / Biología, Cell biology, MICOS, 030104 developmental biology, medicine.anatomical_structure, Metabolism, Oncology, 030220 oncology & carcinogenesis, Molecular Medicine, Signal transduction, RNA-seq
Abstract: [Background] Binding of the programmed death-1 (PD-1) receptor to its ligands (PD-L1/2) transduces inhibitory signals that promote exhaustion of activated T cells. Blockade of the PD-1 pathway is widely used for cancer treatment, yet the inhibitory signals transduced by PD-1 in T cells remain elusive., [Methods] Expression profiles of human CD8+ T cells in resting, activated (CD3 + CD28) and PD-1-stimulated cells (CD3 + CD28 + PD-L1-Fc) conditions were evaluated by RNA-seq. Bioinformatic analyses were used to identify signaling pathways differentially regulated in PD-1-stimulated cells. Metabolic analyses were performed with SeaHorse technology, and mitochondrial ultrastructure was determined by transmission electron microscopy. PD-1-regulated mitochondrial genes were silenced using short-hairpin RNA in primary cells. Blue native gel electrophoresis was used to determine respiratory supercomplex assembly., [Results] PD-1 engagement in human CD8+ T cells triggers a specific, progressive genetic program different from that found in resting cells. Gene ontology identified metabolic processes, including glycolysis and oxidative phosphorylation (OXPHOS), as the main pathways targeted by PD-1. We observed severe functional and structural alterations in the mitochondria of PD-1-stimulated cells, including a reduction in the number and length of mitochondrial cristae. These cristae alterations were associated with reduced expression of CHCHD3 and CHCHD10, two proteins that form part of the mitochondrial contact site and cristae organizing system (MICOS). Although PD-1-stimulated cells showed severe cristae alterations, assembly of respiratory supercomplexes was unexpectedly greater in these cells than in activated T cells. CHCHD3 silencing in primary CD8+ T cells recapitulated some effects induced by PD-1 stimulation, including reduced mitochondrial polarization and interferon-γ production following T cell activation with anti-CD3 and -CD28 activating antibodies., [Conclusions] Our results suggest that mitochondria are the main targets of PD-1 inhibitory activity. PD-1 reprograms CD8+ T cell metabolism for efficient use of fatty acid oxidation; this mitochondrial phenotype might explain the long-lived phenotype of PD-1-engaged T cells., This work was funded by grants from the Spanish Ministerio de Economía y Competitividad (MINECO) (SAF2014–54475-R and SAF2017–83732-R to SM; SAF2016–75916-R to JMC; AEI/FEDER, EU), the Instituto de Salud Carlos III (PT17 PT17/0009/0019, AEI/FEDER, EU), the Comunidad de Madrid (B2017/BMD-3733; Inmunothercan-CM, to SM), and the Merck-Salud Foundation (to SM). JO, JS and CN-T are supported by predoctoral fellowships from the MINECO and the EU European Social Fund.
Published: 2019

11. Nucleosome Dynamics: a new tool for the dynamic analysis of nucleosome positioning

Author: Modesto Orozco, Federica Battistini, Diana Buitrago, Isabelle Brun Heath, Laia Codó, Romina Royo, Pau de Jorge, Marc Del Pino, Simon Heath, Oscar Flores, Josep Lluís Gelpí, Ricard Illa, Genís Bayarri, and Barcelona Supercomputing Center
Subjects: Informàtica::Aplicacions de la informàtica::Bioinformàtica [Àrees temàtiques de la UPC], Bioinformatics, ADN, Genomics, Context (language use), Computational biology, Saccharomyces cerevisiae, Biology, Cell cycle phase, Cromatina, 03 medical and health sciences, 0302 clinical medicine, Software, Bioinformàtica, Genetics, Computational methods, Nucleosome, Genòmica -- Informàtica, 030304 developmental biology, 0303 health sciences, Genome, business.industry, Dynamics (mechanics), Cell Cycle, Computational Biology, Nucleosome Dynamics, Chromatin Assembly and Disassembly, Chromatin, Nucleosomes, Test case, Chromatin and epigenetics, Nucleosome architecture, Genomic information, Epigenetics, Transcription Initiation Site, business, Transcriptome, 030217 neurology & neurosurgery
Abstract: We present Nucleosome Dynamics, a suite of programs integrated into a virtual research environment and created to define nucleosome architecture and dynamics from noisy experimental data. The package allows both the definition of nucleosome architectures and the detection of changes in nucleosomal organization due to changes in cellular conditions. Results are displayed in the context of genomic information thanks to different visualizers and browsers, allowing the user a holistic, multidimensional view of the genome/transcriptome. The package shows good performance for both locating equilibrium nucleosome architecture and nucleosome dynamics and provides abundant useful information in several test cases, where experimental data on nucleosome position (and for some cases expression level) have been collected for cells under different external conditions (cell cycle phase, yeast metabolic cycle progression, changes in nutrients or difference in MNase digestion level). Nucleosome Dynamics is a free software and is provided under several distribution models. M.O. is an ICREA (Institució Catalana de Recerca i Estudis Avancats) academia researcher; Spanish Ministry of Science [RTI2018-096704-B-100]; Catalan Government [2017-SGR-134]; Instituto de Salud Carlos III–Instituto Nacional de Bioinformática, the European Union's Horizon 2020 research and innovation program, and the Biomolecular and Bioinformatics Resources Platform [ISCIII PT 17/0009/0007 co-funded by the Fondo Europeo de Desarrollo Regional FEDER; Grants Elixir-Excelerate: 676559 and BioExcel2: 823830; ERC:812850; MuG-676566]; MINECO Severo Ochoa Award of Excellence from the Government of Spain (awarded to IRB Barcelona). Funding for open access charge: Spanish Ministry of Science [RTI2018-096704-B-100].
Published: 2019
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12. Inference of genomic spatial organization from a whole genome bisulfite sequencing sample

Author: Martin-Subero I, Marc A. Marti-Renom, Ivo Gut, García Torre B, Simon Heath, Emanuele Raineri, Vilarrasa-Blasi R, François Serra, and Renée Beekman
Subjects: 0303 health sciences, Bisulfite sequencing, Computational biology, Methylation, Biology, Genome, Chromatin, Chromosome conformation capture, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, 030220 oncology & carcinogenesis, DNA methylation, GC-content, DNA, 030304 developmental biology
Abstract: Common approaches to characterize the structure of the DNA in the nucleus, such as the different Chromosome Conformation Capture methods, have not currently been widely applied to different tissue types due to several practical difficulties including the requirement for intact cells to start the sample preparation. In contrast, techniques based on sodium bisulfite conversion of DNA to assay DNA methylation, have been widely applied to many different tissue types in a variety of organisms. Recent work has shown the possibility of inferring some aspects of the three dimensional DNA structure from DNA methylation data, raising the possibility of three dimensional DNA structure prediction using the large collection of already generated DNA methylation datasets. We propose a simple method to predict the values of the first eigenvector of the Hi-C matrix of a sample (and hence the positions of the A and B compartments) using only the GC content of the sequence and a single whole genome bisulfite sequencing (WGBS) experiment which yields information on the methylation levels and their variability along the genome. We train and test our model on 10 samples for which we have data from both bisulfite sequencing and chromosome conformation experiments and our most relevant finding is that the variability of DNA methylation along the sequence is often a better predictor than methylation itself. We then run a prediction on 206 DNA methylation profiles produced by the Blueprint project and use ChIP-Seq and RNA-Seq data to confirm that the forecasted eigenvector delineates correctly the physical chromatin compartments observed with the Hi-C experiment.
Published: 2018
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13. A FBN1 3'UTR mutation variant is associated with endoplasmic reticulum stress in aortic aneurysm in Marfan syndrome

Author: Simon Heath, Anna-Maria Siegert, Jordi Alberch, Darya Gorbenko del Blanco, María Galán, Gerardo Garcia Diaz-Barriga, Gustavo Egea, Anna Esteve-Codina, and Miquel Navas-Madroñal
Subjects: 0301 basic medicine, Marfan syndrome, musculoskeletal diseases, Male, congenital, hereditary, and neonatal diseases and abnormalities, Pathology, medicine.medical_specialty, Fibrillin-1, Connective tissue, 030204 cardiovascular system & hematology, medicine.disease_cause, Muscle, Smooth, Vascular, Marfan Syndrome, 03 medical and health sciences, Aortic aneurysm, 0302 clinical medicine, Risk Factors, 3′UTR mutations, medicine, Humans, Genetic Predisposition to Disease, Nerve Growth Factors, RNA, Messenger, Molecular Biology, 3' Untranslated Regions, Endoplasmic Reticulum Chaperone BiP, Aorta, Heat-Shock Proteins, Mutation, Extracellular Matrix Proteins, business.industry, Endoplasmic reticulum, Proteins, medicine.disease, Endoplasmic Reticulum Stress, Aortic Aneurysm, Up-Regulation, 030104 developmental biology, medicine.anatomical_structure, MRNA Sequencing, Gene Expression Regulation, Unfolded protein response, Molecular Medicine, business, ER stress, Fibrillin, Cell Adhesion Molecules, Transcription Factor CHOP
Abstract: Marfan syndrome (MFS) is caused by mutations in the protein fibrillin-1 (FBN1) which affects the integrity of connective tissue elastic fibres. The most severe clinical outcome is the formation of ascending aortic aneurysms. FBN1 mutations are extremely variable and the prediction of disease phenotype and aortic risk is challenging under the prevailing mutation type classification. Finding a better correlation between mutation type and disease development is crucial for patient treatment. By mRNA sequencing of cultured vascular smooth muscle cells derived from control subjects and from the dilated and non-dilated aortic tunica media of MFS patients, we found a scarcely described FBN1 3'UTR mutation. This mutation was accompanied by a clear gene ontological endoplasmic reticulum (ER) stress response in the non-dilated aortic zone, which was confirmed by the increased transcriptional expression of MANF, HSPA5, SEL1L, DDIT3/CHOP and CRELD2 as well as protein expression levels of BiP/GRP78, CHOP and sXBP1. Moreover, the ER stress response was accompanied by a decrease in the phosphorylation levels of the protein translation regulator elF2α. In conclusion, we here identify a 3'UTR mutation of FBN1 in MFS patients, whose molecular mechanism suggest the involvement of the ER stress response in the formation of the aortic aneurysm. Our results emphasise the importance of mutations in non-coding regions and their resulting molecular mechanisms in the development of connective tissue diseases with impact on the cardiovascular system. This work was supported by grants to G.E. (SAF 2015-64136-R and SAF 2017-80309-R). M.G. is supported by the Miguel Servet Program (ISCIII; CP15/00126). The support of the NMF to GE is acknowledge.
Published: 2018

14. Dynamics of Transcription Regulation in Human Bone Marrow Myeloid Differentiation to Mature Blood Neutrophils

Author: Eva M. Janssen-Megens, Myrto Kostadima, Marta Gut, Farzin Pourfarzad, Sebastian Ullrich, Mattia Frontini, Luigi Grassi, Daniel Rico, Ida H. Hiemstra, Alfonso Valencia, Ehsan Habibi, Juliane Perner, Anton T.J. Tool, Hinri Kerstens, Angelika Merkel, Ivo Gut, Paul Flicek, Erik Mul, Taco W. Kuijpers, Ernesto Lowy, Enrique Carrillo-de-Santa-Pau, Joost H.A. Martens, Kim Berentsen, Laura Clarke, Marie-Laure Yaspo, Timo K. van den Berg, Willem H. Ouwehand, Avik Datta, Guoqiang Yi, Hendrik G. Stunnenberg, Dirk Roos, Martin Vingron, Matthias Linser, Simon Heath, Felipe Were, Dutch Cancer Foundation, European Research Council, British Health Foundation, Wellcome Trust, European Molecular Biology Organization, Bristol-Myers Squibb, Medical Research Council (Reino Unido), Paediatric Infectious Diseases / Rheumatology / Immunology, Landsteiner Laboratory, ARD - Amsterdam Reproduction and Development, Molecular cell biology and Immunology, Pediatric surgery, APH - Aging & Later Life, Grassi, Luigi [0000-0002-6308-7540], Frontini, Mattia [0000-0001-8074-6299], Ouwehand, Willem [0000-0002-7744-1790], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Myeloid, Neutrophils, epigenome, Bone Marrow Cells, Biology, Myeloid differentiation, General Biochemistry, Genetics and Molecular Biology, Article, Transcriptome, 03 medical and health sciences, Epigenome, 0302 clinical medicine, medicine, Transcriptional regulation, Cytotoxic T cell, Humans, Epigenetics, lcsh:QH301-705.5, Molecular Biology, Neutrophil, neutrophil, Cell Differentiation, Chromatin, 3. Good health, Respiratory burst, Cell biology, 030104 developmental biology, medicine.anatomical_structure, lcsh:Biology (General), Gene Expression Regulation, 030220 oncology & carcinogenesis, myeloid differentiation, Bone marrow, transcriptome
Abstract: Neutrophils are short-lived blood cells that play a critical role in host defense against infections. To better comprehend neutrophil functions and their regulation, we provide a complete epigenetic overview, assessing important functional features of their differentiation stages from bone marrow-residing progenitors to mature circulating cells. Integration of chromatin modifications, methylation, and transcriptome dynamics reveals an enforced regulation of differentiation, for cellular functions such as release of proteases, respiratory burst, cell cycle regulation, and apoptosis. We observe an early establishment of the cytotoxic capability, while the signaling components that activate these antimicrobial mechanisms are transcribed at later stages, outside the bone marrow, thus preventing toxic effects in the bone marrow niche. Altogether, these data reveal how the developmental dynamics of the chromatin landscape orchestrate the daily production of a large number of neutrophils required for innate host defense and provide a comprehensive overview of differentiating human neutrophils. The work presented here was supported by the Landsteiner Foundation forBlood Transfusion Research (LSBR-1121 to T.W.K.) and by the Dutch CancerFoundation (KUN 2011-4 937 to J.H.A.M.). The work was funded by a grantfrom the European Commission 7th Framework Program (FP72007-2013,grant 282510, BLUEPRINT). M.F. ssupported sh Heart Foundation(BHF) Cambridge Centre of Excellence (RE/13/6/30180). Additional support wasrovided by the Wellcome Trust (WT108749/Z/15/Z to P.F.) and by the Eu-ropean Molecular Biology Laboratory (E.L., A.D.,L.C., P.F.). Research in theOuwehand laboratory is also supported by grants from Bristol-Myers Squibb,the British Heart Foundation, the Medical Research Council, the National Insti-tutefor Health Research (NIHR) (W.H.O. is senior investigator), and NHSBlood and Transplant (NHSB T). Sí
Published: 2018
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15. Epigenomic and functional dynamics of human bone marrow myeloid differentiation to mature blood neutrophils

Author: Sebastian Ullrich, Gut M, Erik Mul, Taco W. Kuijpers, Henk Stunnenberg, Simon Heath, Pau ECdS, Paul Flicek, D. Roos, Guoqiang Yi, Linser M, Valencia A, Martin Vingron, Anton Tj Tool, Hinri Kerstens, Angelika Merkel, Daniel Rico, Avik Datta, Ernesto Lowy, Luigi Grassi, Willem H. Ouwehand, Felipe Were, Ehsan Habibi, Juliane Perner, Ida H. Hiemstra, Laura Clarke, Gut I, Joost H.A. Martens, Myrto Kostadima, Kim Berentsen, Berg TKvd, Mattia Frontini, Eva M. Janssen-Megens, Farzin Pourfarzad, and Marie-Laure Yaspo
Subjects: 0303 health sciences, Myeloid, Biology, Cell biology, Respiratory burst, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, medicine, Cytotoxic T cell, Epigenetics, Bone marrow, Progenitor cell, 030304 developmental biology, Epigenomics
Abstract: SummaryNeutrophils are short-lived blood cells that play a critical role in host defense against infections. To better comprehend neutrophil functions and their regulation, we provide a complete epigenetic and functional overview of their differentiation stages from bone marrow-residing progenitors to mature circulating cells. Integration of epigenetic and transcriptome dynamics reveals an enforced regulation of differentiation, through cellular functions such as: release of proteases, respiratory burst, cell cycle regulation and apoptosis. We observe an early establishment of the cytotoxic capability, whilst the signaling components that activate antimicrobial mechanisms are transcribed at later stages, outside the bone marrow, thus preventing toxic effects in the bone marrow niche. Altogether, these data reveal how the developmental dynamics of the epigenetic landscape orchestrate the daily production of large number of neutrophils required for innate host defense and provide a comprehensive overview of the epigenomes of differentiating human neutrophils.Key pointsDynamic acetylation enforces human neutrophil progenitor differentiation.Neutrophils cytotoxic capability is established early at the (pro)myelocyte stage.Coordinated signaling component expression prevents unwanted toxic effects to the bone marrow niche.
Published: 2018
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16. Re: Managing dyslipidaemia for the primary prevention of cardiovascular disease

Author: Aidan Ryan, Simon Heath, and Paul Cook
Subjects: Apolipoprotein E, medicine.medical_specialty, Dyslipidaemia, Statin, Apolipoprotein B, medicine.drug_class, 030204 cardiovascular system & hematology, Risk Assessment, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Chylomicron remnant, Ezetimibe, Risk Factors, Internal medicine, Cardiovascular Disease, medicine, Humans, 030212 general & internal medicine, Dyslipidemias, Hypolipidemic Agents, Intermediate-density lipoprotein, biology, Cholesterol, business.industry, Prevention, Statins, QResearch, General Medicine, Primary Prevention, Endocrinology, chemistry, Cardiovascular Diseases, biology.protein, lipids (amino acids, peptides, and proteins), business, medicine.drug, Chylomicron
Abstract: What you need to know ### Sources and selection criteria We carried out an electronic search through PubMed and Cochrane database of systematic reviews using the following search terms: “primary prevention,” “dyslipidaemia,” “cardiovascular disease,” “statins,” “statin intolerance,” “ezetimibe,” “PCSK9,” “hypercholesterolaemia diagnosis and treatment.” We also interrogated relevant dyslipidaemia guidelines and personal archives for supporting evidence as discussed and as referenced. Cardiovascular disease (CVD) is the most common underlying cause of death worldwide, accounting for 17.3 million of 54 million total deaths per year. Of these, 8.2 million were caused by ischaemic heart disease and 6.5 million by stroke.1 Mean total cholesterol, calculated low density lipoprotein (LDLc), and triglyceride concentrations have declined over the last 20 years. However, some observational cohort evidence suggests that long term exposure to even modestly elevated cholesterol concentrations is associated with CVD in later life.12 Cholesterol made in the liver and from the diet is transported to peripheral cells by apoB-containing lipoproteins in the blood (fig 1). In a fasting sample, the LDL particles constitute most of the circulating apoB lipoproteins. However, in clinical practice LDL is not measured directly but is calculated (LDLc) (box 1). LDLc has become a metric for treatment success and for diagnosis. Fig 1 Apolipoprotein B, non-HDL lipid transport, and atherosclerosis. Lipoproteins involved in cholesterol are transported from gut and liver to the peripheral tissues, providing fuel, membrane structure, and hormones. Lipoproteins carrying apolipoprotein B (apart from chylomicrons) have the potential to be atherogenic. APOE: apoliprotein e receptor; Chol: cholesterol; FA: fatty acids; IDL: intermediate density lipoprotein; TG: triglyceride; C: chylomicron; CR: chylomicron remnant; LDL: low density …
Published: 2018

17. DNA methylation oscillation defines classes of enhancers

Author: Henk Stunnenberg, Cutler A, Ivliev A, Lancashire L, Mattia Frontini, Simon Heath, Stephan Beck, Wallace C, Steven W. Wingett, Peter Fraser, Kate Downes, Biola-Maria Javierre, Emanuele Libertini, Garcia Ar, Martens Jha, Gut M, Luigi Grassi, Debjani Paul, Jonathan Cairns, Willem H. Ouwehand, Gut I, Mikhail Spivakov, and Rifat Hamoudi
Subjects: 0303 health sciences, biology, dNaM, Genomics, Computational biology, Genome project, Bisulfite, 03 medical and health sciences, 0302 clinical medicine, Histone, 030220 oncology & carcinogenesis, DNA methylation, biology.protein, Enhancer, 030304 developmental biology, Epigenomics
Abstract: Understanding the regulatory landscape of human cells requires the integration of genomic and epigenomic maps, capturing combinatorial levels of cell type-specific and invariant activity states.Here, we segmented whole-genome bisulfite sequencing-derived methylomes into consecutive blocks of co-methylation (COMETs) to obtain spatial variation patterns of DNA methylation (DNAm oscillations) integrated with histone modifications and promoter-enhancer interactions derived from promoter capture Hi-C (PCHi-C) sequencing of the same purified blood cells.Mapping DNAm oscillations onto regulatory genome annotation revealed that enhancers are enriched for DNAm hyper-oscillations (>30-fold), where multiple machine learning models support DNAm as predictive of enhancer location. Based on this analysis, we report overall predictive power of 99% for DNAm oscillations, 77.3% for DNaseI, 41% for CGIs, 20% for UMRs and 0% for LMRs, demonstrating the power of DNAm oscillations over other methods for enhancer prediction. Methylomes of activated and non-activated CD4+ T cells indicate that DNAm oscillations exist in both states irrespective of activation; hence they can be used to determine the location of latent enhancers.Our approach advances the identification of tissue-specific regulatory elements and outperforms previous approaches defining enhancer classes based on DNA methylation.
Published: 2018
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18. Comparative analysis of neutrophil and monocyte epigenomes

Author: Rubio M, van Bommel A, Nilofar Sharifi, Alessandra Breschi, David G. Pisano, David J. Richardson, Paul Bertone, Marie-Laure Yaspo, Stephen B. Watt, Emanuele Raineri, de la Torre, Hinri Kerstens, Angelika Merkel, Pancaldi, Gelpí Jl, Emilio Palumbo, Martin Vingron, van der Ent Ma, Joost H.A. Martens, Royo R, Daniel R. Zerbino, Myrto Kostadima, Ian Dunham, Augusto Rendon, Laura Clarke, Sadia Saeed, Gut I, S. Farrow, Dirk S. Paul, Ali Aghajanirefah, Enrique Carrillo-de-Santa-Pau, Valencia A, Love Mi, Kuijpers T, Marc Sultan, Frances Burden, Anna Esteve-Codina, Nicola Foad, Jessica Quintin, Steven P. Wilder, Iotchkova, Remco Loos, Daniela C. Ifrim, Stephan Beck, Simon Heath, Henk Stunnenberg, Daniel Rico, Lu Chen, Roderic Guigó, Torrents D, Kim Berentsen, Gut M, Fernandez Jm, Abhishek Singh, Paul Flicek, Willem H. Ouwehand, Mihai G. Netea, Hans Lehrach, Thomas Lengauer, Kate Downes, Erber W, Christoph Bock, Stamatina Fragkogianni, Franz-Josef Müller, Sarah Djebali, Colin Logie, Anita Kaan, Eva M. Janssen-Megens, Mattia Frontini, Nicole Soranzo, and Antony P. Attwood
Subjects: 0303 health sciences, Innate immune system, Cellular differentiation, Monocyte, Epigenome, Biology, 3. Good health, Cell biology, Chromatin, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, DNA methylation, medicine, Epigenetics, 030304 developmental biology, Epigenomics
Abstract: Neutrophils and monocytes provide a first line of defense against infections as part of the innate immune system. Here we report the integrated analysis of transcriptomic and epigenetic landscapes for circulating monocytes and neutrophils with the aim to enable downstream interpretation and functional validation of key regulatory elements in health and disease. We collected RNA-seq data, ChIP-seq of six histone modifications and of DNA methylation by bisulfite sequencing at base pair resolution from up to 6 individuals per cell type. Chromatin segmentation analyses suggested that monocytes have a higher number of cell-specific enhancer regions (4-fold) compared to neutrophils. This highly plastic epigenome is likely indicative of the greater differentiation potential of monocytes into macrophages, dendritic cells and osteoclasts. In contrast, most of the neutrophil-specific features tend to be characterized by repressed chromatin, reflective of their status as terminally differentiated cells. Enhancers were the regions where most of differences in DNA methylation between cells were observed, with monocyte-specific enhancers being generally hypomethylated. Monocytes show a substantially higher gene expression levels than neutrophils, in line with epigenomic analysis revealing that gene more active elements in monocytes. Our analyses suggest that the overexpression of c-Myc in monocytes and its binding to monocyte-specific enhancers could be an important contributor to these differences. Altogether, our study provides a comprehensive epigenetic chart of chromatin states in primary human neutrophils and monocytes, thus providing a valuable resource for studying the regulation of the human innate immune system.
Published: 2017
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19. The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery

Author: Sergio Abrignani, David Adams, Melanie de Almeida, ALTUCCI, Lucia, Viren Amin, Ido Amit, Stylianos E, Antonarakis, Samuel Aparicio, Takahiro Arima, Laura Arrigoni, Rob Arts, Vahid Asnafi, Manel Esteller, Jae Bum Bae, Kevin Bassler, Stephan Beck, Benjamin Berkman, Bradley E, Bernstein, Mikhail Bilenky, Adrian Bird, Christoph Bock, Bernhard Boehm, Guillaume Bourque, Charles E, Breeze, Benedikt Brors, David Bujold, Oliver Burren, Marion J, Bussemakers, Adam Butterworth, Elias Campo, Enrique Carrillo de Santa Pau, Lisa Chadwick, Kui Ming Chan, Wei Chen, Tom H, Cheung, Luca Chiapperino, Nak Hyen Choi, Ho Ryun Chung, Laura Clarke, Joseph M, Connors, Philippe Cronet, John Danesh, Manolis Dermitzakis, Gerard Drewes, Pawel Durek, Stephanie Dyke, Tomasz Dylag, Connie J, Eaves, Peter Ebert, Roland Eils, Jürgen Eils, Catherine A, Ennis, Tariq Enver, Elise A, Feingold, Bärbel Felder, Anne Ferguson Smith, Jude Fitzgibbon, Paul Flicek, Roger S, Y, Foo, Peter Fraser, Mattia Frontini, Eileen Furlong, Sitanshu Gakkhar, Nina Gasparoni, Gilles Gasparoni, Daniel H, Geschwind, Petar Glažar, Thomas Graf, Frank Grosveld, Xin Yuan Guan, Roderic Guigo, Ivo G, Gut, Alf Hamann, Bok Ghee Han, R, Alan Harris, Simon Heath, Kristian Helin, Jan G, Hengstler, Alireza Heravi Moussavi, Karl Herrup, Steven Hill, Jason A, Hilton, Benjamin C, Hitz, Bernhard Horsthemke, Ming Hu, Joo Yeon Hwang, Nancy Y, Takashi Ito, Biola Maria Javierre, Sasa Jenko, Thomas Jenuwein, Yann Joly, Steven J, M, Jones, Yae Kanai, Hee Gyung Kang, Aly Karsan, Alexandra K, Kiemer, Song Cheol Kim, Bong Jo Kim, Hyeon Hoe Kim, Hiroshi Kimura, Sarah Kinkley, Filippos Klironomos, In Uk Koh, Myrto Kostadima, Christopher Kressler, Roman Kreuzhuber, Anshul Kundaje, Ralf Küppers, Carolyn Larabell, Paul Lasko, Mark Lathrop, S, Lee, Suman Lee, Hans Lehrach, Elsa Leitão, Thomas Lengauer, Åke Lernmark, David Leslie, Gilberto K, K, Leung, Danny Leung, Markus Loeffler, Yussanne Ma, Antonello Mai, Thomas Manke, Eric R, Marcotte, Marco A, Marra, Joost H, A, Martens, Jose Ignacio Martin Subero, Karen Maschke, Christoph Merten, Aleksandar Milosavljevic, Saverio Minucci, Totai Mitsuyama, Richard A, Moore, Fabian Müller, Andrew J, Mungall, Mihai G, Netea, Karl Nordström, Irene Norstedt, Hiroaki Okae, Vitor Onuchic, Francis Ouellette, Willem Ouwehand, Massimiliano Pagani, Vera Pancaldi, Thomas Pap, Tomi Pastinen, Ronak Patel, Dirk S, Paul, Michael J, Pazin, Pier Giuseppe Pelicci, Anthony G, Phillips, Julia Polansky, Bo Porse, J, Andrew Pospisilik, Shyam Prabhakar, Dena C, Procaccini, Andreas Radbruch, Nikolaus Rajewsky, Vardham Rakyan, Wolf Reik, Bing Ren, David Richardson, Andreas Richter, Daniel Rico, David J, Roberts, Philip Rosenstiel, Mark Rothstein, Abdulrahman Salhab, Hiroyuki Sasaki, John S, Satterlee, Sascha Sauer, Claudia Schacht, Florian Schmidt, Gerd Schmitz, Stefan Schreiber, Christopher Schröder, Dirk Schübeler, Joachim L, Schultze, Ronald P, Schulyer, Marcel Schulz, Martin Seifert, Katsuhiko Shirahige, Reiner Siebert, Thomas Sierocinski, Laura Siminoff, Anupam Sinha, Nicole Soranzo, Salvatore Spicuglia, Mikhail Spivakov, Christian Steidl, Seth Strattan, Michael Stratton, Peter Südbeck, Hao Sun, Narumi Suzuki, Yutaka Suzuki, Amos Tanay, David Torrents, Frederick L, Tyson, Thomas Ulas, Sebastian Ullrich, Toshikazu Ushijima, Alfonso Valencia, Edo Vellenga, Martin Vingron, Chris Wallace, Stefan Wallner, Jörn Walter, Huating Wang, Stephanie Weber, Nina Weiler, Andreas Weller, Andrew Weng, Steven Wilder, Sam M, Wiseman, Angela R, Zhenguo Wu, Jieyi Xiong, Yasuhiro Yamashita, Xinyi Yang, Desmond Y, Yap, Kevin Y, Yip, Stephen Yip, Jae Il Yoo, Daniel Zerbino, Gideon Zipprich, Antonarakis, Stylianos, International Human Epigenome Consortium, [0000-0002-8682-6748], Apollo - University of Cambridge Repository, Centro Nacional de Análisi Genómico (CNAG), Centro Nacional de Análisis Genómico, Radboud University Medical Center [Nijmegen], Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Hematology, University of Groningen and University Medical Center Groningen, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universitat de Barcelona, Sergio, Abrignani, David, Adam, Melanie de, Almeida, Altucci, Lucia, Viren, Amin, Ido, Amit, Stylianos, E, Antonarakis, Samuel, Aparicio, Takahiro, Arima, Laura, Arrigoni, Rob, Art, Vahid, Asnafi, Manel, Esteller, Jae Bum, Bae, Kevin, Bassler, Stephan, Beck, Benjamin, Berkman, Bradley, E, Bernstein, Mikhail, Bilenky, Adrian, Bird, Christoph, Bock, Bernhard, Boehm, Guillaume, Bourque, Charles, E, Breeze, Benedikt, Bror, David, Bujold, Oliver, Burren, Marion, J, Bussemakers, Adam, Butterworth, Elias, Campo, Enrique Carrillo de Santa, Pau, Lisa, Chadwick, Kui Ming, Chan, Wei, Chen, Tom, H, Cheung, Luca, Chiapperino, Nak Hyen, Choi, Ho Ryun, Chung, Laura, Clarke, Joseph, M, Connors, Philippe, Cronet, John, Danesh, Manolis, Dermitzaki, Gerard, Drewe, Pawel, Durek, Stephanie, Dyke, Tomasz, Dylag, Connie, J, Eaves, Peter, Ebert, Roland, Eil, Jürgen, Eil, Catherine, A, Ennis, Tariq, Enver, Elise, A, Feingold, Bärbel, Felder, Anne Ferguson, Smith, Jude, Fitzgibbon, Paul, Flicek, Roger, S, Y, Foo, Peter, Fraser, Mattia, Frontini, Eileen, Furlong, Sitanshu, Gakkhar, Nina, Gasparoni, Gilles, Gasparoni, Daniel, H, Geschwind, Petar, Glažar, Thomas, Graf, Frank, Grosveld, Xin Yuan, Guan, Roderic, Guigo, Ivo, G, Gut, Alf, Hamann, Bok Ghee, Han, R, Alan, Harri, Simon, Heath, Kristian, Helin, Jan, G, Hengstler, Alireza Heravi, Moussavi, Karl, Herrup, Steven, Hill, Jason, A, Hilton, Benjamin, C, Hitz, Bernhard, Horsthemke, Ming, Hu, Joo Yeon, Hwang, Nancy, Y, Ip, Takashi, Ito, Biola Maria, Javierre, Sasa, Jenko, Thomas, Jenuwein, Yann, Joly, Steven, J, M, Jone, Yae, Kanai, Hee Gyung, Kang, Aly, Karsan, Alexandra, K, Kiemer, Song Cheol, Kim, Bong Jo, Kim, Hyeon Hoe, Kim, Hiroshi, Kimura, Sarah, Kinkley, Filippos, Klironomo, In Uk, Koh, Myrto, Kostadima, Christopher, Kressler, Roman, Kreuzhuber, Anshul, Kundaje, Ralf, Küpper, Carolyn, Larabell, Paul, Lasko, Mark, Lathrop, S, Lee, Suman, Lee, Hans, Lehrach, Elsa, Leitão, Thomas, Lengauer, Åke, Lernmark, David, Leslie, Gilberto, K, K, Leung, Danny, Leung, Markus, Loeffler, Yussanne, Ma, Antonello, Mai, Thomas, Manke, Eric, R, Marcotte, Marco, A, Marra, Joost, H, A, Marten, Jose Ignacio Martin, Subero, Karen, Maschke, Christoph, Merten, Aleksandar, Milosavljevic, Saverio, Minucci, Totai, Mitsuyama, Richard, A, Moore, Fabian, Müller, Andrew, J, Mungall, Mihai, G, Netea, Karl, Nordström, Irene, Norstedt, Hiroaki, Okae, Vitor, Onuchic, Francis, Ouellette, Willem, Ouwehand, Massimiliano, Pagani, Vera, Pancaldi, Thomas, Pap, Tomi, Pastinen, Ronak, Patel, Dirk, S, Paul, Michael, J, Pazin, Pier Giuseppe, Pelicci, Anthony, G, Phillips, Julia, Polansky, Bo, Porse, J, Andrew, Pospisilik, Shyam, Prabhakar, Dena, C, Procaccini, Andreas, Radbruch, Nikolaus, Rajewsky, Vardham, Rakyan, Wolf, Reik, Bing, Ren, David, Richardson, Andreas, Richter, Daniel, Rico, David, J, Roberts, Philip, Rosenstiel, Mark, Rothstein, Abdulrahman, Salhab, Hiroyuki, Sasaki, John, S, Satterlee, Sascha, Sauer, Claudia, Schacht, Florian, Schmidt, Gerd, Schmitz, Stefan, Schreiber, Christopher, Schröder, Dirk, Schübeler, Joachim, L, Schultze, Ronald, P, Schulyer, Marcel, Schulz, Martin, Seifert, Katsuhiko, Shirahige, Reiner, Siebert, Thomas, Sierocinski, Laura, Siminoff, Anupam, Sinha, Nicole, Soranzo, Salvatore, Spicuglia, Mikhail, Spivakov, Christian, Steidl, Seth, Strattan, Michael, Stratton, Peter, Südbeck, Hao, Sun, Narumi, Suzuki, Yutaka, Suzuki, Amos, Tanay, David, Torrent, Frederick, L, Tyson, Thomas, Ula, Sebastian, Ullrich, Toshikazu, Ushijima, Alfonso, Valencia, Edo, Vellenga, Martin, Vingron, Chris, Wallace, Stefan, Wallner, Jörn, Walter, Huating, Wang, Stephanie, Weber, Nina, Weiler, Andreas, Weller, Andrew, Weng, Steven, Wilder, Sam, M, Wiseman, Angela, R, Wu, Zhenguo, Wu, Jieyi, Xiong, Yasuhiro, Yamashita, Xinyi, Yang, Desmond, Y, Yap, Kevin, Y, Yip, Stephen, Yip, Jae Il, Yoo, Daniel, Zerbino, and Gideon, Zipprich
Subjects: Epigenomics, 0301 basic medicine, [SDV]Life Sciences [q-bio], ADN, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Medizin, Biology, Genoma humà, General Biochemistry, Genetics and Molecular Biology, Epigenesis, Genetic, World Wide Web, 03 medical and health sciences, Human health, 0302 clinical medicine, Blueprint, Databases, Genetic, Humans, Disease, ddc:576.5, DNA methylation, databases, genetic, disease, histone code, humans, epigenesis, genetic, epigenomics, genome, human, biochemistry, genetics and molecular biology (all), Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetics, 0303 health sciences, Human genome, Genome, Human, DNA, Epigenome, DNA Methylation, Human cell, Epigenètica, Histone Code, 030104 developmental biology, 030220 oncology & carcinogenesis, Epigenetics
Abstract: Item does not contain fulltext The International Human Epigenome Consortium (IHEC) coordinates the generation of a catalog of high-resolution reference epigenomes of major primary human cell types. The studies now presented (see the Cell Press IHEC web portal at http://www.cell.com/consortium/IHEC) highlight the coordinated achievements of IHEC teams to gather and interpret comprehensive epigenomic datasets to gain insights in the epigenetic control of cell states relevant for human health and disease. PAPERCLIP.
Published: 2016
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20. Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy

Author: Nuria Juanpere, Elena Lopez-Knowles, Ana Losada, Sergi Beltran, Julie Earl, David G. Pisano, Juan C. Cigudosa, Orlando Domínguez, Eleonora Lapi, Miguel Vazquez, Ivo Gut, Cristina Balbás-Martínez, Alfonso Valencia, Jesús Herranz, José A. Lorente, Laia Richart, Simon Heath, Francisco X. Real, Ana Sagrera, Adonina Tardón, Mònica Bayés, Núria Malats, Daniel Rico, Stephen J. Chanock, Manolis Kogevinas, Josep Lloreta, Mirari Marquez, Rocío Salgado, Francesc Castro-Giner, Marta Gut, Enrique Carrillo-de-Santa-Pau, Alfredo Carrato, and Xavier Langa
Subjects: Cohesin complex, DNA repair, STAG2, Aneuploidy, cohesin, SMC1A, Biology, medicine.disease_cause, Article, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, aneuploidy, Exome sequencing, 030304 developmental biology, 0303 health sciences, Mutation, Bladder cancer, medicine.disease, FANCA, 3. Good health, tumorsuppressor, 030220 oncology & carcinogenesis, Cancer research, bladder cancer, exome sequencing
Abstract: Francisco Real and colleagues report exome sequencing in urothelial bladder tumors. They show that STAG2, a subunit of the cohesin complex, is recurrently mutated and provide evidence that STAG2 loss does not lead to increases in aneuploidy. Urothelial bladder cancer (UBC) is heterogeneous at the clinical, pathological and genetic levels. Tumor invasiveness (T) and grade (G) are the main factors associated with outcome and determine patient management1. A discovery exome sequencing screen (n = 17), followed by a prevalence screen (n = 60), identified new genes mutated in this tumor coding for proteins involved in chromatin modification (MLL2, ASXL2 and BPTF), cell division (STAG2, SMC1A and SMC1B) and DNA repair (ATM, ERCC2 and FANCA). STAG2, a subunit of cohesin, was significantly and commonly mutated or lost in UBC, mainly in tumors of low stage or grade, and its loss was associated with improved outcome. Loss of expression was often observed in chromosomally stable tumors, and STAG2 knockdown in bladder cancer cells did not increase aneuploidy. STAG2 reintroduction in non-expressing cells led to reduced colony formation. Our findings indicate that STAG2 is a new UBC tumor suppressor acting through mechanisms that are different from its role in preventing aneuploidy.
Published: 2013

21. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Author: Per Hall, Simon C. Potter, Richard Reynolds, Robert Heard, Gil McVean, An Goris, Joseph T. Glessner, Pamela Whittaker, Niall Tubridy, Olivier Gout, Ann-Christine Syvaenen, Leena Peltonen, Bénédicte Dubois, Anders Hamsten, Alastair Compston, Hugh S. Markus, Mariaemma Rodegher, Lisa F. Barcellos, Wendy Cozen, Rosetta M. Chiavacci, Jenefer M. Blackwell, William M. Carroll, Patricia P. Ramsay, Amie Baker, Krzysztof Selmaj, Serge Dronov, Zhan Su, C. Smestad, Stanley Hawkins, Janna Saarela, Matti Pirinen, Sabine Cepok, Gavin Band, Norman Klopp, Simon Heath, Sandra D'Alfonso, Peter Donnelly, Ina-Maria Rueckert, Deborah F. Mason, Alagurevathi Jayakumar, Hakon Hakonarson, Cecilia Kim, Colin Freeman, Jeannette Lechner-Scott, Marc Debouverie, Neil Robertson, Inger-Lise Mero, Paola Cavalla, Sabine Roesner, H-Erich Wichmann, Daniele Cusi, Wendy Ingram, Sarah Edkins, Tania Mihalova, Mark J. Daly, Mark Marriott, Roland Martin, Adrian J. Ivinson, Hong L. Quach, Jeremy Hobart, Filippo Martinelli Boneschi, Carmen Infante-Duarte, Catherine Schaefer, Irina Elovaara, Jonathan L. Haines, John Zajicek, Michelle Ricketts, Ananth C. Viswanathan, Colin A. Graham, Allan G. Kermode, Helmut Butzkueven, Kai Wang, John Mottershead, Francesca Taddeo, Stefan Schreiber, Aarno Palotie, Trevor Pickersgill, Naomi Hammond, David A. Hafler, Robert Plomin, Robin R. Lincoln, David Sexton, Jianjun Liu, Finn Sellebjerg, Françoise Clerget-Darpoux, David Brassat, Sarah E. Hunt, Per Soelberg Sørensen, Vittorio Martinelli, Eleni Giannoulatou, Paul I.W. de Bakker, Alexander T. Dilthey, Stephen Leslie, Ulrika Liljedahl, Hanne F. Harbo, Alison Page, Keijo Koivisto, Ingrid Kockum, Stephen L. Hauser, Ewa Tronczynska, Ayman Tourbah, K Baker, Panos Deloukas, Hannah Blackburn, Janusz Jankowski, Mauri Reunanen, Trevor J. Kilpatrick, Sheila Skidmore, Sergio E. Baranzini, Nicholas W. Wood, Fredrik Piehl, Lars Alfredsson, Daniela Galimberti, Federica Esposito, Marco Salvetti, Jennifer Liddle, Jenny Link, Helle Bach Søndergaard, Suzannah Bumpstead, Jonathan P. Bradfield, Richard C. Strange, Céline Bellenguez, David R. Booth, Refujia Gomez, Michael Wittig, Matthew A. Brown, Laura Bergamaschi, Elisabeth Gulowsen Celius, William E R Ollier, Juan P. Casas, Ling Shen, Loukas Moutsianas, Fabio Macciardi, Anne H. Cross, Maja Jagodic, Marie B. D'hooghe, Tomas Olsson, Mark D. Cossburn, O. T. McCann, Justin P. Rubio, Isabelle Cournu-Rebeix, Struan F.A. Grant, Colin N. A. Palmer, Matthew W. Gillman, John D. Rioux, Christopher G. Mathew, Maria Ban, Anna-Maija Sulonen, Garrett Hellenthal, Dorothea Buck, Jorge R. Oksenberg, Frauke Zipp, James Wason, Stephen Sawcer, Franca Rosa Guerini, Clive Hawkins, Cristin Aubin, Elvira Bramon, Paul A. Weston, Andre Franke, Laura Piccio, Jane Vickery, Nikolaos A. Patsopoulos, Jacob L. McCauley, Kristin G. Ardlie, A. Strange, Marcin P. Mycko, Richard C. Trembath, Giancarlo Comi, Gillian Ingram, Graeme J. Stewart, Allan L. Bernstein, Emilie Sundqvist, Xavier Montalban, Juliane Winkelmann, Rhian Gwilliam, Ruggero Capra, Bruce V. Taylor, Maurizio Leone, Brigid Simms-Acuna, Emma J. Davis, Bertrand Fontaine, Chris C. A. Spencer, Malin Larsson, Hans-Peter Hartung, Emma Gray, Virpi M. Leppä, Pablo Villoslada, Audrey Duncanson, Åslaug R. Lorentzen, Rathi Ravindrarajah, Izaura Lima Bomfim, Christian Schulze, Talat Islam, Manuel Comabella, Rita Dobosi, Simon Broadley, Bernhard Hemmer, Margaret A. Pericak-Vance, Jan Hillert, Michael Kabesch, J. Yaouanq, Mark Lathrop, Angelo Ghezzi, Rodney J. Scott, K Dixon, Jean Pelletier, Annette Bang Oturai, Mike Boggild, Philip L. De Jager, Anne Spurkland, M. Perez, Roby Abraham, Pentti J. Tienari, Matthew Waller, Katleen Clysters, Adam Santaniello, David Ellinghaus, Cordelia Langford, Anna Rautanen, Frank D. Mentch, Achim Berthele, Kjell-Morten Myhr, Simon J. Foote, Thomas M. Mack, Bruce A.C. Cree, Susan Pobywajlo, Ernest Willoughby, Haitao Zhang, M. B. Cox, Anu Kemppinen, Muna Hoshi, Sara Widaa, Claire Fontenille, Erika Salvi, Sara Lupoli, Aiden Corvin, Roberto Bergamaschi, Jim Stankovich, Rebecca L. Zuvich, Paola Naldi, Patrick M. A. Sleiman, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, and Faculty of Psychology and Educational Sciences
Subjects: Immunity, Cellular/genetics, Cellular immunity, Multiple Sclerosis, Genome-wide association study, CLEC16A, Biology, Polymorphism, Single Nucleotide, Cell Differentiation/immunology, Europe/ethnology, Major Histocompatibility Complex/genetics, Major Histocompatibility Complex, 03 medical and health sciences, 0302 clinical medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, HLA-A Antigens/genetics, Alleles, 030304 developmental biology, Genetic association, Genetics, 0303 health sciences, Immunity, Cellular, Multidisciplinary, HLA-A Antigens, Genome, Human, Multiple sclerosis, Genetic Predisposition to Disease/genetics, HLA-DR Antigens/genetics, Lymphocyte differentiation, Cell Differentiation, HLA-DR Antigens, T-Lymphocytes, Helper-Inducer, RC346, medicine.disease, Polymorphism, Single Nucleotide/genetics, Genetic architecture, 3. Good health, Europe, Sample Size, Immunology, Genome, Human/genetics, Multiple Sclerosis/genetics, 030217 neurology & neurosurgery, T-Lymphocytes, Helper-Inducer/cytology, Genome-Wide Association Study, HLA-DRB1 Chains
Abstract: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
Published: 2016
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22. A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease

Author: Markku S. Nieminen, Engert Jc, Anders Hamsten, Mark I. McCarthy, Khan Shah Zaman, Nilesh J. Samani, Silvia Pietri, Nadeem Hayat Mallick, Robert Clarke, Anna Helgadottir, John C. Chambers, Peter Sleight, Lasse Folkersen, Simon C. Potter, Fazal-ur-Rehman Memon, Gonçalo R. Abecasis, Shapour Jalilzadeh, Louise Bowman, Anders Mälarstig, Abdus Samad, Veikko Salomaa, John F. Peden, Juha Sinisalo, Jane Armitage, Asif Rasheed, Simona Barlera, Eirini V. Theodoraki, Suthesh Sivapalaratnam, Halit Ongen, Alison Offer, Theodosios Kyriakou, Hugh Watkins, John J.P. Kastelein, Philippe Froguel, Emma Gray, Tim D. Spector, Panos Deloukas, Mai-Lis Hellénius, Anders Gabrielsen, Martin Farrall, Jemma C. Hopewell, Mark Lathrop, Nicole Soranzo, Nabeel Ahmed, Bruna Gigante, Roberto Marchioli, Muhammad Azhar, Danish Saleheen, Salim Yusuf, Simon Heath, Anders Franco-Cereceda, Ulf de Faire, James Scott, Ann-Christine Syvänen, Marc Delepine, Maria Samuel, John Öhrvik, M. Ishaq, Fiona Green, Leena Peltonen, Paul Elliott, Moazzam Zaidi, Gerd Assmann, Rhian Gwilliam, Gianni Tognoni, Nabi Shah, John Danesh, Jorg Hager, Weihua Zhang, Mark J. Caulfield, Jaspal S. Kooner, Angad S. Kooner, Suzannah Bumpstead, Richard Peto, Francesca Gori, Maria Grazia Franzosi, Anuj Goel, Sarah E. Hunt, Karin Leander, Ferdinand M. van't Hooft, Angela Silveira, Rory Collins, Samuli Ripatti, Muhammed Murtaza, Pamela Linksted, Per Eriksson, George V. Dedoussis, Sarah Edkins, Sonia S. Anand, Philippe M. Frossard, Tomas Axelsson, Ali Raza Gardezi, Peter Donnelly, Mieke D. Trip, Sarah Parish, Stephan Rust, Udo Seedorf, Gunnar O Olsson, Kathy Stirrups, Rona J. Strawbridge, Joban Sehmi, Derrick A Bennett, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, and Cardiology
Subjects: Adult, Male, South asia, Quantitative Trait Loci, ADAMTS7 Protein, Single-nucleotide polymorphism, Genome-wide association study, Coronary Artery Disease, Biology, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Article, White People, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Asian People, Genotype, Genetics, Medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Myocardial infarction, Genotyping, Genetics (clinical), 030304 developmental biology, Genetic association, Aged, Oligonucleotide Array Sequence Analysis, Platelet-Derived Growth Factor, 0303 health sciences, Lymphokines, business.industry, Heritability, Middle Aged, Sterol Esterase, medicine.disease, ADAM Proteins, Case-Control Studies, Female, Cardiology and Cardiovascular Medicine, business, Imputation (genetics), Genome-Wide Association Study, Transcription Factors
Abstract: Study Hypothesis Recently, genome-wide association studies (GWAS) have identified several common variants associated with increased risk of coronary artery disease (CAD) and myocardial infarction (MI) by 10% to 30%. The authors state that these loci explain only a small proportion of the predicted genetic risk and that all of the current loci for CAD and MI by GWAS have been discovered in European populations. The authors hypothesized that discovery of new susceptibility loci of smaller effect sizes would be aided by conducting much larger studies in addition to an emphasis on early-onset CAD and clearly defined clinical end points. Therefore, they assembled the Coronary Artery Disease (C4D) Genetics Consortium.1 ### How Was the Hypothesis Tested? The authors performed a meta-analysis of 4 large GWAS of CAD, 2 of European ancestry (PROCARDIS and HPS) and 2 of South Asian ancestry (PROMIS and LOLLIPOP), with ≈575 000 genotyped single-nucleotide polymorphisms (SNPs) in a discovery data set comprising 15 420 individuals with CAD (cases) (8424 Europeans and 6996 South Asians) and 15 062 control subjects. They observed little evidence for ancestry-specific associations, supporting the use of combined analyses. Furthermore, the authors state that because all individuals were genotyped on the same platform (whole-genome Illumina BeadChips), a meta-analysis of actual genotypes rather than imputed data enabled analysis of low-frequency variants (1% to 5%), which have been excluded from GWAS either because of sample size or because imputation has been required to combine data from different genotyping platforms. After the meta-analysis, they selected 59 SNPs from 50 loci that showed potential new associations from the meta-analysis of the European and South Asian studies (41 SNPs; P
Published: 2016

23. A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

Author: John R. B. Perry, James B. Meigs, José Dupuis, Luigi Ferrucci, Johan G. Eriksson, Vilmundur Gudnason, Eric J.G. Sijbrands, Jeanette S. Andrews, Jonna L. Grimsby, Lawrence F. Bielak, Peter Kovacs, Panos Deloukas, Marijana Peričić, Johannes H. Smit, Ruth J. F. Loos, Gonneke Willemsen, Eric Boerwinkle, Ben A. Oostra, Manuel Serrano-Ríos, Alena Stančáková, Meena Kumari, Antti Jula, Michael Marmot, Caroline S. Fox, Simon Heath, Guo Li, Ola Hansson, Gerard Waeber, Anne U. Jackson, Nicholas L. Smith, Markku Laakso, George Dedoussis, Aarno Palotie, Sara M. Willems, John F. Peden, Elisabeth Widen, Caroline Hayward, Alan F. Wright, Claes Ladenvall, May E. Montasser, María Teresa Martínez-Larrad, Peter Vollenweider, Louis Pérusse, Tamara B. Harris, Wen Hong L. Kao, Danijela Budimir, Denis Rybin, David B. Savage, Michael A. Province, Alisa K. Manning, Bruna Gigante, Najaf Amin, Lenore J. Launer, Naveed Sattar, Lori L. Bonnycastle, Göran Hallmans, Jeffrey R. O'Connell, Stéphane Lobbens, Jacques S. Beckmann, Gemma Cadby, J. Wouter Jukema, Maria Dimitriou, Michael Stumvoll, Max Vikström, Rona J. Strawbridge, Hugh Watkins, Lyle J. Palmer, Johanna Kuusisto, Aimo Ruokonen, Hanieh Yaghootkar, Yan V. Sun, Inês Barroso, Amy J. Swift, Nancy L. Pedersen, Lars Lind, Mladen Boban, Nita G. Forouhi, Ken K. Ong, Ivana Kolcic, Anke Tönjes, Timothy M. Frayling, Paul W. Franks, Narisu Narisu, Karin Leander, Serge Hercberg, Diana Zelenika, Sharon L.R. Kardia, Min A. Jhun, Marjo-Riitta Järvelin, Stella Trompet, Jaakko Kaprio, Toshiko Tanaka, David S. Siscovick, Toby Johnson, Cornelia M. van Duijn, Veikko Salomaa, Jose C. Florez, James F. Wilson, Leena Peltonen, Pilar Galan, Robert Clarke, Andrew A. Hicks, Claudia Langenberg, Anders Hamsten, David Couper, Albert Hofman, Dawn M. Waterworth, John Blangero, James S. Pankow, Nabila Bouatia-Naji, Sirkka Keinänen-Kiukaanniemi, Mark I. McCarthy, Valeriya Lyssenko, Leif Groop, Brenda W.J.H. Penninx, Ching-Ti Liu, Anuj Goel, Marina Pehlić, Michael Boehnke, Mika Kivimäki, Maria Sabater-Lleal, Emil Rehnberg, Ingrid B. Borecki, Ozren Polasek, Eco J. C. de Geus, Peter P. Pramstaller, Igor Rudan, Richard M. Watanabe, Pierre Meneton, Iva Miljkovic, Vincent Mooser, G. Mark Lathrop, John Beilby, Laura J. Rasmussen-Torvik, Arturo Corbató-Anchuelo, Yvonne Böttcher, Richard N. Bergman, Daniel R. Barnes, Paul C. D. Johnson, Mustafa Atalay, Aroon D. Hingorani, Olga D. Carlson, Perttu Salo, Jacqueline C.M. Witteman, Udo Seedorf, Timo Saaristo, Jian'an Luan, Nicholas J. Wareham, Gudny Eiriksdottir, Matti Uusitupa, Yongmei Liu, Jaakko Tuomilehto, Yurii S. Aulchenko, Peter Schwarz, Robert A. Scott, Lina Zgaga, Joseph Hung, Reedik Mägi, Maria Grazia Franzosi, Eric J. Brunner, Claude Bouchard, Ian Ford, Francis S. Collins, Ulf de Faire, Benjamin F. Voight, Erik Ingelsson, Mario A. Morken, Stefania Bandinelli, Nicole L. Glazer, Dmitry Shungin, Lars Lannfelt, André G. Uitterlinden, Tatijana Zemunik, Markus Perola, Kenneth Rice, Veronique Vitart, Kerrin S. Small, Jouke-Jan Hottenga, Han Chen, Jerome I. Rotter, Philippe Froguel, Karen L. Mohlke, Marie-Claude Vohl, Dorret I. Boomsma, Harry Campbell, Peter S. Chines, Pau Navarro, Vasiliki Lagou, Albert V. Smith, Kathleen Stirrups, Josephine M. Egan, Alan R. Shuldiner, Katri Räikkönen, Inga Prokopenko, Ping An, Rainer Rauramaa, Beverley Balkau, Thor Aspelund, Eleanor Wheeler, Mariza de Andrade, Richa Saxena, Jari Lahti, Cécile Lecoeur, Timo A. Lakka, Jennie Hui, Michael R. Erdos, Stavroula Kanoni, Kirsten Ohm Kyvik, Bengt Sennblad, Sarah H. Wild, Patricia A. Peyser, Patrik K. E. Magnusson, Claire Bellis, Elodie Eury, Jaana Lindström, Boston University [Boston] (BU), Broad Institute of Harvard and MIT, Partenaires INRAE, Massachusetts General Hospital, Massachusetts General Hospital [Boston], Department of Genetics [Boston], Harvard Medical School [Boston] (HMS), Department of Medicine, Université de Sherbrooke (UdeS), Addenbrooke's Hospital, Harvard Medical School [Boston] (HMS)-Beth Israel Deaconess Medical Center [Boston] (BIDMC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Université Lille Nord de France (COMUE), Department of Epidemiology, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-Center for Social Epidemiology and Population Health, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford [Oxford], The Wellcome Trust Centre for Human Genetics [Oxford], The Netherlands Cancer Institute, Ontario Institute for Cancer Research, Mount Sinai Hospital [Toronto, Canada] (MSH), VU University Amsterdam, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], University of Michigan System, Queen Mary University of London (QMUL), The Wellcome Trust Sanger Institute [Cambridge], Lund University [Lund], Diabetes Centre, Lund University, University of Helsinki, Wake Forest School of Medicine, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, University of Maryland School of Medicine, University of Maryland System, University of Edinburgh, University of Exeter, Department of Twin Research and Genetic Epidemiology, King's College London, London, Northwestern University [Evanston], National Institute of Health and Welfare, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Lund University Diabetes Centre, Umeå University, National Institutes of Health, Centre for Medical Systems Biology, Netherlands Genomics Initiative, Washington University in Saint Louis (WUSTL), Department of Health Sciences Research, Mayo Clinic, Wake Forest University, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, University of Iceland, Institute of Biomedicine, Physiology, University of Eastern Finland, Institut National de la Santé et de la Recherche Médicale (INSERM), UMR S 1018, Université Paris-Sud - Paris 11 (UP11), Azienda Sanitaria Firenze, Department of Medical Genetics, Université de Lausanne (UNIL), Centre Hospitalier Universitaire Vaudois (CHUV), Queen Elizabeth II Medical Centre, Research Institute, University of Southern California (USC), University of Split, The University of Texas Health Science Center at Houston (UTHealth), Leipzig University, Pennington Biomedical Research Center, Department of Epidemiology & Public Health, University College of London [London] (UCL), San Carlos Clinical Hospital, University of North Carolina, Harokopio University, National Institute on Aging, Folkhälsan Research Centre, Vaasa Central Hospital, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Psychiatry, EMGO - Lifestyle, overweight and diabetes, Epidemiology, Immunology, Erasmus School of Social and Behavioural Sciences, Clinical Genetics, Ophthalmology, Internal Medicine, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Multiple Tissue Human Expression Resource (MUTHER) Consortium, Ahmadi, K.R., Ainali, C., Barrett, A., Bataille, V., Bell, J.T., Buil, A., Deloukas, P., Dermitzakis, E.T., Dimas, A.S., Durbin, R., Glass, D., Grundberg, E., Hassanali, N., Hedman, Å.K., Ingle, C., Knowles, D., Krestyaninova, M., Lindgren, C.M., Lowe, C.E., McCarthy, M.I., Meduri, E., di Meglio, P., Min, J.L., Montgomery, S.B., Nestle, F.O., Nica, A.C., Nisbet, J., O'Rahilly, S., Parts, L., Potter, S., Sekowska, M., Shin, S.Y., Small, K.S., Soranzo, N., Spector, T.D., Surdulescu, G., Travers, M.E., Tsaprouni, L., Tsoka, S., Wilk, A., Yang, T.P., Zondervan, K.T., Voight, B.F., Scott, L.J., Steinthorsdottir, V., Morris, A.P., Dina, C., Welch, R.P., Zeggini, E., Huth, C., Aulchenko, Y.S., Thorleifsson, G., McCulloch, L.J., Ferreira, T., Grallert, H., Amin, N., Wu, G., Willer, C.J., Raychaudhuri, S., McCarroll, S.A., Langenberg, C., Hofmann, O.M., Dupuis, J., Qi, L., Segrè, A.V., van Hoek, M., Navarro, P., Ardlie, K., Balkau, B., Benediktsson, R., Bennett, A.J., Blagieva, R., Boerwinkle, E., Bonnycastle, L.L., Boström, K.B., Bravenboer, B., Bumpstead, S., Burtt, N.P., Charpentier, G., Chines, P.S., Cornelis, M., Couper, D.J., Crawford, G., Doney, A.S., Elliott, K.S., Elliott, A.L., Erdos, M.R., Fox, C.S., Franklin, C.S., Ganser, M., Gieger, C., Grarup, N., Green, T., Griffin, S., Groves, C.J., Guiducci, C., Hadjadj, S., Herder, C., Isomaa, B., Jackson, A.U., Johnson, P.R., Jørgensen, T., Kao, W.H., Klopp, N., Kong, A., Kraft, P., Kuusisto, J., Lauritzen, T., Li, M., Lieverse, A., Lyssenko, V., Marre, M., Meitinger, T., Midthjell, K., Morken, M.A., Narisu, N., Nilsson, P., Owen, K.R., Payne, F., Perry, J.R., Petersen, A.K., Platou, C., Proença, C., Prokopenko, I., Rathmann, W., Rayner, N.W., Robertson, N.R., Rocheleau, G., Roden, M., Sampson, M.J., Saxena, R., Shields, B.M., Shrader, P., Sigurdsson, G., Sparsø, T., Strassburger, K., Stringham, H.M., Sun, Q., Swift, A.J., Thorand, B., Tichet, J., Tuomi, T., van Dam, R.M., van Haeften, T.W., van Herpt, T., van Vliet-Ostaptchouk, J.V., Walters, G.B., Weedon, M.N., Wijmenga, C., Witteman, J., Bergman, R.N., Cauchi, S., Collins, F.S., Gloyn, A.L., Gyllensten, U., Hansen, T., Hide, W.A., Hitman, G.A., Hofman, A., Hunter, D.J., Hveem, K., Laakso, M., Mohlke, K.L., Morris, A.D., Palmer, C.N., Pramstaller, P.P., Rudan, I., Sijbrands, E., Stein, L.D., Tuomilehto, J., Uitterlinden, A., Walker, M., Wareham, N.J., Watanabe, R.M., Abecasis, G.R., Boehm, B.O., Campbell, H., Daly, M.J., Hattersley, A.T., Hu, F.B., Meigs, J.B., Pankow, J.S., Pedersen, O., Wichmann, H.E., Barroso, I., Florez, J.C., Frayling, T.M., Groop, L., Sladek, R., Thorsteinsdottir, U., Wilson, J.F., Illig, T., Froguel, P., van Duijn, C.M., Stefansson, K., Altshuler, D., Boehnke, M., Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA)
Subjects: Blood Glucose, Netherlands Twin Register (NTR), medicine.medical_treatment, [SDV]Life Sciences [q-bio], LOCI, Genome-wide association study, Type 2 diabetes, SUSCEPTIBILITY, Body Mass Index, GLUCOSE, Blood Glucose/metabolism, Cholesterol, HDL/metabolism, Diabetes Mellitus, Type 2/genetics, Genome-Wide Association Study, Humans, Insulin/metabolism, Insulin Resistance/genetics, Polymorphism, Single Nucleotide, 0302 clinical medicine, Insulin, 2. Zero hunger, Genetics, 0303 health sciences, COMMON VARIANTS, 3. Good health, ENVIRONMENT INTERACTION, OBESITY, CORONARY-ARTERY-DISEASE, medicine.medical_specialty, 030209 endocrinology & metabolism, Accounting, Biology, Article, 03 medical and health sciences, Insulin resistance, SDG 3 - Good Health and Well-being, Internal medicine, Diabetes mellitus, medicine, 030304 developmental biology, Genetic association, Glycemic, loci, SNP, insulin, business.industry, Cholesterol, HDL, medicine.disease, Obesity, POLYMORPHISM, ASSOCIATION ANALYSIS, Endocrinology, Diabetes Mellitus, Type 2, TYPE-2 DIABETES RISK, Insulin Resistance, business
Abstract: Group Authors : DIAGRAM Consortium MUTHER Consortium variants influencing fasting glycemic traits and insulin resistance Seuls les 100 premiers auteurs ont été conservés dans la publication. La liste complète des auteurs et des des affiliations est disponible sur la publication https://www.nature.com/articles/ng.2274.pdf p. 667-669.; International audience; Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 x 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
Published: 2012
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24. Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia

Author: María Rozman, Xose S. Puente, Marta Aymerich, Daniel Rico, Laura Conde, Miriam Rubio, Modesto Orozco, Jian-Bing Fan, Guillem Clot, Marina Bibikova, Josep Lluís Gelpí, Mónica López-Guerra, Magda Pinyol, David G. Pisano, Vincent T. Ho, Brandy Klotzle, Panagiotis Papasaikas, Lluis Hernández, Neus Villamor, Simone Ecker, Alba Navarro, Ana C. Queirós, Sergio Barberan-Soler, Alejandra Martínez-Trillos, Carlos López-Otín, Armando López-Guillermo, José I. Martín-Subero, Isabelle Brun-Heath, Marta Kulis, Romina Royo, Ivo Gut, Víctor Quesada, Giancarlo Castellano, Mònica Bayés, Simon Heath, Dolors Colomer, Alfonso Valencia, Elias Campo, Pedro Jares, Marta Gut, and Sílvia Beà
Subjects: Adult, Male, Bisulfite sequencing, Biology, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, Epigenetics, 030304 developmental biology, Epigenomics, Aged, Regulation of gene expression, Aged, 80 and over, 0303 health sciences, B-Lymphocytes, Genome, Human, High-Throughput Nucleotide Sequencing, Methylation, DNA Methylation, Middle Aged, Leukemia, Lymphocytic, Chronic, B-Cell, Alternative Splicing, Gene Expression Regulation, 030220 oncology & carcinogenesis, DNA methylation, Cancer research, CpG Islands, Female, IGHV@, DNA hypomethylation
Abstract: We have extensively characterized the DNA methylomes of 139 patients with chronic lymphocytic leukemia (CLL) with mutated or unmutated IGHV and of several mature B-cell subpopulations through the use of whole-genome bisulfite sequencing and high-density microarrays. The two molecular subtypes of CLL have differing DNA methylomes that seem to represent epigenetic imprints from distinct normal B-cell subpopulations. DNA hypomethylation in the gene body, targeting mostly enhancer sites, was the most frequent difference between naive and memory B cells and between the two molecular subtypes of CLL and normal B cells. Although DNA methylation and gene expression were poorly correlated, we identified gene-body CpG dinucleotides whose methylation was positively or negatively associated with expression. We have also recognized a DNA methylation signature that distinguishes new clinico-biological subtypes of CLL. We propose an epigenomic scenario in which differential methylation in the gene body may have functional and clinical implications in leukemogenesis.
Published: 2012
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25. Primary prevention with statins for older adults

Author: Simon Heath, Aidan Ryan, and Paul Cook
Subjects: Secondary prevention, medicine.medical_specialty, business.industry, MEDLINE, Retrospective cohort study, General Medicine, 030204 cardiovascular system & hematology, medicine.disease, 03 medical and health sciences, Hydroxymethylglutaryl-CoA Reductase Inhibitors, 0302 clinical medicine, Primary prevention, Internal medicine, Diabetes mellitus, Medicine, 030212 general & internal medicine, business
Published: 2018
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26. Genome-wide association study of major recurrent depression in the U.K. population

Author: Frederica Tozzi, Mandy Y.M. Ng, Pierandrea Muglia, Ursula M. Paredes, Ania Korszun, John C. Whittaker, Gerome Breen, Jianxin Shi, Gérard Waeber, Rudolf Uher, Katrina Pirlo, Ian Jones, Amy W. Butler, Sarah Cohen-Woods, Alexandra Schosser, Florian Holsboer, Katherine J. Aitchison, Peter McGuffin, Michael R. Barnes, Margarita Rivera, Ian W. Craig, Martin Preisig, Nicholas John Craddock, Cathryn M. Lewis, Alasdair MacKenzie, Simon Heath, Michael John Owen, Anne Farmer, Michael E. Weale, Lisa Jones, Mark Lathrop, John P. Quinn, and Peter Vollenweider
Subjects: Adult, Genetic Markers, Male, medicine.medical_specialty, Genotype, Population, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Meta-Analysis as Topic, Recurrence, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, education, Allele frequency, Aged, 030304 developmental biology, Genetics, Depressive Disorder, Major, 0303 health sciences, education.field_of_study, business.industry, Case-control study, Middle Aged, Heritability, United Kingdom, 3. Good health, Minor allele frequency, Psychiatry and Mental health, Case-Control Studies, Female, business, 030217 neurology & neurosurgery, Imputation (genetics), Genome-Wide Association Study
Abstract: Objective Studies of major depression in twins and families have shown moderate to high heritability, but extensive molecular studies have failed to identify susceptibility genes convincingly. To detect genetic variants contributing to major depression, the authors performed a genome-wide association study using 1,636 cases of depression ascertained in the U.K. and 1,594 comparison subjects screened negative for psychiatric disorders. Method Cases were collected from 1) a case-control study of recurrent depression (the Depression Case Control [DeCC] study; N=1346), 2) an affected sibling pair linkage study of recurrent depression (probands from the Depression Network [DeNT] study; N=332), and 3) a pharmacogenetic study (the Genome-Based Therapeutic Drugs for Depression [GENDEP] study; N=88). Depression cases and comparison subjects were genotyped at Centre National de Genotypage on the Illumina Human610-Quad BeadChip. After applying stringent quality control criteria for missing genotypes, departure from Hardy-Weinberg equilibrium, and low minor allele frequency, the authors tested for association to depression using logistic regression, correcting for population ancestry. Results Single nucleotide polymorphisms (SNPs) in BICC1 achieved suggestive evidence for association, which strengthened after imputation of ungenotyped markers, and in analysis of female depression cases. A meta-analysis of U.K. data with previously published results from studies in Munich and Lausanne showed some evidence for association near neuroligin 1 (NLGN1) on chromosome 3, but did not support findings at BICC1. Conclusions This study identifies several signals for association worthy of further investigation but, as in previous genome-wide studies, suggests that individual gene contributions to depression are likely to have only minor effects, and very large pooled analyses will be required to identify them.
Published: 2010
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27. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Author: Kenneth Rice, Amy J. Swift, Veronique Vitart, Lu Qi, Kaisa Silander, Olivier Le Bacquer, Laura Crisponi, David S. Siscovick, Bo Isomaa, Anne U. Jackson, Anke Tönjes, Richard N. Bergman, Rosa Maria Roccasecca, Luigi Ferrucci, Narisu Narisu, Kari Stefansson, Holly E. Syddall, Giuseppe Paolisso, Kim L. Ward, Paul Elliott, Scott M. Grundy, Paul Johnson, Jerome I. Rotter, Philippe Froguel, James B. Meigs, George Davey Smith, Andrew T. Hattersley, Leena Peltonen, Eric J.G. Sijbrands, Serena Sanna, María TeresaMartínez-Larrad, David Altshuler, Harald Grallert, Caroline S. Fox, Nita G. Forouhi, Dorret I. Boomsma, Harry Campbell, Jean Tichet, Angelo Scuteri, Aroon D. Hingorani, Daniel S. Pearson, Meena Kumari, Silvia Naitza, Shah Ebrahim, Manjinder S. Sandhu, Jose C. Florez, Cyrus Cooper, David M. Nathan, Joseph Hung, Fredrik Karpe, Ozren Polasek, Philip J. Barter, Ruth McPherson, Benjamin F. Voight, Wolfgang Rathmann, Abbas Dehghan, Udo Seedorf, Beverley M. Shields, Antti Jula, Pau Navarro, Josephine M. Egan, Rune R. Frants, Leif Groop, Gunnar Sigursson, Seppo Koskinen, Vincent Mooser, François Pattou, Jing Hua Zhao, Irene Pichler, John F. Peden, Göran Hallmans, Toshiko Tanaka, Ruth J. F. Loos, Peter Kovacs, Andrew D. Morris, Cécile Lecoeur, Jeffrey R. O'Connell, Massimo Mangino, Nicole Vogelzangs, Rhian Gwilliam, Gordon H. Williams, Carina Zabena, Naomi Hammond, Amélie Bonnefond, Björn Zethelius, Joachim Spranger, Nancy L. Pedersen, Christopher J. Groves, Nicholas J. Timpson, George Dedoussis, Veikko Salomaa, Peter Henneman, Andrew Walley, Serge Hercberg, Ian N. M. Day, Simon Heath, Matt Neville, Alex S. F. Doney, Robert Clarke, Olov Rolandsson, Panos Deloukas, Eric Boerwinkle, Y. AnteroKesaniemi, Mike Sampson, Gerard Waeber, Sven Bergmann, Ben A. Oostra, Manuel Serrano-Ríos, Mandy van Hoek, Christine Cavalcanti-Proença, Anna L. Gloyn, Ulla Sovio, Andrew P. Morris, Anneli Pouta, Amanda J. Bennett, Paul Scheet, Peter Schwarz, Jaakko Tuomilehto, Hugh Watkins, Johanna Kuusisto, Denis Rybin, Anna LiisaHartikainen, Maria GraziaFranzosi, Unnur Thorsteinsdottir, Rafn Benediktsson, Alan F. Wright, Colin N. Apalmer, Anuj Goel, Yavuz Ariyurek, Lars Lind, Robert Sladek, Stefan R. Bornstein, Reedik Mägi, Laila Simpson, Tim D. Spector, Paul W. Franks, Nicholas L. Smith, John R. B. Perry, Peter Vollenweider, Suzannah Bumpstead, Ruth E. Pakyz, Christa Meisinger, Alan R. Shuldiner, Josée Dupuis, Man Li, Eric J. Brunner, Francis S. Collins, Torben Hansen, James F. Wilson, Guangju Zhai, Igor Rudan, Nicole L. Glazer, Marco Orrù, Pierre Meneton, Knut Borch-Johnsen, Eleanor Wheeler, Gonçalo R. Abecasis, Mark I. McCarthy, Jouke JanHottenga, Inga Prokopenko, Ping An, Jérôme Delplanque, Albert Hofman, Andrew B. Singleton, Gabe Crawford, Thomas A. Buchanan, Avan Aihie Sayer, Richard M. Watanabe, David Schlessinger, A C Fedson, André G. Uitterlinden, Frank B. Hu, Jaqueline C. MWitteman, Dhiraj Varma, Ingrid B. Borecki, Sutapa Mukherjee, Murielle Bochud, Barbara Thorand, Christian Gieger, Lori L. Bonnycastle, Stephen J. Sharp, Markus Perola, Caroline Hayward, Kristin Ardlie, J. Graessler, Robert W. Mahley, Toby Johnson, Jian'an Luan, Joshua C. Randall, Cornelia M. van Duijn, Samuli Ripatti, Ko Willems van Dijk, Valgerdur Steinthorsdottir, Yurii S. Aulchenko, G. Mark Lathrop, Christian Dina, Eleftheria Zeggini, Cecilia M. Lindgren, Stavroula Kanoni, Timothy M. Frayling, Dawn M. Waterworth, Marika Kaakinen, Timo T. Valle, Diana Zelenika, Yii Der IdaChen, Angela Silveira, Nigel W. Rayner, Aimo Ruokonen, Yun Li, Cristian Pattaro, Annelli Sandbæk, Richa Saxena, Danielle Posthuma, Steven A. McCarroll, Niels Grarup, Samy Hadjadj, Pilar Galan, Xijing Han, Lyle J. Palmer, Ulf Gyllensten, Peter P. Pramstaller, Manuela Uda, Jarred B. McAteer, Brenda W.J.H. Penninx, Debbie A Lawlor, Torben Jørgensen, Beatrice Knight, Yvonne Böttcher, Claudia Langenberg, Nicole Soranzo, Ghislain Rocheleau, Erik Ingelsson, Mario A. Morken, Michael Roden, Felicity Payne, David R. Hillman, Michael Marmot, Karen L. Mohlke, Heather M. Stringham, Bruce M. Psaty, Gudmar Thorleifsson, Yoav Ben-Shlomo, Inês Barroso, W. H. Linda Kao, James S. Pankow, Valeriya Lyssenko, Nicholas J. Wareham, Tiinamaija Tuomi, Ann ChristineSyvänen, Braxton D. Mitchell, Alisa K. Manning, Mika Kivimäki, Peter Wagner, Praveen Sethupathy, G. BragiWalters, Jaakko Kaprio, Kijoung Song, Marjo Riitta-Järvelin, Michael A. Province, Andrew A. Hicks, Marilyn C. Cornelis, Sarah H. Wild, David Meyre, Guillaume Charpentier, Patrik K. E. Magnusson, David Melzer, Jennie Hui, Peter Shrader, Michael Stumvoll, Mark O. Goodarzi, Michael R. Erdos, Oluf Pedersen, Andreas Pfeiffer, Augustine Kong, Christian Herder, Laura J. Scott, John W. GYarnell, Kirsten Ohm Kyvik, Beverley Balkau, Antje Fischer-Rosinsky, Gonneke Willemsen, Thomas Illig, Neelam Hassanali, Markku Laakso, Michael Boehnke, John Beilby, Christopher S. Franklin, Fernando Rivadeneira, M. Carola Zillikens, Michael N. Weedon, Antonio Cao, Mark E. Cooper, Simon C. Potter, Eco J. C. de Geus, H.-Erich Wichmann, Amanda F. Elliott, Lachlan J. McOin, Sophie Visvikis-Siest, Thomas Sparsø, Laura J. McCulloch, Taina K. Lajunen, Peter S. Chines, Nabila Bouatia-Naji, Medical Research Council (MRC), Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Anxiety & Depression, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Mental Health, Ophthalmology, Epidemiology, Clinical Genetics, Dermatology, Internal Medicine, DIAGRAM Consortium, GIANT Consortium, Global BPgen Consortium, Anders Hamsten on behalf of Procardis Consortium, MAGIC investigators, Human genetics, Psychiatry, EMGO - Mental health, NCA - Attention & Cognition, and NCA - Anxiety & Depression
Subjects: Blood Glucose, Netherlands Twin Register (NTR), Candidate gene, Genome-wide association study, Type 2 diabetes, CIRCADIAN CLOCK, TRIGLYCERIDE LEVELS, 0302 clinical medicine, Delta-5 Fatty Acid Desaturase, Databases, Genetic, Homeostasis, GENETICS & HEREDITY, Anders Hamsten on behalf of Procardis Consortium, Child, Genetics, PLASMA-GLUCOSE, 0303 health sciences, Glucokinase regulatory protein, COMMON VARIANTS, 11 Medical And Health Sciences, Fasting, MAGIC investigators, 3. Good health, MODEL ASSESSMENT, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, ESSENTIAL COMPONENTS, Adolescent, DNA Copy Number Variations, Alleles, Blood Glucose/genetics, Blood Glucose/metabolism, DNA Copy Number Variations/genetics, Diabetes Mellitus, Type 2/genetics, Fasting/blood, Gene Expression Regulation, Genetic Loci/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeostasis/genetics, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide/genetics, Quantitative Trait Loci/genetics, Quantitative Trait, Heritable, Reproducibility of Results, Quantitative Trait Loci, 030209 endocrinology & metabolism, Biology, DIAGRAM Consortium, INSULIN-SECRETION, Polymorphism, Single Nucleotide, Article, Fasting glucose, 03 medical and health sciences, Insulin resistance, SDG 3 - Good Health and Well-being, Diabetes mellitus, Internal medicine, genome wide association study, glucose, diabetes type 2, medicine, GIANT Consortium, Allele, GENOME-WIDE ASSOCIATION, Global BPgen Consortium, 030304 developmental biology, Glycemic, Science & Technology, genome-wide association beta-cell dysfunction plasma-glucose insulin-secretion triglyceride levels essential components model assessment common variants circadian clock disease risk, DISEASE RISK, 06 Biological Sciences, medicine.disease, Endocrinology, Diabetes Mellitus, Type 2, Genetic Loci, biology.protein, BETA-CELL DYSFUNCTION, Developmental Biology
Abstract: Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46, 186 nondiabetic participants. Follow-up of 25 loci in up to 76, 558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
Published: 2010
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28. Genome-wide association study identifies eight loci associated with blood pressure

Author: Peter Holmans, Udo Seedorf, Beverley M. Shields, Peter McGruffin, Arne Pfeufer, Steve Eyre, Nathalie J. Prescott, Michael Boehnke, Valentina Moskovina, Abiodun Onipinla, Leena Peltonen, Nadira Yuldasheva, Peter M. Nilsson, Valeria Romanazzi, Vincent Mooser, Göran Berglund, Alistair S. Hall, Dominic P. Kwiatkowski, Barry Widmer, Benjamin F. Voight, Stefania Bandinelli, Mark M. Iles, Sven Bergmann, Thomas Meitinger, James P. Boorman, Simonetta Guarrera, Nazneen Rahman, Murielle Bochud, Graham A. Hitman, Emma Keniry, Nelson B. Freimer, Richard Dobson, Francis S. Collins, Gerjan Navis, Jennifer L. Pointon, Richard N. Bergman, Ruth J. F. Loos, Roberto Lorbeer, Carolina A. Braga Marcano, Christian Gieger, Florian Ernst, Xin Yuan, Catherine Potter, Hazel E. Drummond, Allan H. Young, George Kirov, John F. Peden, Helen Stevens, David Clayton, Mattijs E. Numans, Katherine Gordon-Smith, Anne Farmer, Alastair Forbes, M. Khalid Mohiuddin, John A. Todd, Christopher G. Mathew, David A. Collier, Mark I. McCarthy, Francesca Bredin, Clive M. Onnie, Dan Davidson, Markus Perola, Pamela Whittaker, Yvonne T. van der Schouw, Rathi Ravindrarajan, I. C.A. Spencer, Teresa Ferreira, Nilesh J. Samani, Serge Hercberg, Gonçalo R. Abecasis, Christopher J. Groves, Nicholas John Craddock, Angela Döring, Edward G. Lakatta, Muminatou Jallow, Wendy L. McArdle, David Bentley, Susana Eyheramendy, Uwe Völker, Christopher Newton-Cheh, Jaspal S. Kooner, Hugh Watkins, Gavin Lucas, H. T. Leung, Marjo Ritta Jarvelin, Johanna Kuusisto, Wiek H. van Gilst, Wendy Thomson, Lou R. Cardon, Harold Snieder, Marju Orho-Melander, Patricia B. Munroe, Toshiko Tanaka, Jeffrey C. Barrett, Azhar Maqbool, Henry Völzke, John M. C. Connell, Elaine R. Nimmo, John R. B. Perry, Michael R. Stratton, Ralph McGinnis, Pekka Jousilahti, Michiel L. Bots, Ian Jones, Elizabeth Meech, Matthew A. Brown, Johannie Gungadoo, Jian'an Luan, Jilur Ghori, Richard J. Dixon, N. Charlotte Onland-Moret, Fulvio Ricceri, Anthony J. Balmforth, Catherine E. Todhunter, Inês Barroso, Sheila Bingham, Timo T. Valle, Fredrik O. Vannberg, Diana Zelenika, Stephen Sawcer, Anneli Pouta, David M. Evans, Cuno S. P. M. Uiterwaal, Pilar Galan, Georg Homuth, Hannah Donovan, David J. Conway, Paul Elliott, Alessandra Allione, Paul E. de Jong, Miles Parkes, Amy Chaney, John C. Chambers, Toby Johnson, Isaac Subirana, Vesela Gateva, Cathryn M. Lewis, Christopher J. O'Donnell, Hana Lango, David Schlessinger, Mark J. Caulfield, Thorsten Reffelmann, Jamie Barbour, Karen L. Mohlke, Sarah E. Hunt, Thilo Winzer, Frances M K Williams, Christopher Mathew, I. Wallace, Anuj Goel, Jaakko Tuomilehto, Louise V. Wain, Gabriel Crawford, Samantha L. Hider, Detelinea Grozeva, Elaine K. Green, Paul D. Gilbert, Peter S. Braund, Jaume Marrugat, Rainer Rettig, Pim van der Harst, Yik Ying Teo, Andrew P. Morris, Guiseppe Matullo, Serena Sanna, Cristen J. Willer, Suzannah Bumpstead, Niall C. Taylor, Jacques S. Beckmann, Pierre Meneton, Elin Org, Luigi Ferrucci, Doug Easton, Sheila Seal, Joanne M. Heward, Anne U. Jackson, Eleftheria Zeggini, Rachel M. Freathy, Maris Laan, Paul Wordsworth, Sarah Nutland, Kerstin Koch, Sian Ceasar, Anders Hamsten, Judith M. Hussey, Tariq Ahmad, Derek P. Jewell, Paul Scheet, Charlie W. Lees, C Farrar, Christopher Prowse, Markku Laakso, David St Clair, Kate Downes, Diederick E. Grobbee, Paul Burton, Simon C. Potter, Ian N. Bruce, Tim D. Spector, Anne Barton, H.-Erich Wichmann, Matthew J. Simmonds, David Hadley, Cecilia M. Lindgren, Gérard Waeber, Nigel W. Rayner, Melanie J. Newport, Manjinder S. Sandhu, Audrey Duncanson, Guangju Zhai, Simon Heath, Susan M. Ring, Alessandra Di Gregorio, Richard Williamson, Nicholas J. Wareham, Zhan Su, Olle Melander, John R. Thompson, Alexander Teumer, Sheila A. Fisher, Lachlan J. M. Coin, Leif Groop, Giovanni Tognoni, Amanda Elkin, Alan J. Silman, Jack Satsangi, Jane Worthington, Martin Farrall, John Webster, Niall Cardin, Neil Walker, Anna F. Dominiczak, Jeremy D. Sanderson, Damjan Vukcevic, Bryan Howie, Silvia Polidoro, Stephen G. Ball, Mark Tremelling, Stephen Newhouse, Stephen M. Schwartz, Lori L. Bonnycastle, Chris Wallace, Kijoung Song, Mario A. Morken, I. Nicol Ferrier, Beverley Barke, Paolo Vineis, Manuela Uda, Deborah P M Symmons, Emily J. Lyons, Mingzhan Xue, Timothy M. Frayling, Stephen C.L. Cough, David Withers, Adrian V. S. Hill, Suzanne Stevens, Jennifer Jolley, Marcus Dörr, Kirk A. Rockett, David B. Dunger, Mark Walker, Jayne A. Franklyn, Lisa Jones, David S. Siscovick, Ann-Christine Syvänen, Laura J. Scott, Morris J. Brown, Barbera Cant, Michael Inouye, Feng Zhang, Carlotta Sacerdote, Katherine S. Elliott, Jonathan Marchini, Peter Donnely, Michael John Owen, An Goris, Marcus Prembey, Andrew T. Hattersley, Gerome Breen, Marian L. Hamshere, Thomas Illig, Samer S. Najjar, Nicole Soranzo, Kay-Tee Khaw, Graham R. Walters, Willem H. Ouwehand, David P. Strachan, Martin D. Tobin, Alastair Compston, John C. Mansfield, David Altshuler, Salvatore Panico, Sekar Kathiresan, Dawn M. Waterworth, Michael N. Weedon, D. Timothy Bishop, Claire Bryan, Alexandra S. Knight, Kate L. Lee, Paul F. O'Reilly, Massimo Mangino, Michael Conlon O'Donovan, Jing Hua Zhao, Konstantinos A. Papadakis, Jennifer H. Barrett, Joanne Pereira-Gale, N J Timpson, Stephan B. Felix, Panos Deloukas, Nicholas A. Watkins, Anna-Liisa Hartikainen, Peter Vollenweider, Richard Jones, Anne Hinks, Fraser Cummings, Noha Lim, Linda A. Bradbury, Rhian G. William, Nita G. Forouhi, Roberto Eluosa, Ingeleif B. Hallgrimsdottir, Giorgio Sirugo, Robert Luben, Veikko Salomaa, Robert Clarke, Sally John, Ursula Everson, Emma King, Ivan Nikolov, Heather M. Stringham, Antony P. Attwood, Angelo Scuteri, Wellcome Trust Case Control Consortium, Burton, PR., Clayton, DG., Cardon, LR., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, DP., McCarthy, MI., Ouwehand, WH., Samani, NJ., Todd, JA., Donnelly, P., Barrett, JC., Davison, D., Easton, D., Evans, D., Leung, HT., Marchini, JL., Morris, AP., Spencer, IC., Tobin, MD., Attwood, AP., Boorman, JP., Cant, B., Everson, U., Hussey, JM., Jolley, JD., Knight, AS., Koch, K., Meech, E., Nutland, S., Prowse, CV., Stevens, HE., Taylor, NC., Walters, GR., Walker, NM., Watkins, NA., Winzer, T., Jones, RW., McArdle, WL., Ring, SM., Strachan, DP., Pembrey, M., Breen, G., St Clair, D., Caesar, S., Gordon-Smith, K., Jones, L., Fraser, C., Green, EK., Grozeva, D., Hamshere, ML., Holmans, PA., Jones, IR., Kirov, G., Moskvina, V., Nikolov, I., O'Donovan, MC., Owen, MJ., Collier, DA., Elkin, A., Farmer, A., Williamson, R., McGuffin, P., Young, AH., Ferrier, IN., Ball, SG., Balmforth, AJ., Barrett, JH., Bishop, DT., Iles, MM., Maqbool, A., Yuldasheva, N., Hall, AS., Braund, PS., Dixon, RJ., Mangino, M., Stevens, S., Thompson, JR., Bredin, F., Tremelling, M., Parkes, M., Drummond, H., Lees, CW., Nimmo, ER., Satsangi, J., Fisher, SA., Forbes, A., Lewis, CM., Onnie, CM., Prescott, NJ., Sanderson, J., Mathew, CG., Barbour, J., Mohiuddin, MK., Todhunter, CE., Mansfield, JC., Ahmad, T., Cummings, FR., Jewell, DP., Webster, J., Brown, MJ., Lathrop, GM., Connell, J., Dominiczak, A., Braga Marcano, CA., Burke, B., Dobson, R., Gungadoo, J., Lee, KL., Munroe, PB., Newhouse, SJ., Onipinla, A., Wallace, I., Xue, M., Caulfield, M., Farrall, M., Barton, A., Bruce, IN., Donovan, H., Eyre, S., Gilbert, PD., Hider, SL., Hinks, AM., John, SL., Potter, C., Silman, AJ., Symmons, DP., Thomson, W., Worthington, J., Dunger, DB., Widmer, B., Frayling, TM., Freathy, RM., Lango, H., Perry, JR., Shields, BM., Weedon, MN., Hattersley, AT., Hitman, GA., Walker, M., Elliott, KS., Groves, CJ., Lindgren, CM., Rayner, NW., Timpson, NJ., Zeggini, E., Newport, M., Sirugo, G., Lyons, E., Vannberg, F., Hill, AV., Bradbury, LA., Farrar, C., Pointon, JJ., Wordsworth, P., Brown, MA., Franklyn, JA., Heward, JM., Simmonds, MJ., Gough, SC., Seal, S., Stratton, MR., Rahman, N., Ban, M., Goris, A., Sawcer, SJ., Compston, A., Conway, D., Jallow, M., Rockett, KA., Bryan, C., Bumpstead, SJ., Chaney, A., Downes, K., Ghori, J., Gwilliam, R., Hunt, SE., Inouye, M., Keniry, A., King, E., McGinnis, R., Potter, S., Ravindrarajah, R., Whittaker, P., Withers, D., Cardin, NJ., Ferreira, T., Pereira-Gale, J., Hallgrimsdóttir, IB., Howie, BN., Su, Z., Teo, YY., Vukcevic, D., Bentley, D., Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), and Medical Research Council (MRC)
Subjects: Hemodynamics, Genome-wide association study, Blood Pressure, 030204 cardiovascular system & hematology, 0302 clinical medicine, Diastole, 11 Medical and Health Sciences, POPULATION, Genetics, Genetics & Heredity, RISK, 0303 health sciences, education.field_of_study, Econometric and Statistical Methods: General, CELL-DIFFERENTIATION, biology, Intracellular Signaling Peptides and Proteins, Chromosome Mapping, Steroid 17-alpha-Hydroxylase, COMMON VARIANTS, 3. Good health, DNA-Binding Proteins, Europe, Cardiovascular Diseases, PUBLIC-HEALTH, BARTTERS-SYNDROME, Blood Pressure/genetics, Cardiovascular Diseases/genetics, Cardiovascular Diseases/physiopathology, Cytochrome P-450 CYP1A2/genetics, DNA-Binding Proteins/genetics, Diastole/genetics, European Continental Ancestry Group/genetics, Fibroblast Growth Factor 5/genetics, Genetic Variation, Genome-Wide Association Study, Humans, India, Methylenetetrahydrofolate Reductase (NADPH2)/genetics, Open Reading Frames/genetics, Phospholipase C delta/genetics, Polymorphism, Single Nucleotide, Proteins/genetics, Steroid 17-alpha-Hydroxylase/genetics, Systole/genetics, Wellcome Trust Case Control Consortium, Life Sciences & Biomedicine, hypertension, Fibroblast Growth Factor 5, Systole, Population, European Continental Ancestry Group, METHYLENETETRAHYDROFOLATE REDUCTASE GENE, Single-nucleotide polymorphism, LOW-RENIN HYPERTENSION, White People, Article, 03 medical and health sciences, Open Reading Frames, Fibroblast growth factor-5, Cytochrome P-450 CYP1A2, Geneeskunde(GENK), education, Methylenetetrahydrofolate Reductase (NADPH2), Adaptor Proteins, Signal Transducing, 030304 developmental biology, Genetic association, genome-wide association, Science & Technology, MUTATIONS, Proteins, 06 Biological Sciences, POLYMORPHISM, Blood pressure, Methylenetetrahydrofolate reductase, biology.protein, biology.gene, Phospholipase C delta, Developmental Biology
Abstract: Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
Published: 2009
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29. Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease

Author: KR O’Leary, Fernando Gomollón, Nicholas T. Ventham, Irena Trbojević Akmačić, Frano Vučković, Angie Fawkes, Fredrik A. Dahl, David C. Wilson, Jerko Štambuk, Fredrik Hjelm, Malcolm G. Dunlop, Simon Heath, Céline Sabatel, Eddie Modig, Noortje de Haan, Laura Cantoro, C. Casén, Maja Pučić-Baković, Jonas Christoffer Lindstrøm, Aina Elisabeth Fossum Moen, Mauro D'Amato, Dermot P.B. McGovern, Florent Clerc, Nicholas A. Kennedy, Anne Clémence Veillard, Daniel Bergemalm, Nicola Wrobel, Gunn S. Ekeland, Manfred Wuhrer, Colin L. Noble, Anna B. Frengen, Niklas Nordberg, Daisy Jonkers, Daryl L. Fernandes, Anette Ocklind, Dominique Poncelet, Rahul Kalla, Gionata Fiorino, Paolo Lionetti, Victoria Merrick, Petr Ricanek, Aleksandar Vojta, Alan G. Shand, Mikael Sundell, Johan D. Söderholm, Archana Shubhakar, Tim van den Heuve, Ivo Gut, Torbjørn Lindahl, Paula Dobrinić, Mislav Novokmet, G.C. Sturniolo, Natalia Manetti, Elaine R. Nimmo, Iain K. Permberton, Jasminka Krištić, Ray Boyapati, Igor Rudan, Olga Gornik, Anna Kohn, Leif Törkvist, Erik Pettersson, Gordan Lauc, Marieke Pierik, Ian D. Arnott, Lee Murphy, Monica Bayes, Ewa Ciemniejewska, Louise Evenden, Mats Gullberg, Jack Satsangi, Ivana Samaržija, Anna Latiano, Charlie W. Lees, Angelo Andriulli, Renata D'Incà, Jørgen Jahnsen, Renaud Schoemans, Panpan You, Yurii S. Aulchenko, Hazel E. Drummond, Gwo-Tzer Ho, Jonas Halfvarson, Vlatka Zoldoš, Tamara Gilchrist, Evropi Theorodorou, Marta Gut, Henrik Hjortswang, Daniel I. R. Spencer, Jude Gibson, Ray Doran, Silvio Danese, Simen Vatn, Alex Adams, Tone Møller Tannæs, Marija Klasić, Vito Annese, Daniel Ekman, Harry Campbell, Trond Espen Detlie, Dora Markulin, Åsa V. Keita, Guinevere S. M. Kammeijer, Janne Sølvernes, Morten H. Vatn, Richard A. Gardner, Daniel Kolarich, and Analytical Biochemistry
Subjects: Epigenomics, Male, 0301 basic medicine, inflammatory bowel disease, DNA methylation, epigenetics, General Physics and Astronomy, Bioinformatics, Inflammatory bowel disease, Linkage Disequilibrium, Epigenesis, Genetic, Cohort Studies, 0302 clinical medicine, Crohn Disease, Genotype, Promoter Regions, Genetic, skin and connective tissue diseases, Epigenesis, Multidisciplinary, Middle Aged, Protein-Tyrosine Kinases, 030220 oncology & carcinogenesis, Female, Adult, Science, Quantitative Trait Loci, Biology, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, microRNA, medicine, Humans, Genetic Predisposition to Disease, Epigenetics, Gene Expression Profiling, Membrane Proteins, General Chemistry, Epigenome, medicine.disease, digestive system diseases, MicroRNAs, 030104 developmental biology, Case-Control Studies, Colitis, Ulcerative, Gene-Environment Interaction, Gene expression, sense organs
Abstract: Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP (RPS6KA2) and DMRs (VMP1, ITGB2 and TXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci; VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within the TXK promoter region negatively correlates with gene expression in whole-blood and CD8+ T cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression., Epigenetic perturbations may be an important factor in diseases where both genes and environment play a role. Here, Ventham and colleagues show that DNA methylation changes in inflammatory bowel disease are related to the underlying genotype, and are associated with cell-specific changes to gene expression.
Published: 2016
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30. Confirmation of Psoriasis Susceptibility Loci on Chromosome 6p21 and 20p13 in French Families

Author: Emmanuel Mahe, Jean-François Prud'homme, Fabienne Lesueur, Caroline Lefèvre, Tiphaine Oudot, Michel Guilloud-Bataille, Mark Lathrop, Simon Heath, Judith Fischer, Eric M. Sobel, Marie-Hélène Dizier, Morad Lahfa, Cristina Has, Haydeh Mosharraf-Olmolk, Samira Mansouri, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Généthon, Department of Human Genetics [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, APLCP, NPF, CNG, AFM, University of California (UC)-University of California (UC), and Vaillant, Christine
Subjects: Adult, Male, Genotype, Genetic Linkage, Chromosomes, Human, Pair 20, Locus (genetics), [SDV.GEN] Life Sciences [q-bio]/Genetics, Disease, Dermatology, Major histocompatibility complex, Biochemistry, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Genetic linkage, Psoriasis, medicine, Humans, Genetic Predisposition to Disease, Molecular Biology, 030304 developmental biology, Genetics, Family Health, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, biology, business.industry, Chromosome, Atopic dermatitis, Cell Biology, Middle Aged, medicine.disease, 3. Good health, biology.protein, Chromosomes, Human, Pair 6, Female, France, business
Abstract: Plaque psoriasis is a chronic inflammatory disorder of the skin. It is inherited as a multifactorial trait, with a strong genetic component. Linkage studies have identified a large number of disease loci, but very few could be replicated in independent family sets. In this study, we present the results of a genome-wide scan carried out in 14 French extended families. Candidate regions were then tested in a second set of 32 families. Analysis of the pooled samples confirmed linkage to chromosomes 6p21 ( Z MLB score=3.5, P =0.0002) and 20p13 ( Z MLB score=2.9, P =0.002), although there was little contribution of the second family set to the 20p13 linkage signal. Moreover, we identified four additional loci potentially linked to psoriasis. The major histocompatibility complex region on 6p21 is a major susceptibility locus, referred to as PSORS1 , which has been found in most of the studies published to date. The 20p13 locus segregates independently of PSORS1 in psoriasis families. It has previously been thought to be involved in the predisposition to psoriasis and other inflammatory disorders such as atopic dermatitis (AD) and asthma. Although psoriasis and AD rarely occur together, this reinforces the hypothesis that psoriasis is influenced by genes with general effects on inflammation and immunity.
Published: 2007
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31. Analysis of 14 Candidate Genes for Diabetic Nephropathy on Chromosome 3q in European Populations

Author: Hans-Henrik Parving, Martin Farrall, Samy Hadjadj, David-Alexandre Trégouët, Fumihiko Matsuda, Rachel Rousseau, Nathalie Vionnet, Gbenga Kazeem, Per-Henrik Groop, Michel Marre, Ivo Gut, Dominique Gauguier, François Cambien, Simon Heath, Alexandre Thévard, Lise Tarnow, Carol Forsblom, Roger D. Cox, and Mark Lathrop
Subjects: Genetics, 0303 health sciences, medicine.medical_specialty, Candidate gene, Adiponectin, business.industry, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Transmission disequilibrium test, medicine.disease, 3. Good health, Nephropathy, Diabetic nephropathy, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Genetic linkage, Diabetes mellitus, Internal medicine, Internal Medicine, Medicine, business, 030304 developmental biology
Abstract: Linkage studies have mapped loci for diabetic nephropathy and associated phenotypes on chromosome 3q. We studied 14 plausible candidate genes in the linkage region because of their potential role in vascular complications. In a large-scale study of patients from Denmark, Finland, and France who have type 1 diabetes, 1,057 case and 1,127 control subjects, as well as 532 trios, were investigated for association with diabetic nephropathy. We analyzed 69 haplotype-tagging single nucleotide polymorphisms and nonsynonymous variants that were identified by sequencing. Polymorphisms in three genes, glucose transporter 2 (SLC2A2), kininogen (KNG1), and adiponectin (ADIPOQ), showed nominal association with diabetic nephropathy in single-point analysis. The T-allele of SLC2A2_16459CT was associated with a decreased risk of diabetic nephropathy (odds ratio 0.79 [95% CI 0.66–0.96], P = 0.016), whereas the T-allele of KNG_7965CT and the A-allele of ADIPOQ_prom2GA were associated with increased risk of nephropathy (1.17 [1.03–1.32], P = 0.016; 1.46 [1.11–1.93], P = 0.006, respectively). Analyses of the transmission disequilibrium test showed similar trends only for ADIPOQ_prom2GA with the overtransmission of the A-allele to patients with diabetic nephropathy (1.52 [0.86–2.66], P = NS) and of the G-allele to patients without diabetic nephropathy (0.50 [0.27–0.92], P = 0.026). The overall significance for this variant (nominal P = 0.011) suggests that ADIPOQ might be involved in the development of diabetic nephropathy.
Published: 2006
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32. Whole-genome fingerprint of the DNA methylome during human B cell differentiation

Author: Simone Ecker, Reiner Siebert, Néria Verdaguer-Dot, Guillem Clot, Renée Beekman, Alfonso Valencia, Ralf Küppers, Julie Blanc, Seung-Tae Lee, Hendrik G. Stunnenberg, Marina E. Fomin, Marta Kulis, Daniel Rico, Bruno Paiva, Diego Alignani, Gersende Caron, Ivo Gut, Joseph L. Wiemels, Vera Pancaldi, Paul Flicek, Giancarlo Castellano, José I. Martín-Subero, Elias Campo, Lidia Agueda, Laura Clarke, Felipe Prosper, Marta Gut, Marcus O. Muench, Nuria Russiñol, Ronald P. Schuyler, Roser Vilarrasa-Blasi, Martí Duran-Ferrer, Thierry Fest, Simon Heath, Angelika Merkel, Avik Datta, Ana C. Queirós, Marien Pascual, Xabier Agirre, Emanuele Raineri, David S. Richardson, Anna Esteve, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centro Nacional de Análisi Genómico (CNAG), Centro Nacional de Análisis Genómico, Centre for Epidemiological Studies on HIV/AIDS and STI of Catalonia (CEEISCAT), Spanish National Cancer Research Center (CNIO), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Clinica Universitaria, faculdad de medicina, universidad de Navarra (UNIVERSIDAD DE NAVARRA), Universidad de Navarra, Microenvironnement et cancer (MiCa), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Department of Laboratory Medicine [San Francisco], University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Blood Systems Research Institute, Yonsei University College of Medicine, Department of Epidemiology and Biostatistics, Department of Molecular Biology [Nijmegen], Radboud University Medical Center [Nijmegen], Institute of Human Genetics, Christian-Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, Institute of Cell Biology, IFZ, University Hospital Essen, This work was funded by the European Union's Seventh Framework Programme through the Blueprint Consortium (grant agreement 282510), the Spanish Ministry of Economy and Competitivity (MINECO) (project SAF2009-08663)., Jonchère, Laurent, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University of California [San Francisco] (UCSF), and University of California-University of California
Subjects: Epigenomics, Cellular differentiation, [SDV]Life Sciences [q-bio], Bisulfite sequencing, Medizin, [SDV.GEN] Life Sciences [q-bio]/Genetics, Medical and Health Sciences, Epigenesis, Genetic, 0302 clinical medicine, Cells, Cultured, Leukemic, Regulation of gene expression, B-Lymphocytes, 0303 health sciences, Cultured, Leukemia, Genome, Gene Expression Regulation, Leukemic, Cell Differentiation, Methylation, Biological Sciences, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, CpG site, 030220 oncology & carcinogenesis, DNA methylation, Sequence Analysis, Human, Cells, Biology, Article, 03 medical and health sciences, Genetic, Leukemia, B-Cell, Genetics, medicine, Humans, Molecular Biology, B cell, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Base Sequence, Genome, Human, Human Genome, B-Cell, Sequence Analysis, DNA, DNA, DNA Methylation, Molecular biology, Gene Expression Regulation, CpG Islands, Epigenesis, Developmental Biology
Abstract: International audience; We analyzed the DNA methylome of ten subpopulations spanning the entire B cell differentiation program by whole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpG methylation disappeared upon B cell commitment, whereas CpG methylation changed extensively during B cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpG sites. Early differentiation stages mainly displayed enhancer demethylation, which was associated with upregulation of key B cell transcription factors and affected multiple genes involved in B cell biology. Late differentiation stages, in contrast, showed extensive demethylation of heterochromatin and methylation gain at Polycomb-repressed areas, and genes with apparent functional impact in B cells were not affected. This signature, which has previously been linked to aging and cancer, was particularly widespread in mature cells with an extended lifespan. Comparing B cell neoplasms with their normal counterparts, we determined that they frequently acquire methylation changes in regions already undergoing dynamic methylation during normal B cell differentiation.
Published: 2015
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33. Epigenetic remodeling in B-cell acute lymphoblastic leukemia occurs in two tracks and employs embryonic stem cell-like signatures

Author: Seung-Tae Lee, John K. Wiencke, E. Andres Houseman, Joseph L. Wiemels, Mi Zhou, Simon Heath, José I. Martín-Subero, Margaret Wrensch, Marina E. Fomin, Catherine Metayer, Adam J. de Smith, Jianqiao Xiao, Ritu Roy, Marcus O. Muench, and Universitat de Barcelona
Subjects: Epigenomics, Embryonic stem cells, Bisulfite sequencing, Nerve Tissue Proteins, Methylation, Histones, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, Epigenetics, Child, Embryonic Stem Cells, 030304 developmental biology, Oligonucleotide Array Sequence Analysis, 0303 health sciences, B-Lymphocytes, Leukemia, biology, Cèl·lules mare embrionàries, Gene Expression Profiling, Lysine, Precursor Cells, B-Lymphoid, Gene regulation, Chromatin and Epigenetics, Polycomb Repressive Complex 2, Leucèmia, Cell cycle, DNA Methylation, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Epigenètica, Embryonic stem cell, Molecular biology, Cell biology, Neoplasm Proteins, Alcohol Oxidoreductases, Histone, 030220 oncology & carcinogenesis, DNA methylation, biology.protein, CpG Islands, Co-Repressor Proteins, Signal Transduction, Transcription Factors
Abstract: We investigated DNA methylomes of pediatric B-cell acute lymphoblastic leukemias (B-ALLs) using whole-genome bisulfite sequencing and high-definition microarrays, along with RNA expression profiles. Epigenetic alteration of B-ALLs occurred in two tracks: de novo methylation of small functional compartments and demethylation of large inter-compartmental backbones. The deviations were exaggerated in lamina-associated domains, with differences corresponding to methylation clusters and/or cytogenetic groups. Our data also suggested a pivotal role of polycomb and CTBP2 in de novo methylation, which may be traced back to bivalency status of embryonic stem cells. Driven by these potent epigenetic modulations, suppression of polycomb target genes was observed along with disruption of developmental fate and cell cycle and mismatch repair pathways and altered activities of key upstream regulators.
Published: 2015

34. A Comprehensive Assessment of Somatic Mutation Calling in Cancer Genomes

Author: Marc Dabad, John Douglas Mcpherson, Xose S. Puente, Liu Xi, Ivo Gut, Anne-Marie Patch, Semin Lee, Cyriac Kandoth, Ruben M. Drews, Charlotte Anderson, Eivind Hovig, Paul C. Boutros, Peter J. Campbell, Louis Letourneau, Paolo Ribeca, Hidewaki Nakagawa, Natalie Jäger, Daniel Vodak, Thomas J. Hudson, Anne Sophie Sertier, Pablo H. Hennings-Yeomans, John Zhang, Philip Ginsbach, Laurie Tonon, Emanuele Raineri, Sahil Seth, Sophia Derdak, Benedikt Brors, David T. W. Jones, Minghui He, Sergi Beltran, Rafael Valdés-Mas, David Torrents, Singer Ma, Myron Peto, Nagarajan Paramasivam, Matthew D. Eldridge, Robert E. Denroche, Paul T. Spellman, Francesc Castro Giner, Roland Eils, Timothy Beck, Sigve Nakken, Daniela S. Gerhard, Lawrence E. Heisler, Jared T. Simpson, Víctor Quesada, Rolf Kabbe, Andy G. Lynch, Patrick S. Tarpey, Lawrence Bower, Akihiro Fujimoto, Barbara Hutter, Matthias Schlesner, Marta Gut, Ivo Buchhalter, David A. Wheeler, Takafumi N. Yamaguchi, Simon Heath, Nicholas J. Harding, and Tyler Alioto
Subjects: Genetics, Whole genome sequencing, 0303 health sciences, Concordance, Cancer, Genomics, Computational biology, Biology, medicine.disease, Genome, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), medicine, 030304 developmental biology
Abstract: The emergence of next generation DNA sequencing technology is enabling high-resolution cancer genome analysis. Large-scale projects like the International Cancer Genome Consortium (ICGC) are systematically scanning cancer genomes to identify recurrent somatic mutations. Second generation DNA sequencing, however, is still an evolving technology and procedures, both experimental and analytical, are constantly changing. Thus the research community is still defining a set of best practices for cancer genome data analysis, with no single protocol emerging to fulfil this role. Here we describe an extensive benchmark exercise to identify and resolve issues of somatic mutation calling. Whole genome sequence datasets comprising tumor-normal pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, were shared within the ICGC and submissions of somatic mutation calls were compared to verified mutations and to each other. Varying strategies to call mutations, incomplete awareness of sources of artefacts, and even lack of agreement on what constitutes an artefact or real mutation manifested in widely varying mutation call rates and somewhat low concordance among submissions. We conclude that somatic mutation calling remains an unsolved problem. However, we have identified many issues that are easy to remedy that are presented here. Our study highlights critical issues that need to be addressed before this valuable technology can be routinely used to inform clinical decision-making.
Published: 2014
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35. Genome-wide association study identifies loci on 12q24 and 13q32 associated with Tetralogy of Fallot

Author: Judith A. Goodship, Frances A. Bu'Lock, Alex V. Postma, Jeroen Breckpot, A. H. Zwinderman, Chris Thornborough, J. David Brook, Heather J. Cordell, Anita Rauch, Bernard Keavney, Chrysovalanto Mamasoula, G. Mark Lathrop, Catherine Cosgrove, Diana Zelenika, Shoumo Bhattacharya, Jamie Bentham, Jonathan M. Parsons, Klaartje van Engelen, David S. Winlaw, Seema Mital, Ana Töpf, Antoon F.M. Moorman, Gillian M. Blue, Rachel Soemedi, Kristin L. Ayers, Thahira Rahman, Simon Heath, Marc Gewillig, Rebecca Darlay, Kerry Setchfield, Darroch Hall, Javier Granados Riveron, A Graham Stuart, Ian J. Wilson, Barbara J.M. Mulder, John O'Sullivan, Koenraad Devriendt, Human genetics, ACS - Amsterdam Cardiovascular Sciences, ARD - Amsterdam Reproduction and Development, Human Genetics, Medical Biology, Cardiology, APH - Amsterdam Public Health, and Epidemiology and Data Science
Subjects: Male, Linkage disequilibrium, Heart malformation, Single-nucleotide polymorphism, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Genetic variation, Genetics, Humans, Allele, Molecular Biology, Allele frequency, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 13, Chromosome, General Medicine, Articles, Genetic Loci, Case-Control Studies, Tetralogy of Fallot, Female, Genome-Wide Association Study
Abstract: We conducted a genome-wide association study to search for risk alleles associated with Tetralogy of Fallot (TOF), using a northern European discovery set of 835 cases and 5159 controls. A region on chromosome 12q24 was associated (P = 1.4 × 10-7) and replicated convincingly (P = 3.9 × 10-5) in 798 cases and 2931 controls [per allele odds ratio (OR) = 1.27 in replication cohort, P = 7.7 × 10-11 in combined populations]. Single nucleotide polymorphisms in the glypican 5 gene on chromosome 13q32 were also associated (P = 1.7 × 10-7) and replicated convincingly (P = 1.2 × 10-5) in 789 cases and 2927 controls (per allele OR = 1.31 in replication cohort, P = 3.03 × 10-11 in combined populations). Four additional regions on chromosomes 10, 15 and 16 showed suggestive association accompanied by nominal replication. This study, the first genome-wide association study of a congenital heart malformation phenotype, provides evidence that common genetic variation influences the risk of TOF.
Published: 2013
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36. Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16

Author: Frances A. Bu'Lock, Chris Thornborough, Shoumo Bhattacharya, Antoon F.M. Moorman, Marc Gewillig, Catherine Cosgrove, Judith A. Goodship, Klaartje van Engelen, Christobal Dos Remedios, Thahira Rahman, Ana Töpf, Phil Barnett, Connie R. Bezzina, G Mark Lathrop, Jeroen Breckpot, Tamara T. Koopmann, Michiel E. Adriaens, Koenraad Devriendt, Gillian M. Blue, Bernard Keavney, Barbara J.M. Mulder, Darroch Hall, Alfred L. George, J. David Brook, Heather J. Cordell, Jamie Bentham, Nanette H. Bishopric, John O'Sullivan, Ruairidh Martin, Alex V. Postma, A. H. Zwinderman, Martin Farrall, Diana Zelenika, Simon Heath, Seema Mital, Rachel Soemedi, David S. Winlaw, Kerry Setchfield, Javier T. Granados-Riveron, András Varró, Chrysovalanto Mamasoula, Human genetics, ACS - Amsterdam Cardiovascular Sciences, Human Genetics, Medical Biology, APH - Amsterdam Public Health, Epidemiology and Data Science, Cardiology, and ARD - Amsterdam Reproduction and Development
Subjects: Heart Defects, Congenital, Male, medicine.medical_specialty, Heart disease, Genotype, Heart Diseases, Genome-wide association study, 030204 cardiovascular system & hematology, Biology, Heart Septal Defects, Atrial, Article, Cohort Studies, 03 medical and health sciences, Mice, 0302 clinical medicine, Internal medicine, Genetics, medicine, Animals, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, cardiovascular diseases, 030304 developmental biology, 0303 health sciences, Case-control study, Odds ratio, medicine.disease, Confidence interval, 3. Good health, Phenotype, Genetic Loci, Case-Control Studies, Cohort, Cardiology, Female, Chromosomes, Human, Pair 4, Cohort study, Genome-Wide Association Study
Abstract: We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated (P = 9.5 × 10 -7) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort (N = 340 cases), and this association was replicated in a further 417 ASD cases and 2,520 controls (replication P = 5.0 × 10 -5; odds ratio (OR) in replication cohort = 1.40, 95% confidence interval (CI) = 1.19-1.65; combined P = 2.6 × 10 -10). Genotype accounted for ∼9% of the population-attributable risk of ASD. © 2013 Nature America, Inc. All rights reserved.
Published: 2012
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37. Distinct DNA methylomes of newborns and centenarians

Author: Sebastian Moran, Jordi Serra-Musach, David G. Pisano, Alfonso Valencia, Humberto J. Ferreira, Simon Heath, Ning Li, Fernando Setien, F. Javier Carmona, Miguel Angel Pujana, Jun Wang, Ivo Gut, Manel Esteller, Javier Díez, Sergi Sayols, Francesc Formiga, Jose V. Sanchez-Mut, Annibale Alessandro Puca, Agustín F. Fernández, Mario F. Fraga, Isabel Iglesias-Platas, Holger Heyn, and Antonio Gomez
Subjects: Genetics, 0303 health sciences, Aging, Multidisciplinary, Newborn infants, Bisulfite sequencing, ADN, Methylation, DNA, Biology, Biological Sciences, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Intergenic region, CpG site, Envelliment, DNA methylation, Infants nadons, Epigenetics, 030217 neurology & neurosurgery, 030304 developmental biology, Epigenomics
Abstract: Human aging cannot be fully understood in terms of the constrained genetic setting. Epigenetic drift is an alternative means of explaining age-associated alterations. To address this issue, we performed whole-genome bisulfite sequencing (WGBS) of newborn and centenarian genomes. The centenarian DNA had a lower DNA methylation content and a reduced correlation in the methylation status of neighboring cytosine—phosphate—guanine (CpGs) throughout the genome in comparison with the more homogeneously methylated newborn DNA. The more hypomethylated CpGs observed in the centenarian DNA compared with the neonate covered all genomic compartments, such as promoters, exonic, intronic, and intergenic regions. For regulatory regions, the most hypomethylated sequences in the centenarian DNA were present mainly at CpG-poor promoters and in tissue-specific genes, whereas a greater level of DNA methylation was observed in CpG island promoters. We extended the study to a larger cohort of newborn and nonagenarian samples using a 450,000 CpG-site DNA methylation microarray that reinforced the observation of more hypomethylated DNA sequences in the advanced age group. WGBS and 450,000 analyses of middle-age individuals demonstrated DNA methylomes in the crossroad between the newborn and the nonagenarian/centenarian groups. Our study constitutes a unique DNA methylation analysis of the extreme points of human life at a single-nucleotide resolution level.
Published: 2012

38. Tuning of natural killer cell reactivity by NKp46 and Helios calibrates T cell responses

Author: Bruce Beutler, Marta Gut, Sam Kung, Bernard Malissen, Claire Bernat, Simon Heath, Marie Malissen, Eric Vivier, Jordi Estellé, Frédéric Vély, Aude De Gassart, Louis Noël Gastinel, Emilie Narni-Mancinelli, Aurore Fenis, Sophie Ugolini, Baptiste N. Jaeger, Elodie Bertosio, Sajid Mahmood, Ivo Gut, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11), University of Manitoba [Winnipeg], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centro Nacional de Análisi Genómico (CNAG), Centro Nacional de Análisis Genómico, Service de Chirurgie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Immunology and Microbial Science, The Scripps Research Institute [La Jolla, San Diego], Centre Nacional D'Anàlisi Genómica, Parc Cientific de Barcelona, Apotex Center - University of Manitoba, Haon, Marie Laure, Institut National de la Santé et de la Recherche Médicale (INSERM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Université de Limoges (UNILIM)-CHU Limoges, Scripps Research Institute, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
Subjects: Muromegalovirus, Transcription, Genetic, T-Lymphocytes, Cell, Mutant, MESH: Herpesviridae Infections, Adaptive Immunity, CD8-Positive T-Lymphocytes, medicine.disease_cause, MESH: Down-Regulation, MESH: Antibodies, Monoclonal, Mice, 0302 clinical medicine, Antigens, Ly, MESH: Animals, Listeriosis, MESH: Mutagenesis, 0303 health sciences, Mutation, MESH: Genetic Complementation Test, Multidisciplinary, Antibodies, Monoclonal, MESH: Antigens, Ly, MESH: Transcription Factors, Herpesviridae Infections, Viral Load, MESH: Amino Acid Substitution, MESH: CD8-Positive T-Lymphocytes, 3. Good health, Cell biology, DNA-Binding Proteins, Killer Cells, Natural, medicine.anatomical_structure, MESH: Immunologic Memory, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Viral Load, MESH: Killer Cells, Natural, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Mice, Transgenic, T cell, MESH: Natural Cytotoxicity Triggering Receptor 1, MESH: Muromegalovirus, Down-Regulation, Mice, Transgenic, Biology, Natural killer cell, Cell Line, 03 medical and health sciences, Immune system, MESH: Mice, Inbred C57BL, MESH: Antibodies, Blocking, medicine, Gene silencing, Animals, Antibodies, Blocking, Transcription factor, MESH: Mice, 030304 developmental biology, Natural Cytotoxicity Triggering Receptor 1, MESH: Transcription, Genetic, Genetic Complementation Test, MESH: Cell Line, Mice, Inbred C57BL, MESH: T-Lymphocytes, Amino Acid Substitution, MESH: Listeriosis, Mutagenesis, Immunology, Immunologic Memory, MESH: Adaptive Immunity, MESH: DNA-Binding Proteins, 030215 immunology, Transcription Factors
Abstract: Natural Killer Controls Cytolytic natural killer (NK) cells participate in both antimicrobial and antitumor immunity. Their responsiveness is tuned through signals received through a variety of inhibitory and activating receptors expressed on their cell surface. Narni-Mancinelli et al. (p. 344 ) now show that signaling through the activating receptor NKp46 paradoxically keeps NK cell responses in check. NK cells from mice with disrupted NKp46 expression were hyperresponsive to stimulation and better protected against viral infection. NK cell responses, which are part of the early response to infection, may thus need to be carefully tuned to ensure optimal initiation of adaptive immunity and formation of protective long-lived memory cells.
Published: 2012
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39. Abdominal Aortic Aneurysm Is Associated with a Variant in Low-Density Lipoprotein Receptor-Related Protein 1

Author: Wolfgang Lieb, Bruna Gigante, Thodur M. Vasudevan, Georg Homuth, Joseph B. Muhlestein, Mark J. Daly, Andrew P. Morris, Jacqueline de Graaf, Peter Kraft, Ann-Kristin Petersen, André G. Uitterlinden, Jaqueline C M Witteman, Valgerdur Steinthorsdottir, Jutta Palmen, Amanda L. Elliott, Cecilia M. Lindgren, Richard N. Bergman, Benjamin D. Horne, Tony R. Merriman, Robert W. Davies, Jaspal S. Kooner, Gavin Lucas, Carl G. P. Platou, Diederick E. Grobbee, Ruth J. F. Loos, Fulvio Ricceri, Karin Leander, Wen H. L. Kao, Torsten Lauritzen, Qi Sun, Narisu Narisu, Stephan B. Felix, N. William Rayner, Aaron R. Folsom, Robert D. Sayers, Ross D. Blair, John F. Carlquist, Jing Hua Zhao, L. Vicky Phillips, Gabe Crawford, Anne Johnson, Chris Wallace, Paul F. O'Reilly, Jose C. Florez, Andreas Ziegler, Salvatore Panico, Neil R. Robertson, Ruth Frikke-Schmidt, Leif Groop, Pier Mannuccio Mannucci, Stanley L. Hazen, Gerjan Navis, Peter P. Pramstaller, Laura J. Scott, Niels Grarup, Klaus Berger, Christian Gieger, Stephen E. Epstein, Cornelia Huth, Stephanie Tennstedt, Morris J. Brown, Timothy A. Barnes, Naomi Hammond, Ulf de Faire, Vilmundur Gudnason, Marcus Fischer, Nita G. Forouhi, Paolo Vineis, Thomas Quertermous, Christopher Patterson, W.H. Wilson Tang, Konstantinos A. Papadakis, Lincoln Stein, Maciej Tomaszewski, Suthesh Sivapalaratnam, M. S. Sandhu, Feng Zhang, Christa Meisinger, David R. Lewis, Norman Klopp, Roza Blagieva, Gonçalo R. Abecasis, Jeffrey L. Anderson, Lu Qi, Amy J. Swift, Albert Hofman, George Dedoussis, Robert Luben, Daniel J. Rader, Thomas Münzel, Bert Bravenboer, Christopher J. O'Donnell, Elin Org, Veikko Salomaa, Philipp S. Wild, Stephen G. Ellis, Dawn M. Waterworth, Vesela Gateva, Loukianos S. Rallidis, Joseph M. Devaney, kevin Burnand, Robert Clarke, George A. Wells, Harold Snieder, Kay-Tee Khaw, Panos Deloukas, Jaakko Tuomilehto, Louise V. Wain, Eric Boerwinkle, Inke R. König, Amanda J. Bennett, Uwe Völker, Florian Ernst, Markus M. Nöthen, Thomas Sparsø, Jean Tichet, Inga Prokopenko, Paul Johnson, Jaume Marrugat, Marju Orho-Melander, Aloysius G Lieverse, Ian Thomson, Vincent Mooser, Teresa Ferreira, Man Li, Benjamin J. Wright, Ryan P. Welch, Alessandra Allione, Stefan Blankenberg, Veryan Codd, Philippe Froguel, James C. Engert, Pekka Jousilahti, Klaus Stark, Toby Johnson, Cornelia M. van Duijn, Ivo Gut, John J.P. Kastelein, Thomas M. Morgan, Noël P. Burtt, Laura J. McCulloch, Tim D. Spector, Peter S. Chines, Timo T. Valle, Peter Shrader, Christian Dina, Diana Zelenika, Monika Stoll, Peter S. Braund, Harry Campbell, Rainer Rettig, Joep A.W. Teijink, Thomas Illig, Anne Tybjærg-Hansen, Peter Vollenweider, Guangju Zhai, Frits R. Rosendaal, Pau Navarro, James B. Meigs, Ghislain Rocheleau, Li Chen, Pilar Galan, Giuseppe Matullo, Henry Völzke, Samer S. Najjar, Christina Loley, N. Charlotte Onland-Moret, Alison H. Goodall, Riyaz S. Patel, S. Matthijs Boekholdt, Pim van der Harst, John R. B. Perry, Angela Doering, James S. Pankow, Gudmundur Thorgeirsson, Xin Yuan, Patricia B. Munroe, Abbas Dehghan, Tamara B. Smith, Valeriya Lyssenko, Mark I. McCarthy, Andrew T. Hattersley, Simon Futers, Barbara Thorand, Andre G. Uitterlinden, Simon J. Griffin, Winfried März, Nilesh J. Samani, Frank B. Hu, Valeria Romanazzi, Michael N. Weedon, Zouhair Aherrahrou, Ruth McPherson, Benjamin F. Voight, Wolfgang Rathmann, Markus Perola, Stefania Bandinelli, Kathy Stirrups, Hilma Holm, Maja Barbalić, Kiran Musunuru, David Couper, David S. Siscovick, Guillaume Charpentier, Alexandre F.R. Stewart, Patrick Diemert, Leena Peltonen, Serge Hercberg, Robert Roberts, Michael Roden, Rhian Gwilliam, Guillaume Lettre, Eric J.G. Sijbrands, Lambertus A. Kiemeney, Martha Ganser, Silvia Polidoro, Kristin G. Ardlie, Stephen G. Ball, Kristina Bengtsson Boström, Katharine R. Owen, Paul E. de Jong, Felicity Payne, Wendy L. McArdle, Frances M K Williams, Paul Elliott, Roberto Elosua, Devin Absher, Kristian Midthjell, Jan D. Blankensteijn, Nelson B. Freimer, John C. Chambers, G. Kolovou, Karl Andersen, John Webster, Nicholas J. Wareham, Eric E. Schadt, Simon Heath, Diana Rubin, Solveig Gretarsdottir, Willem H. Ouwehand, Oluf Pedersen, Liming Qu, Sandra Eifert, Mary Susan Burnett, Paul Burton, Frank M. van Bockxmeer, Eleftheria Zeggini, Stephen M. Schwartz, Simon C. Potter, Tiinamaija Tuomi, Jeffrey R. Gulcher, David Altshuler, Harald Grallert, Hooman Allayee, Kari Stefansson, Anne H. Child, Sekar Kathiresan, Torben Hansen, Unnur Thorsteinsdottir, Isaac Subirana, Serena Sanna, Muredach P. Reilly, J. Wouter Jukema, H.-Erich Wichmann, François Cambien, Pier Angelica Merlini, Wiek H. van Gilst, Caroline S. Fox, Andrew Smith, Oliviero Olivieri, S Sohrabi, James F. Wilson, Gillian W. Cockerill, Guanming Wu, Andrew D. Morris, Carlos Iribarren, Joshua W. Knowles, Angelo Scuteri, Göran Berglund, Marilyn C. Cornelis, Pascal P. McKeown, Thorsten Reffelmann, Gérard Waeber, Les McNoe, Maris Laan, Dilip K. Naik, Karen L. Mohlke, Matthew Waltham, Rachel E. Clough, Claudia Langenberg, Seamus C. Harrison, Hany Hafez, Timon W. van Haeften, Carlotta Sacerdote, Robert Sladek, Nicola Martinelli, Declan Bradley, Cristen J. Willer, Sarah E. Hunt, Sven Cichon, Udo Seedorf, Winston Hide, Arne Schillert, Cuno S.P.M. Uiterwaal, Steve E. Humphries, Andre A van Rij, Stéphane Cauchi, Michael Boehnke, Beverley M. Shields, Suzannah Bumpstead, Diane M. Becker, Ron Do, Heribert Schunkert, Jacques S. Beckmann, Alistair S. Hall, Mike Sampson, Christine Proença, Lachlan J. M. Coin, Rob M. van Dam, Mohan U. Sivananthan, Martin Farrall, B. Gerry Hill, Simonetta Guarrera, Thijs T. W. van Herpt, Sonia S. Anand, Peter M. Nilsson, Arne Pfeufer, Rafn Benediktsson, Candace Guiducci, Lee M. Kaplan, Michel Marre, Thomas Meitinger, Annette F. Baas, Graham A. Hitman, Roberto Lorbeer, Flora Peyvandi, David J. Hunter, Seraya Maouche, G. Mark Lathrop, Michael R. Erdos, Thomas W. Mühleisen, L. Adrienne Cupples, Anne E. Hughes, Ayellet V. Segrè, Igor Rudan, Kijoung Song, Reijo Laaksonen, G. Bragi Walters, Christopher P. Nelson, Christopher S. Franklin, Richard M. Watanabe, Mattijs E. Numans, Christina Willenborg, Jeanette Erdmann, Alessandra Di Gregorio, John M. C. Connell, Soumya Raychaudhuri, Jian'an Luan, Anthony J. Balmforth, Yurii S. Aulchenko, Arne Schäfer, Catherine M. Rice, Tanja Zeller, Grace Yu, Augustine Kong, Matthew M Thompson, Diego Ardissino, Oliver Hofmann, John R. Thompson, J.B. Wild, Alexander Teumer, Ulf Gyllensten, David P. Strachan, Martin D. Tobin, Michael A. Kaiser, Steve McCarroll, Beverley Balkau, Stephen J. Newhouse, Michael Preuss, John A. Spertus, Janja Nahrstaedt, Neelam Hassanali, Gunnar Sigurdsson, Jaapjan D. Snoep, Angela Döring, Todd Green, D. Julian A. Scott, Christian Herder, Bo Isomaa, Anne U. Jackson, David Hadley, Domenico Girelli, Jes S. Lindholt, Toshiko Tanaka, Ruth Topless, Bernhard O. Boehm, Jana V. van Vliet-Ostaptchouk, Anna-Liisa Hartikainen, Anneli Pouta, Anuj Goel, Stefan Schreiber, Kristian Hveem, Gabriel Crawford, Pierre Meneton, Jürgen Schrezenmeir, Andre M. van Rij, Markku Laakso, Richa Saxena, Joshua C. Bis, Samy Hadjadj, Anders Franco-Cereceda, Noha Lim, Christopher J. Groves, Klaus Strassburger, Stefan E Matthiasson, M. Lourdes Sampietro, Josée Dupuis, Morris J. Bown, Cisca Wijmenga, Shu Ye, Jennifer Freyer, Anders Hamsten, Christian Hengstenberg, Olle Melander, Sarah Edkins, Alberto Smith, Luigi Ferrucci, Murielle Bochud, Lori L. Bonnycastle, Gregory T. Jones, Manuela Uda, Lasse Folkersen, Timothy M. Frayling, Giovanni Tognoni, Torben Jørgensen, Anna F. Dominiczak, Michiel L. Bots, Mario A. Morken, Ian Buysschaert, Colin N. A. Palmer, Andrew Hill, Mark J. Caulfield, Nicolas Sylvius, Nicole Soranzo, Susana Eyheramendy, Christopher Newton-Cheh, Eran Halperin, Mandy van Hoek, Stephen A. Badger, Paul Scheet, Gudmar Thorleifsson, Themistocles L. Assimes, Inês Barroso, Sheila Bingham, Nour Eddine El Mokhtari, Yvonne T. van der Schouw, Andrew J. Lotery, Heather M. Stringham, Marcus Dörr, Per Eriksson, Mark Walker, Mette Refstrup, Anna L. Gloyn, Ann-Christine Syvänen, John F. Peden, Diether Lambrechts, Arshed A. Quyyumi, Katherine S. Elliott, Jonathan Golledge, Edward G. Lakatta, Serkalem Demissie, Lewis C. Becker, Alex S. F. Doney, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Paul Norman, Marjo-Riitta Järvelin, Annette Peters, David Schlessinger, Janet T. Powell, Surgery, ICaR - Ischemia and repair, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
Subjects: Male, VASCULAR WALL, Genome-wide association study, 030204 cardiovascular system & hematology, Bioinformatics, Aortic aneurysm, 0302 clinical medicine, Risk Factors, Odds Ratio, Genetics(clinical), Genetics (clinical), Aorta, 0303 health sciences, Cardiovascular diseases [NCEBP 14], Homozygote, Abdominal aortic aneurysm, Organ Specificity, Data Interpretation, Statistical, CORONARY-ARTERY-DISEASE, Female, METALLOPROTEINASE, Sterol Regulatory Element Binding Protein 1, Low Density Lipoprotein Receptor-Related Protein-1, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Locus (genetics), Biology, Polymorphism, Single Nucleotide, DISSECTIONS, Article, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genome-wide associaton, Coronary-artery-disease, Susceptibility loci, Sequence variant, Vascular wall, Metalloproteinase, Atherosclerosis, Identification, Metaanalysis, Dissections, medicine.artery, Internal medicine, Cell Line, Tumor, medicine, Genetics, Humans, Genetic Predisposition to Disease, ddc:610, GENOME-WIDE ASSOCIATION, METAANALYSIS, 030304 developmental biology, Genetic association, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], Aged, IDENTIFICATION, Case-control study, Odds ratio, medicine.disease, Endocrinology, ATHEROSCLEROSIS, SEQUENCE VARIANT, Genetic Loci, Case-Control Studies, Aortic Aneurysm, Abdominal, Follow-Up Studies, Genome-Wide Association Study
Abstract: Contains fulltext : 97601.pdf (Publisher’s version ) (Closed access) Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 x 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 x 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 x 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression. 9 p.
Published: 2011
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40. Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3

Author: Jorge R. Toro, Vladimir Janout, Zhaoming Wang, Françoise Clavel-Chapelon, Petra H.M. Peeters, Paul Brennan, Camilla Stoltenberg, Hélène Blanché, Diana Zelenika, Vsevolod Matveev, Naomi E. Allen, Rosario Tumino, Vladimir Bencko, H. Bas Bueno-de-Mesquita, Lee E. Moore, María José Sánchez, Mark P. Purdue, Stephen J. Chanock, Kim Overvad, Kvetoslava Koppova, Joanne S. Colt, Eleonora Fabianova, Yuanqing Ye, Grethe S. Tell, Simon Heath, José Ramón Quirós, Egbert Oosterwijk, Amy Hutchinson, Jan Lubinski, Kristian Hveem, Peter Rudnai, Alexandru Bucur, Elio Riboli, James McKay, Ivo Gut, Paolo Vineis, Rosamonde E. Banks, Douglas F. Easton, Jarmo Virtamo, Wong-Ho Chow, Neonila Szeszenia-Dabrowska, Isabelle Romieu, Mark Lathrop, Demetrius Albanes, Kevin B. Jacobs, Sita H. Vermeulen, Egor Prokhortchouk, Carmen Navarro, Ann W. Hsing, Doris Lechner, M. Dorronsoro, Kendra Schwartz, Konstantin G. Skryabin, Mattias Johansson, Eric J. Duell, Valerie Gaborieau, W. Ryan Diver, Susan M. Gapstur, Börje Ljungberg, Dimitrios Trichopoulos, Paul D.P. Pharoah, Gilles Thomas, Victoria L. Stevens, Paolo Boffetta, Vittorio Krogh, David Zaridze, Lambertus A. Kiemeney, Joseph F. Fraumeni, Eugenia S. Boulygina, Kay-Tee Khaw, Olivier Cussenot, Heiner Boeing, Nathaniel Rothman, Michael J. Thun, Saskia S. L. van der Marel, Anush Mukeria, Alexander M. Mazur, Salvatore Panico, Peter Selby, Ghislaine Scelo, Faith G. Davis, Simone Benhamou, Joanna Trubicka, Christine D. Berg, Anne Tjønneland, Eva Ardanaz, Jolanta Lissowska, Katja K.H. Aben, Xifeng Wu, Rajesh Kumar, Jakob Linseisen, Nikolai N. Chekanov, Domenico Palli, Stephanie J. Weinstein, Inger Njølstad, Mario Foglio, Lars J. Vatten, Meredith Yeager, Xia Pu, Robert L. Grubb, Oxana Shangina, Christopher G. Wood, Patricia Harnden, Lenka Foretova, Purdue, M.P., Johansson, M., Zelenika, D., Toro, J.R., Scelo, G., Moore, L.E., Prokhortchouk, E., Wu, X., Kiemeney, L.A., Gaborieau, V., Jacobs, K.B., Chow, W.-H., Zaridze, D., Matveev, V., Lubinski, J., Trubicka, J., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., Fabianova, E., Bucur, A., Bencko, V., Foretova, L., Janout, V., Boffetta, P., Colt, J.S., Davis, F.G., Schwartz, K.L., Banks, R.E., Selby, P.J., Harnden, P., Berg, C.D., Hsing, A.W., Grubb, R.L., Boeing, H., Vineis, P., Clavel-Chapelon, F., Palli, D., Tumino, R., Krogh, V., Panico, S., Duell, E.J., Quiós, J.R., Sanchez, M.-J., Navarro, C., Ardanaz, E., Dorronsoro, M., Khaw, K.-T., Allen, N.E., Bueno-De-Mesquita, H.B., Peeters, P.H.M., Trichopoulos, D., Linseisen, J., Ljungberg, B., Overvad, K., Tjønneland, A., Romieu, I., Riboli, E., Mukeria, A., Shangina, O., Stevens, V.L., Thun, M.J., Diver, W.R., Gapstur, S.M., Pharoah, P.D., Easton, D.F., Albanes, D., Weinstein, S.J., Virtamo, J., Vatten, L., Hveem, K., Njølstad, I., Tell, G.S., Stoltenberg, C., Kumar, R., Koppova, K., Cussenot, O., Benhamou, S., Oosterwijk, E., Vermeulen, S.H., Aben, K.K.H., Van Der Marel, S.L., Ye, Y., Wood, C.G., Pu, X., Mazur, A.M., Boulygina, E.S., Chekanov, N.N., Foglio, M., Lechner, D., Gut, I., Heath, S., Blanche, H., Hutchinson, A., Thomas, G., Wang, Z., Yeager, M., Fraumeni Jr., J.F., Skryabin, K.G., McKay, J.D., Rothman, N., Chanock, S.J., Lathrop, M., and Brennan, P.
Subjects: Genetics and epigenetic pathways of disease [NCMLS 6], Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Biology, carcinoma, association study, Genome, Polymorphism, Single Nucleotide, susceptibility, Article, Càncer de ronyó, Genomic disorders and inherited multi-system disorders [IGMD 3], Molecular epidemiology [NCEBP 1], 03 medical and health sciences, 0302 clinical medicine, Gene mapping, Risk Factors, Genetics, Humans, Genetic Predisposition to Disease, Genome-wide, Gene, Carcinoma, Renal Cell, 030304 developmental biology, 11q13.3, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], 0303 health sciences, Genome, Human, Chromosomes, Human, Pair 11, Kidney cancer, Genomics, 2p21, SCARB1, Kidney Neoplasms, 3. Good health, Genòmica, 030220 oncology & carcinogenesis, Case-Control Studies, Chromosomes, Human, Pair 2, loci, Human genome, renal, Genome-Wide Association Study
Abstract: Contains fulltext : 97937.pdf (Publisher’s version ) (Closed access) We conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 affected individuals (cases) and 8,505 controls of European background from 11 studies and followed up 6 SNPs in 3 replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and 11q13.3 were associated with RCC susceptibility below genome-wide significance. Two correlated variants (r(2) = 0.99 in controls), rs11894252 (P = 1.8 x 10) and rs7579899 (P = 2.3 x 10), map to EPAS1 on 2p21, which encodes hypoxia-inducible-factor-2 alpha, a transcription factor previously implicated in RCC. The second locus, rs7105934, at 11q13.3, contains no characterized genes (P = 7.8 x 10(1)). In addition, we observed a promising association on 12q24.31 for rs4765623, which maps to SCARB1, the scavenger receptor class B, member 1 gene (P = 2.6 x 10). Our study reports previously unidentified genomic regions associated with RCC risk that may lead to new etiological insights.
Published: 2011
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41. Myelin basic protein as a novel genetic risk factor in rheumatoid arthritis--a genome-wide study combined with immunological analyses

Author: Chikashi Terao, Koichiro Ohmura, Masaki Katayama, Meiko Takahashi, Miki Kokubo, Gora Diop, Yoshinobu Toda, Natsuki Yamamoto, Human Disease Genomics Working Group, Rheumatoid Arthritis (RA) Clinical and Genetic Study Consortium, Reiko Shinkura, Masakazu Shimizu, Ivo Gut, Simon Heath, Inga Melchers, Toshiaki Manabe, Mark Lathrop, Tsuneyo Mimori, Ryo Yamada, and Fumihiko Matsuda
Subjects: Male, Transcription, Genetic, Inflammatory arthritis, lcsh:Medicine, Rheumatoid Arthritis, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, Antibodies, Autoimmune Diseases, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Genetics of the Immune System, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Allele, lcsh:Science, 030304 developmental biology, 030203 arthritis & rheumatology, 0303 health sciences, Multidisciplinary, biology, Synovial Membrane, lcsh:R, Autoantibody, Reproducibility of Results, Myelin Basic Protein, Genomics, medicine.disease, 3. Good health, Myelin basic protein, Gene Expression Regulation, Genetic Loci, Case-Control Studies, Rheumatoid arthritis, Immunology, biology.protein, Medicine, Clinical Immunology, lcsh:Q, Research Article, Genome-Wide Association Study
Abstract: Rheumatoid arthritis (RA) is a major cause of adult chronic inflammatory arthritis and a typical complex trait. Although several genetic determinants have been identified, they account for only a part of the genetic susceptibility. We conducted a genome-wide association study of RA in Japanese using 225,079 SNPs genotyped in 990 cases and 1,236 controls from two independent collections (658 cases and 934 controls in collection1; 332 cases and 302 controls in collection2), followed by replication studies in two additional collections (874 cases and 855 controls in collection3; 1,264 cases and 948 controls in collection4). SNPs showing p
Published: 2011

42. A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium

Author: J. Ramón Quirós, Eva Ardanaz, Stefania Boccia, Wilbert H.M. Peters, Dimitrios Trichopoulos, Mario Foglio, Luigi Barzan, Lenka Foretova, Joshua E. Muscat, Françoise Clavel-Chapelon, Elio Riboli, Diana Zelenika, Paul Brennan, Salvatore Panico, Eleonora Fabianova, Lars J. Vatten, Kay-Tee Khaw, David I. Conway, Pilar Galan, Doris Lechner, Erich M. Sturgis, Shilong Zhong, Shama Buch, Jolanta Lissowska, Franco Merletti, Carmen Enid Martínez, Li E. Wang, H. Bas Bueno-de-Mesquita, Vittorio Krogh, Andres Metspalu, Anne Tjønneland, Shen Chih Chang, Rayjean J. Hung, Silvia Franceschi, Amelie Chabrier, Kristina Kjærheim, Gabriella Cadoni, Sergio Koifman, Ariana Znaor, Chu Chen, Pagona Lagiou, Ivana Holcatova, Richard B. Hayes, James McKay, Graham Byrnes, Philip Lazarus, Christine Bouchardy, Ray Lowry, Vladimir Bencko, Merethe Kumle, Jingchun Luo, Antonio Agudo, Mark Lathrop, David R. Doody, Victor Wünsch-Filho, Joanna Trubicka, Lorenzo Simonato, Martin Lacko, Cristina Canova, John K. Field, Sherianne Fish, Valerie Gaborieau, Xavier Castellsagué, Mary Toner, Thérèse Truong, Tomoko Nukui, Carla J. Gallagher, Wolfgang Ahrens, Triantafillos Liloglou, Kim Overvad, Vladimir Janout, Ivo Gut, Paolo Boffetta, Shu Chun Chuang, Göran Hallmans, Jakob Linseisen, Marjorie Romkes, David Zaridze, Mark C. Weissler, Simone Benhamou, Antonia Trichopoulou, Nerea Larrañaga, José Eluf Neto, Neonila Szeszenia-Dabrowska, Jan Lubinski, Stephen M. Schwartz, Peter Rudnai, Hélène Blanché, Mia Hashibe, William K. Funkhouser, Paolo Vineis, Maria Paula Curado, Gary J. Macfarlane, Marcin Lener, Claire M. Healy, Michael D. McClean, Domenico Palli, Marc Delepine, Tõnu Voodern, Carmen J. Marsit, Zuo-Feng Zhang, Kristjan Välk, Dorota Oszutowska, Heiner Boeing, Ana M. B. Menezes, Rolando Herrero, Leticia Fernández Garrote, Heather H. Nelson, Renato Talamini, Anne Boland, Alexandru Bucur, Qingyi Wei, Gary E. Goodman, Lorenzo Richiardi, Carmen Navarro, Karl T. Kelsey, Rosario Tumino, Inger Njølstad, Johannes J. Manni, Carlos A. González, Oxana Shangina, John R. McLaughlin, Patricia A. McKinney, Timothy J. Key, Andrew F. Olshan, Dario Arzani, Tatiana V. Macfarlane, Simon Heath, Petra H.M. Peeters, International Agency for Research on Cancer (IARC), Russian Academy of Medical Sciences, Department of Epidemiology, Institute of Occupational Medicine, Maria Skłodowska Curie Memorial Cancer Center, National Institute for Environment, Partenaires INRAE, Regional Authority of Public Health, Institute of Public Health, Charles University [Prague] (CU), Palacky University Olomouc, Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute (RECAMO), National and Kapodistrian University of Athens (NKUA), The Netherlands Cancer Institute, Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Université de Genève (UNIGE), Bremen Institute for Prevention Research and Social Medicine (BIPS), University of Bremen, Universita di Torino, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), General Hospital, Cancer Registry of Norway, School of Medicine and Dentistry, Universita di Padova, Imperial College London, Catalan Institute of Oncology, CIBER de Epidemiología y Salud Pública (CIBERESP), Newcastle University [Newcastle], Dental School, Centre for Epidemiology and Biostatistics, University of Leeds, NHS NSS ISD, School of Dental Science, University of Liverpool, National Institute of Public Health, National School of Public Health, Universidade Federal de Pelotas = Federal University of Pelotas (UFPel), Universidade de São Paulo (USP), Institute of Oncology and Radiobiology, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Institute of Hygiene, Università cattolica del Sacro Cuore [Milano] (Unicatt), University of North Carolina, Pomeranian Medical University, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Penn State College of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Penn State System, University of California [Los Angeles] (UCLA), University of California, Anderson Cancer Center, The University of Texas Health Science Center at Houston (UTHealth), Instituto de Investigación Epidemiológica, Brown University, School of public health, The University of Hong Kong (HKU), Masonic Cancer Center, University of Minnesota [Twin Cities] (UMN), University of Minnesota System-University of Minnesota System, University of Pittsburgh (DEPARTMENT OF MATHEMATICS), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Maastricht University [Maastricht], Radboud University Medical Center [Nijmegen], Mount Sinai Hospital [Toronto, Canada] (MSH), Cancer Care Ontario, Norwegian University of Science and Technology (NTNU), University of Tromsø (UiT), Piedmont Reference Center for Epidemiology and Cancer Prevention, Department of Epidemiology and Public Health, Institut National de la Santé et de la Recherche Médicale (INSERM), Istituto per lo Studio e la Prevezione Oncologica, Civile - M.P.Arezzo Hospital, Department of Clinical and Experimental Medicine, Università degli studi di Napoli Federico II, Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université (HESAM)-HESAM Université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), INCa, France, US NCI [R01 CA092039 05/05S1], Benhamou, Simone, Bouchardy Magnin, Christine, Charles University in Prague, Università cattolica del Sacro Cuore [Roma] (Unicatt), Penn State System-Pennsylvania Commonwealth System of Higher Education (PCSHE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), [McKay, JD, Truong, T, Gaborieau, V, Chabrier, A, Chuang, SC, Byrnes, G, Curado, MP, Franceschi, S, Hashibe, M, Boffetta, P, Brennan, P] IARC, Lyon, France. [Zaridze, D, Shangina, O] Russian Acad Med Sci, Canc Res Ctr, Inst Carcinogenesis, Moscow, Russia. [Szeszenia-Dabrowska, N] Inst Occupat Med, Dept Epidemiol, Lodz, Poland. [Lissowska, J] M Sklodowska Curie Mem Canc Ctr, Warsaw, Poland. [Lissowska, J] Inst Oncol, Warsaw, Poland. [Rudnai, P] Natl Inst Environm Hlth, Budapest, Hungary. [Fabianova, E] Reg Author Publ Hlth, Banska Bystrica, Slovakia. [Bucur, A] Inst Publ Hlth, Bucharest, Romania. [Bencko, V, Holcatova, I] Charles Univ Prague, Inst Hyg & Epidemiol, Fac Med 1, Prague, Czech Republic. [Janout, V] Palacky Univ, CR-77147 Olomouc, Czech Republic. [Foretova, L] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Trichopoulos, D] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Benhamou, S] INSERM U946, Paris, France. [Benhamou, S] Inst Gustave Roussy, CNRS UMR8200, Villejuif, France. [Bouchardy, C] Univ Geneva, Geneva Canc Registry, Inst Social & Prevent Med, Geneva, Switzerland. [Ahrens, W] Univ Bremen, Bremen Inst Prevent Res & Social Med BIPS, Bremen, Germany. [Merletti, F, Richiardi, L] Univ Turin, Canc Epidemiol Unit, Turin, Italy. [Talamini, R] IRCCS, Natl Canc Inst, Aviano, Italy. [Barzan, L] Gen Hosp Pordenone, Pordenone, Italy. [Kjaerheim, K] Canc Registry Norway, Oslo, Norway. [Macfarlane, GJ, Macfarlane, TV] Univ Aberdeen, Sch Med & Dent, Aberdeen, Scotland. [Simonato, L, Canova, C] Univ Padua, Dept Environm Med & Publ Hlth, Padua, Italy. [Canova, C] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Agudo, A, Castellsague, X] ICO, Barcelona, Spain. [Castellsague, X, Navarro, C, Ardanaz, E] CIBERESP, Madrid, Spain. [Lowry, R] Univ Newcastle Dent Sch, Newcastle Upon Tyne, Tyne & Wear, England. [Conway, DI] Univ Glasgow Dent Sch, Glasgow, Lanark, Scotland. [McKinney, PA] Univ Leeds Ctr Epidemiol & Biostat, Leeds, W Yorkshire, England. [McKinney, PA] NHS NSS ISD, Edinburgh, Midlothian, Scotland. [Healy, CM, Toner, ME] Trinity Coll Sch Dent Sci, Dublin, Ireland. [Znaor, A] Croatian Natl Inst Publ Hlth, Croatian Natl Canc Registry, Zagreb, Croatia. [Koifman, S] Natl Sch Publ Hlth FIOCRUZ, Rio De Janeiro, Brazil. [Menezes, A] Univ Fed Pelotas, Pelotas, Brazil. [Wuensch, V, Neto, JE] Univ Sao Paulo, Sao Paulo, Brazil. [Garrote, LF] Inst Oncol & Radiobiol, Havana, Cuba. [Boccia, S, Cadoni, G, Arzani, D] Univ Cattolica Sacro Cuore, Inst Hyg, Rome, Italy. [Boccia, S] IRCCS San Raffaele Pisana, Rome, Italy. [Olshan, AF] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Weissler, MC, Funkhouser, WK, Luo, JC] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Lubinski, J, Trubicka, J, Lener, M, Oszutowska, D] Pomeranian Med Univ, Dept Genet & Pathomorphol, Int Hereditary Canc Ctr, Szczecin, Poland. [Oszutowska, D] Pomeranian Med Univ, Dept Hyg Epidemiol & Publ Hlth, Szczecin, Poland. [Schwartz, SM, Chen, C, Fish, S, Doody, DR, Goodman, GE] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Muscat, JE, Lazarus, P, Gallagher, CJ] Penn State Coll Med, Hershey, PA USA. [Chang, SC, Zhang, ZF] Univ Calif Los Angeles Sch Publ Hlth, Los Angeles, CA USA. [Wei, QY, Sturgis, EM, Wang, LE] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Herrero, R] Inst Invest Epidemiol, San Jose, Costa Rica. [Kelsey, KT, Marsit, CJ] Brown Univ, Providence, RI 02912 USA. [McClean, MD] Boston Univ Sch Publ Hlth, Boston, MA USA. [Nelson, HH] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN USA. [Romkes, M, Buch, S, Nukui, T, Zhong, SL] Univ Pittsburgh, Pittsburgh, PA USA. [Lacko, M, Manni, JJ] Maastricht Univ Med Ctr, Dept Otorhinolaryngol & Head & Neck Surg, Maastricht, Netherlands. [Peters, WHM] St Radboud Univ Nijmegen Med Ctr, Dept Gastroenterol, Nijmegen, Netherlands. [Hung, RJ] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [McLaughlin, J] Canc Care Ontario, Toronto, ON, Canada. [Vatten, L] Norwegian Univ Sci & Technol, N-7034 Trondheim, Norway. [Njolstad, I] Univ Tromso, Dept Community Med, Fac Hlth Sci, Tromso, Norway. [Field, JK, Liloglou, T] Univ Liverpool Canc Res Ctr, Roy Castle Lung Canc Res Programme, Liverpool, Merseyside, England. [Vineis, P] Univ Turin, Serv Epidemiol Tumori, Turin, Italy. [Vineis, P] CPO Piemonte, Turin, Italy. [Vineis, P, Riboli, E] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London, England. [Clavel-Chapelon, F] E3N EPIC Grp Inst Gustave Roussy, INSERM, Villejuif, France. [Palli, D] Canc Res & Prevent Inst ISPO, Mol & Nutr Epidemiol Unit, Florence, Italy. [Tumino, R] Azienda Osped Civile MP Arezzo, Canc Registry, Ragusa, Italy. [Tumino, R] Azienda Osped Civile MP Arezzo, Histopathol Unit, Ragusa, Italy. [Krogh, V] Fdn IRCCS, Ist Nazl Tumori, Milan, Italy. [Panico, S] Univ Naples Federico 2, Dipartimento Med Clin & Sperimentale, Naples, Italy. [Gonzalez, CA] ICO, RETICC DR06 0020, IDIBELL, Unit Nutr Environm & Canc, Barcelona, Spain. [Quiros, JR] Principado Asturias, Consejeria Serv Sociales, Jefe Secc Informac Sanitaria, Oviedo, Spain. [Martinez, C] Escuela Andaluza Salud Publ, Granada, Spain. [Navarro, C] Murcia Hlth Council, Dept Epidemiol, Murcia, Spain. [Ardanaz, E] Navarra Publ Hlth Inst, Pamplona, Spain. [Larranaga, N] Gobierno Vasco, Subdirecc Salud Publ Gipuzkoa, San Sebastian, Spain. [Khaw, KT] Univ Cambridge, Sch Clin Med, Cambridge, England. [Key, T] Univ Oxford, Canc Res UK, Oxford, England. [Bueno-de-Mesquita, HB] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands. [Peeters, PHM] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, Utrecht, Netherlands. [Trichopoulou, A] Univ Athens Sch Med, WHO Collaborating Ctr Nutr, Dept Hyg Epidemiol & Med Stat, Athens, Greece. [Linseisen, J] Helmholtz Ctr Munich, Inst Epidemiol, Neuherberg, Germany. [Linseisen, J] German Canc Res Ctr, Div Clin Epidemiol, D-6900 Heidelberg, Germany. [Boeing, H] Deutsch Inst Ernahrungsforsch, Dept Epidemiol, Potsdam, Germany. [Hallmans, G] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Overvad, K] Aarhus Univ, Dept Epidemiol & Social Med, Aarhus, Denmark. Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Kumle, M] Univ Hosp No Norway, Tromso, Norway. [Valk, K, Voodern, T, Metspalu, A] Univ Tartu, EE-50090 Tartu, Estonia. [Zelenika, D, Boland, A, Delepine, M, Foglio, M, Lechner, D, Gut, IG, Heath, S, Lathrop, M] Commissariat Energie Atom, Inst Genom, Ctr Natl Genotypage, Evry, France. [Blanche, H, Lathrop, M] Fdn Jean Dausset CEPH, Paris, France. [Galan, P] Univ Paris 13, INSERM INRA CNAM U557 U1125, Bobigny, France. [Hayes, RB] New York Univ Langone Med Ctr, New York, NY USA, Support for the central Europe and ARCAGE genome-wide studies and follow-up genotyping was provided by INCa, France. Additional funding for study coordination, genotyping of replication studies, and statistical analysis was provided by the US NCI (R01 CA092039 05/05S1)., Norges teknisk-naturvitenskapelige universitet, Det medisinske fakultet, Institutt for samfunnsmedisin, McKay, J.D., Truong, T., Gaborieau, V., Chabrier, A., Chuang, S.-C., Byrnes, G., Zaridze, D., Shangina, O., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., Fabianova, E., Bucur, A., Bencko, V., Holcatova, I., Janout, V., Foretova, L., Lagiou, P., Trichopoulos, D., Benhamou, S., Bouchardy, C., Ahrens, W., Merletti, F., Richiardi, L., Talamini, R., Barzan, L., Kjaerheim, K., Macfarlane, G.J., Macfarlane, T.V., Simonato, L., Canova, C., Agudo, A., Castellsagué, X., Lowry, R., Conway, D.I., McKinney, P.A., Healy, C.M., Toner, M.E., Znaor, A., Curado, M.P., Koifman, S., Menezes, A., Wünsch-Filho, V., Neto, J.E., Garrote, L.F., Boccia, S., Cadoni, G., Arzani, D., Olshan, A.F., Weissler, M.C., Funkhouser, W.K., Luo, J., Lubinski, J., Trubicka, J., Lener, M., Oszutowska, D., Schwartz, S.M., Chen, C., Fish, S., Doody, D.R., Muscat, J.E., Lazarus, P., Gallagher, C.J., Chang, S.-C., Zhang, Z.-F., Wei, Q., Sturgis, E.M., Wang, L.-E., Franceschi, S., Herrero, R., Kelsey, K.T., McClean, M.D., Marsit, C.J., Nelson, H.H., Romkes, M., Buch, S., Nukui, T., Zhong, S., Lacko, M., Manni, J.J., Peters, W.H.M., Hung, R.J., McLaughlin, J., Vatten, L., Njølstad, I., Goodman, G.E., Field, J.K., Liloglou, T., Vineis, P., Clavel-Chapelon, F., Palli, D., Tumino, R., Krogh, V., Panico, S., González, C.A., Quirós, J.R., Martínez, C., Navarro, C., Ardanaz, E., Larrañaga, N., Khaw, K.-T., Key, T., Bueno-de-Mesquita, H.B., Peeters, P.H.M., Trichopoulou, A., Linseisen, J., Boeing, H., Hallmans, G., Overvad, K., Tjønneland, A., Kumle, M., Riboli, E., Välk, K., Voodern, T., Metspalu, A., Zelenika, D., Boland, A., Delepine, M., Foglio, M., Lechner, D., Blanché, H., Gut, I.G., Galan, P., Heath, S., Hashibe, M., Hayes, R.B., Boffetta, P., Lathrop, M., Brennan, P., Promovendi PHPC, Metamedica, KNO, RS: MHeNs School for Mental Health and Neuroscience, and RS: GROW - School for Oncology and Reproduction
Subjects: Male, Cancer Research, Candidate gene, Linkage disequilibrium, [SDV]Life Sciences [q-bio], Genome-wide association study, FAMILY-HISTORY, genome-wide, Health Care::Environment and Public Health::Public Health::Epidemiologic Methods::Epidemiologic Research Design::Genome-Wide Association Study [Medical Subject Headings], 0302 clinical medicine, Gene Frequency, NECK-CANCER, Risk Factors, Càncer, SUSCEPTIBILITY LOCUS, SENSITIVITY PROTEIN MUS308, Genetics (clinical), Cancer, Genetics & Heredity, Genetics, Publication Characteristics::Study Characteristics::Multicenter Study [Medical Subject Headings], 0303 health sciences, TOBACCO-RELATED CANCERS, Tumor, Continental Population Groups, Middle Aged, 3. Good health, LUNG-CANCER, POOLED ANALYSIS, EPIDEMIOLOGY CONSORTIUM, INTERNATIONAL HEAD, ALCOHOL-DRINKING, Head and Neck Neoplasms, Drinking of alcoholic beverages, 030220 oncology & carcinogenesis, NEOPLASIAS, Consum d'alcohol, Head and Neck Neoplasms/enzymology/epidemiology/genetics, Genetics and Genomics/Gene Discovery, Female, Settore MED/31 - OTORINOLARINGOIATRIA, Life Sciences & Biomedicine, Medical Genetics, Research Article, Adult, VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714, Diseases::Neoplasms::Neoplasms by Site::Head and Neck Neoplasms [Medical Subject Headings], lcsh:QH426-470, Neoplasias de Cabeza y Cuello, VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical genetics: 714, Genetics and Genomics/Complex Traits, Biology, association study, Estudio de Asociación del Genoma Completo, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to Disease [Medical Subject Headings], 03 medical and health sciences, upper aerodigestive tract, Genetic variation, Biomarkers, Tumor, medicine, cancers, cancer, Humans, Genetic Predisposition to Disease, ddc:610, Tumor Markers, Biological/genetics, Genetics and Genomics/Cancer Genetics, Molecular Biology, Genotyping, Allele frequency, Settore MED/42 - IGIENE GENERALE E APPLICATA, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Genetic association, ddc:613, Aged, Medicinsk genetik, Estudio Multicéntrico, Science & Technology, Racial Groups, Genetic Variation, Aldehyde Dehydrogenase, medicine.disease, lcsh:Genetics, Aldehyde Dehydrogenase/genetics, Genome-Wide Association Study, Persons::Persons::Population Groups::Continental Population Groups [Medical Subject Headings], INHANCE consortium, sensitivity protein mus308, tobacco-related cancers, lung-cancer, pooled analysis, susceptibility locus, neck-cancer, epidemiology consortium, international head, alcohol-drinking, family-history, INHANCE Consortium, Biomarkers, Genètica
Abstract: Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility., Author Summary We have used a two-phased study approach to identify common genetic variation involved in susceptibility to upper aero-digestive tract cancer. Using Illumina HumanHap300 beadchips, 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls, were genotyped for a panel 317,000 genetic variants that represent the majority of common genetic in the human genome. The 19 top-ranked variants were then studied in an additional series of 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies. Five variants were significantly associated with UADT cancer risk after the completion of both stages, including three residing within the alcohol dehydrogenase genes (ADH1B, ADH1C, ADH7) that have been previously described. Two additional variants were found, one near the ALDH2 gene and a second variant located in HEL308, a DNA repair gene. These results implicate two variants 4q21 and 12q24 and further highlight three ADH variants UADT cancer susceptibility.
Published: 2011
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43. A follow-up study of a genome-wide association scan identifies a susceptibility locus for venous thrombosis on chromosome 6p24.1

Author: Marie-Christine Alessi, Mark Lathrop, Simon Heath, Diana Zelenika, Jessy Brocheton, Jean-François Schved, Marine Germain, Pilar Galan, Ewa Ninio, Stefan Blankenberg, Thomas Münzel, Joseph Emmerich, Irene D. Bezemer, Christine Biron-Andreani, François Cambien, Aurélien Delluc, Noémie Saut, Tanja Zeller, David-Alexandre Trégouët, Ludovic Drouet, Frits R. Rosendaal, Laurence Tiret, Pierre-Emmanuel Morange, Viviane Nicaud, Hervé Durand, Stefan-Martin Brand-Herrmann, Gwenaelle Burgos, Lance A. Bare, Gilles Pernod, Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Techniques pour l'Evaluation et la Modélisation des Actions de la Santé (TIMC-IMAG-ThEMAS), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Service de Biochimie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR6, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Department of Medicine II, Johannes Gutenberg - Universität Mainz (JGU), Hôpital de la Timone [CHU - APHM] (TIMONE), 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, Department of General and Interventional Cardiology, University Heart Center Hamburg, Risque Thrombotique et Mecanismes de l'Hemostase (U765), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Université Paris-Saclay-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), Risque Thrombotique et Mécanismes de l'Hémostase (U765), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, obésité et risque thrombotique ( NORT ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR14-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Montpellier 1 ( UM1 ) -Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -CHU Saint-Eloi, ThEMAS, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Unité de Recherche en Epidémiologie Nutritionnelle ( UREN ), Université Paris 13 ( UP13 ) -Institut National de la Recherche Agronomique ( INRA ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière-IFR6, Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Département de Médecine Interne et Pneumologie [Brest] ( DMIP - Brest ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Groupe d'Etude de la Thrombose de Bretagne Occidentale ( GETBO ), Université de Brest ( UBO ), Johannes Gutenberg-University Mainz, Hôpital de la Timone [CHU - APHM] ( TIMONE ), Institut de Génomique d'Evry ( IG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Risque Thrombotique et Mecanismes de l'Hemostase ( U765 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-IFR6, Université de Brest (UBO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: MESH : Transcription Factors, [SDV]Life Sciences [q-bio], Genome-wide association study, 030204 cardiovascular system & hematology, MESH : Chromosomes, Human, Pair 6, 0302 clinical medicine, Genetics(clinical), Genetics (clinical), Genetics, Venous Thrombosis, 0303 health sciences, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, MESH: Follow-Up Studies, MESH: Transcription Factors, MESH : Venous Thrombosis, MESH: Case-Control Studies, DNA-Binding Proteins, Chromosomes, Human, Pair 6, MESH : DNA-Binding Proteins, Erratum, MESH : Genome-Wide Association Study, MESH : Case-Control Studies, MESH: Chromosomes, Human, Pair 6, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Genetic determinism, 03 medical and health sciences, Report, Genetic predisposition, Humans, Genetic Predisposition to Disease, Allele, Gene, 030304 developmental biology, MESH: Humans, [ SDV ] Life Sciences [q-bio], MESH : Humans, linking inflammation protein atherothrombosis sequence risk, Case-control study, Chromosome, MESH : Follow-Up Studies, Case-Control Studies, MESH: Genome-Wide Association Study, MESH: Venous Thrombosis, MESH : Genetic Predisposition to Disease, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins, Follow-Up Studies, Genome-Wide Association Study, Transcription Factors
Abstract: International audience; To identify genetic susceptibility factors conferring increased risk of venous thrombosis (VT), we conducted a multistage study, following results of a previously published GWAS that failed to detect loci for developing VT. Using a collection of 5862 cases with VT and 7112 healthy controls, we identified the HIVEP1 locus on chromosome 6p24.1 as a susceptibility locus for VT. Indeed, the HIVEP1 rs169713C allele was associated with an increased risk for VT, with an odds ratio of 1.20 (95% confidence interval 1.13-1.27, p = 2.86 x 10(-9)). HIVEP1 codes for a protein that participates in the transcriptional regulation of inflammatory target genes by binding specific DNA sequences in their promoter and enhancer regions. The current results provide the identification of a locus involved in VT susceptibility that lies outside the traditional coagulation/fibrinolysis pathway.
Published: 2010
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44. Common variants at five new loci associated with early-onset inflammatory bowel disease

Author: Marcin, Imielinski, Robert N, Baldassano, Anne, Griffiths, Richard K, Russell, Vito, Annese, Marla, Dubinsky, Subra, Kugathasan, Jonathan P, Bradfield, Thomas D, Walters, Patrick, Sleiman, Cecilia E, Kim, Aleixo, Muise, Kai, Wang, Joseph T, Glessner, Shehzad, Saeed, Haitao, Zhang, Edward C, Frackelton, Cuiping, Hou, James H, Flory, George, Otieno, Rosetta M, Chiavacci, Robert, Grundmeier, Massimo, Castro, Anna, Latiano, Bruno, Dallapiccola, Joanne, Stempak, Debra J, Abrams, Kent, Taylor, Dermot, McGovern, Gary, Silber, Iwona, Wrobel, Antonio, Quiros, Jeffrey C, Barrett, Sarah, Hansoul, Dan L, Nicolae, Judy H, Cho, Richard H, Duerr, John D, Rioux, Steven R, Brant, Mark S, Silverberg, Kent D, Taylor, M Michael, Barmuda, Alain, Bitton, Themistocles, Dassopoulos, Lisa Wu, Datta, Todd, Green, Anne M, Griffiths, Emily O, Kistner, Michael T, Murtha, Miguel D, Regueiro, Jerome I, Rotter, L Philip, Schumm, A Hillary, Steinhart, Stephen R, Targan, Ramnik J, Xavier, Cécile, Libioulle, Cynthia, Sandor, Mark, Lathrop, Jacques, Belaiche, Olivier, Dewit, Ivo, Gut, Simon, Heath, Debby, Laukens, Myriam, Mni, Paul, Rutgeerts, André, Van Gossum, Diana, Zelenika, Denis, Franchimont, J P, Hugot, Martine, de Vos, Severine, Vermeire, Edouard, Louis, Lon R, Cardon, Carl A, Anderson, Hazel, Drummond, Elaine, Nimmo, Tariq, Ahmad, Natalie J, Prescott, Clive M, Onnie, Sheila A, Fisher, Jonathan, Marchini, Jilur, Ghori, Suzannah, Bumpstead, Rhian, Gwillam, Mark, Tremelling, Panos, Delukas, John, Mansfield, Derek, Jewell, Jack, Satsangi, Christopher G, Mathew, Miles, Parkes, Michel, Georges, Mark J, Daly, Melvin B, Heyman, George D, Ferry, Barbara, Kirschner, Jessica, Lee, Jonah, Essers, Richard, Grand, Michael, Stephens, Arie, Levine, David, Piccoli, John, Van Limbergen, Salvatore, Cucchiara, Dimitri S, Monos, Stephen L, Guthery, Lee, Denson, David C, Wilson, Straun F A, Grant, Mark, Daly, Hakon, Hakonarson, UCL - (SLuc) Service de gastro-entérologie, and UCL - MD/MINT - Département de médecine interne
Subjects: Genome-wide association study, Disease, Biology, Inflammatory bowel disease, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Genetics, Humans, Colitis, Young adult, Age of Onset, 030304 developmental biology, Colitis, Ulcerative - genetics, 0303 health sciences, Crohn's disease, Genome, Human, Chromosome Mapping, Genetic Variation, medicine.disease, Inflammatory Bowel Diseases, Ulcerative colitis, digestive system diseases, 3. Good health, Immunology, Inflammatory Bowel Diseases - epidemiology, genetics, 030211 gastroenterology & hepatology, Colitis, Ulcerative, Age of onset, Genome-Wide Association Study
Abstract: The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 x 10(-9)), 22q12 (rs2412973, P = 1.55 x 10(-9)), 10q22 (rs1250550, P = 5.63 x 10(-9)), 2q37 (rs4676410, P = 3.64 x 10(-8)) and 19q13.11 (rs10500264, P = 4.26 x 10(-10)). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn's disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.
Published: 2009
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45. Genetic structure of Europeans: a view from the North-East

Author: Thomas Meitinger, T. Piskackova, Leena Peltonen, Draga Toncheva, Christelle Borel, Sena Karachanak, Liene Nikitina-Zake, Xavier Estivill, Béla Melegh, Daniela Toniolo, Janis Klovins, Mari Nelis, Andrey Khrunin, H-Erich Wichmann, Raquel Rabionet, Michael Krawczak, Ivan Balascak, Stefan Schreiber, Tõnu Esko, Jūratė Kasnauskienė, Alexander Zimprich, Paolo Gasparini, Pilar Galan, Fritz Zimprich, Karola Rehnström, Simon Heath, Pio D'Adamo, Antonio Julià, Sara Marsal, Arne Pfeufer, Stylianos E. Antonarakis, Eveliina Jakkula, Svetlana A. Limborska, Noémi Polgár, Reedik Mägi, Samuel Deutsch, Tadeusz Dębniak, Homa Attar, Jan Lubinski, Vaidutis Kučinskas, Maryline Gagnebin, Mark Lathrop, Milan Macek, Andres Metspalu, Maido Remm, Nelis, M, Esko, T, Mägi, R, Zimprich, F, Zimprich, A, Toncheva, D, Karachanak, S, Piskácková, T, Balascák, I, Peltonen, L, Jakkula, E, Rehnström, K, Lathrop, M, Heath, S, Galan, P, Schreiber, S, Meitinger, T, Pfeufer, A, Wichmann, He, Melegh, B, Polgár, N, Toniolo, D, Gasparini, Paolo, D'Adamo, ADAMO PIO, Klovins, J, NIKITINA ZAKE, L, Kucinskas, V, Kasnauskiene, J, Lubinski, J, Debniak, T, Limborska, S, Khrunin, A, Estivill, X, Rabionet, R, Marsal, S, Julià, A, Antonarakis, Se, Deutsch, S, Borel, C, Attar, H, Gagnebin, M, Macek, M, Krawczak, M, Remm, M, and Metspalu, A.
Subjects: Population genetics, Genome-wide association study, genetic [Human], Linkage Disequilibrium, Fixation index, 0302 clinical medicine, Gene Frequency, Principal Component Analysi, genetics [Single Nucleotide], Genetic Marker, genetic [Linkage Disequilibrium], Linkage Disequilibrium: genetics, ddc:576.5, ethnology [Europe], Genetics, 0303 health sciences, education.field_of_study, Principal Component Analysis, Multidisciplinary, Genome, European Continental Ancestry Group/ genetics, Single Nucleotide, Genetics and Genomics/Bioinformatics, genetic [European Continental Ancestry Group], Europe, Geography, Genetic structure, Medicine, Polymorphism, Single Nucleotide/ genetics, Research Article, Human, Europe: ethnology, Genetic Markers, Science, Population, European Continental Ancestry Group, Polymorphism, Single Nucleotide, White People, Europe/ethnology, European Continental Ancestry Group: genetics, 03 medical and health sciences, Genetics and Genomics/Population Genetics, Humans, Linkage Disequilibrium/genetics, Polymorphism, education, Allele frequency, 030304 developmental biology, Human: genetics, Single Nucleotide: genetics, Genetic diversity, Genome, Human, Genetics and Genomics/Genome Projects, Genetic marker, Evolutionary biology, Genome, Human/genetics, 030217 neurology & neurosurgery
Abstract: Using principal component (PC) analysis, we studied the genetic constitution of 3,112 individuals from Europe as portrayed by more than 270,000 single nucleotide polymorphisms (SNPs) genotyped with the Illumina Infinium platform. In cohorts where the sample size was >100, one hundred randomly chosen samples were used for analysis to minimize the sample size effect, resulting in a total of 1,564 samples. This analysis revealed that the genetic structure of the European population correlates closely with geography. The first two PCs highlight the genetic diversity corresponding to the northwest to southeast gradient and position the populations according to their approximate geographic origin. The resulting genetic map forms a triangular structure with a) Finland, b) the Baltic region, Poland and Western Russia, and c) Italy as its vertexes, and with d) Central- and Western Europe in its centre. Inter- and intra- population genetic differences were quantified by the inflation factor lambda (lambda) (ranging from 1.00 to 4.21), fixation index (F(st)) (ranging from 0.000 to 0.023), and by the number of markers exhibiting significant allele frequency differences in pair-wise population comparisons. The estimated lambda was used to assess the real diminishing impact to association statistics when two distinct populations are merged directly in an analysis. When the PC analysis was confined to the 1,019 Estonian individuals (0.1\% of the Estonian population), a fine structure emerged that correlated with the geography of individual counties. With at least two cohorts available from several countries, genetic substructures were investigated in Czech, Finnish, German, Estonian and Italian populations. Together with previously published data, our results allow the creation of a comprehensive European genetic map that will greatly facilitate inter-population genetic studies including genome wide association studies (GWAS).
Published: 2009

46. Alpha-synuclein gene rearrangements in dominantly inherited parkinsonism: frequency, phenotype, and mechanisms

Author: Pablo, Ibáñez, Suzanne, Lesage, Sabine, Janin, Ebba, Lohmann, Frank, Durif, Alain, Destée, Anne-Marie, Bonnet, Christine, Brefel-Courbon, Simon, Heath, Diana, Zelenika, Yves, Agid, Alexandra, Dürr, Alexis, Brice, Marie, Vidailhet, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Wellcome Trust Centre for Gene Regulation and Expression, University of Dundee, Service de Neurologie [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Service de neurochirurgie générale et stéréotaxique fonctionnelle, Hôpital Roger Salengro [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Ministère Français de la Recherche and de la technologie Verum Foundation Contrat de l'Union Européenne LSHM-CT-2003-503330/APOPIS de la Commission Européenne Association France Parkinson, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Pollak, Pierre, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], and Savasta, Marc
Subjects: Male, DNA Mutational Analysis, Gene Dosage, MESH: DNA Repeat Expansion, MESH: Gene Dosage, Genes, Dominant/genetics, Parkinsonian Disorders/genetics/metabolism/physiopathology, MESH: Genotype, Exon, 0302 clinical medicine, MESH: Aged, 80 and over, Genotype, MESH: Brain Chemistry, MESH: DNA Mutational Analysis, Genes, Dominant, Oligonucleotide Array Sequence Analysis, Genetics, Aged, 80 and over, MESH: Aged, 0303 health sciences, DNA Repeat Expansion, MESH: Middle Aged, MESH: Genetic Testing, Parkinsonism, Genetic Predisposition to Disease/genetics, MESH: Polymorphism, Single Nucleotide, MESH: Genetic Predisposition to Disease, Chromosome Breakage, Middle Aged, Polymorphism, Single Nucleotide/genetics, Phenotype, 3. Good health, MESH: Chromosome Breakage, alpha-Synuclein, Female, Brain Chemistry/genetics, Adult, Haplotypes/genetics, Microsatellite Repeats/genetics, Biology, Polymorphism, Single Nucleotide, Alpha-Synuclein/genetics, 03 medical and health sciences, DNA Repeat Expansion/genetics, Arts and Humanities (miscellaneous), Parkinsonian Disorders, MESH: alpha-Synuclein, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Genotyping, 030304 developmental biology, Aged, Brain Chemistry, MESH: Humans, MESH: Parkinsonian Disorders, Haplotype, MESH: Adult, Gene rearrangement, MESH: Haplotypes, Gene Dosage/genetics, medicine.disease, MESH: Male, nervous system diseases, ddc:616.8, Haplotypes, Genetic marker, MESH: Oligonucleotide Array Sequence Analysis, Neurology (clinical), MESH: Microsatellite Repeats, MESH: Genes, Dominant, MESH: Female, 030217 neurology & neurosurgery, Microsatellite Repeats
Abstract: International audience; OBJECTIVE: Genomic multiplications of the alpha-synuclein gene (SNCA) cause autosomal dominant Parkinson disease (ADPD). The aim of this study was to assess the frequency and phenotype of SNCA rearrangements in a large series of families with typical or atypical AD parkinsonism. DESIGN: Patients were screened by the exon dosage of the SNCA gene. The genotype of patients and relatives carrying SNCA rearrangements, the size of the multiplied regions, and the centromeric and telomeric breakpoints were determined by microsatellite dosage and 250K Affymetrix Single Polymorphism Nucleotide microarrays (Affymetrix, Santa Clara, California). SUBJECTS: Index cases and, whenever appropriate, relatives of 286 mainly European families with ADPD were screened. RESULTS: Four of 264 families (1.5%) with typical ADPD carried duplications and 1 of 22 families (4.5%) with atypical AD parkinsonism carried a triplication of SNCA. Genotyping and dosage analyses showed that the multiplied regions were variable in size (0.42-5.29 megabase pairs), suggesting that SNCA multiplications occurred independently. Phenotype analyses showed that the severity of the disease correlated with the SNCA copy number, but not with the minimal number of multiplied genes (1 to 33). Haplotype analysis of polymorphic markers suggested that multiplication of the SNCA gene occurred by both interchromosomal and intrachromosomal rearrangement. CONCLUSIONS: Our results suggest that SNCA rearrangements may be more frequent than point mutations in ADPD. Furthermore, our results indicate that the phenotype associated with SNCA multiplications correlates with the number of copies of the gene and provides the first insight into the mechanisms underlying SNCA multiplication.
Published: 2009
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47. G/T substitution in intron 1 of the UNC13B gene is associated with increased risk of nephropathy in patients with type 1 diabetes

Author: François Cambien, Simon Heath, M. Parkkonen, Martin Farrall, Viviane Nicaud, Carol Forsblom, Steven McGinn, Lise Tarnow, David-Alexandre Trégouët, Dominique Gauguier, Fumihiko Matsuda, Roger D. Cox, Michel Marre, Tiphaine Godefroy, Ivo Gut, Stefan Martin Brand-Herrmann, Per-Henrik Groop, Gbenga Kazeem, Nathalie Vionnet, Rachel Rousseau, Hans-Henrik Parving, Mark Lathrop, Anna Hoverfält, Ralph Telgmann, and Samy Hadjadj
Subjects: Candidate gene, Genotype, Endocrinology, Diabetes and Metabolism, Population, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Nerve Tissue Proteins, Biology, Polymorphism, Single Nucleotide, Nephropathy, Cell Line, Diabetic nephropathy, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Risk Factors, Cell Line, Tumor, Internal Medicine, medicine, Genetics, Odds Ratio, Animals, Humans, Diabetic Nephropathies, Genetic Predisposition to Disease, education, Allele frequency, 030304 developmental biology, 0303 health sciences, education.field_of_study, Haplotype, medicine.disease, Introns, 3. Good health, Rats, Diabetes Mellitus, Type 1, Haplotypes, HeLa Cells
Abstract: OBJECTIVE— Genetic and environmental factors modulate the susceptibility to diabetic nephropathy, as initiating and/or progression factors. The objective of the European Rational Approach for the Genetics of Diabetic Complications (EURAGEDIC) study is to identify nephropathy susceptibility genes. We report molecular genetic studies for 127 candidate genes for nephropathy. RESEARCH DESIGN AND METHODS— Polymorphisms were identified through sequencing of promoter, exon, and flanking intron gene regions and a database search. A total of 344 nonredundant SNPs and nonsynonymous variants were tested for association with diabetic nephropathy (persistent albuminuria ≥300 mg/24 h) in a large type 1 diabetes case/control (1,176/1,323) study from three European populations. RESULTS— Only one SNP, rs2281999, located in the UNC13B gene, was significantly associated with nephropathy after correction for multiple testing. Analyses of 21 additional markers fully characterizing the haplotypic variability of the UNC13B gene showed consistent association of SNP rs13293564 (G/T) located in intron 1 of the gene with nephropathy in the three populations. The odds ratio (OR) for nephropathy associated with the TT genotype was 1.68 (95% CI 1.29–2.19) (P = 1.0 × 10−4). This association was replicated in an independent population of 412 case subjects and 614 control subjects (combined OR of 1.63 [95% CI 1.30–2.05], P = 2.3 × 10−5). CONCLUSIONS— We identified a polymorphism in the UNC13B gene associated with nephropathy. UNC13B mediates apopotosis in glomerular cells in the presence of hyperglycemia, an event occurring early in the development of nephropathy. We propose that this polymorphism could be a marker for the initiation of nephropathy. However, further studies are needed to clarify the role of UNC13B in nephropathy.
Published: 2008

48. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25

Author: Lenka Foretova, Chu Chen, Eiliv Lund, Pierre Hainaut, Vladimir Bencko, Mario Foglio, Torgny Rasmuson, Wolfgang Ahrens, Vladimir Janout, Lars J. Vatten, George Xinarianos, Hans E. Krokan, Maiken Bratt Elvestad, Lorenzo Simonato, Paolo Vineis, Simon Heath, Adrian Cassidy, Fumihiko Matsuda, Françoise Clavel-Chapelon, Renato Talamini, Anne Boland, Peter Rudnai, Anush Mukeria, Gary J. Macfarlane, Marc Delepine, Franco Merletti, Doris Lechner, Ariana Znaor, Sheila Bingham, Diana Zelenika, Simone Benhamou, Gary E. Goodman, Geoffrey Liu, Hélène Blanché, Dana Mates, Claire M. Healy, Rayjean J. Hung, H. Bas Bueno-de-Mesquita, Neonilia Szeszenia-Dabrowska, Ivo Gut, John K. Field, David Zaridze, Jolanta Lissowska, Triantafillos Liloglou, Carmen Martinez, Frank Skorpen, Kristina Kjærheim, Dimitrios Trichopoulos, Ivana Holcatova, Kristian Hveem, Valerie Gaborieau, Paul Brennan, James McKay, Jakob Linseisen, Pagona Lagiou, Elio Riboli, Eleonora Fabianova, Mia Hashibe, John R. McLaughlin, Antonio Agudo, David I. Conway, Ray Lowry, Paolo Boffetta, Steven A. Narod, Mark Lathrop, School of Public Health, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Institute of Carcinogenesis, Russian Cancer Research Centre, Cancer Research Centre, Department of Epidemiology, Institute of Occupational Medicine, The M Sklodowska-Curie Cancer Center, Institute of Oncology, National Institute of Environment Health, Specialized Institute of Hygiene and Epidemiology, Regional Authority of Public Health-Specialized State Health Institute, Institute of Public Health, Institute of Hygiene and Epidemiology, Charles University [Prague] (CU)-1st Faculty of Medicine, Masaryk Memorial Cancer Institute (MMCI), Department of Preventive Medicine [Univ Palacký], Faculty of Medicine and Dentistry [Univ Palacký], Palacky University Olomouc-Palacky University Olomouc, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Roy Castle Lung Cancer Research Programme, University of Liverpool, University of Liverpool-Cancer Research Centre, Cancer Care Ontario, Samuel Lunenfeld Research Institute, Princess Margaret Hospital, Ontario Cancer Institute, Women's College Research Institute, University of Toronto, Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), Division of Cancer Epidemiology, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Nutrition, hormones et cancer: épidémiologie et prévention (E3N), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Epidemiology and Public Health, Imperial College London, Centre for Nutrition and Health (CVG), National Institute for Public Health and the Environment [Bilthoven] (RIVM), Institute of Community Medicine, University of Tromsø (UiT), Andalusian School of Public Health [Granada], MRC Centrer for Nutritional Epidemiology and Cancer Prevention and Survival, University of Cambridge [UK] (CAM), Department of Radiation Sciences, Oncology, Umeå University, Bremen Institute for Prevention Research and Social Medicine, University of Bremen, INSERM U794, CEPH, Génomes et cancer (GC (FRE2939)), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School [Athens], Harvard School of Public Health, Cancer Epidemiology Unit, Université de Turin, Cancer registry of Norway, University of Oslo (UiO), Institut Català d'Oncologia, Spain Institute of Oncology, University of Aberdeen, Aviano cancer center, Aviano Cancer Center, Department of Environmental Medicine and Public Health, Università degli Studi di Padova = University of Padua (Unipd), University of Newcastle Dental School, University of Newcastle, UK, University of Glasgow Dental School, University of Glasgow, Croatian National Cancer Registry, National Institute of Public Health, Trinity College School of Dental Science, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Hung, R.J., McKay, J.D., Gaborieau, V., Boffetta, P., Hashibe, M., Zaridze, D., Mukeria, A., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., Fabianova, E., Mates, D., Bencko, V., Foretova, L., Janout, V., Chen, C., Goodman, G., Field, J.K., Liloglou, T., Xinarianos, G., Cassidy, A., McLaughlin, J., Liu, G., Narod, S., Krokan, H.E., Skorpen, F., Elvestad, M.B., Hveem, K., Vatten, L., Linseisen, J., Clavel-Chapelon, F., Vineis, P., Bueno-De-Mesquita, H.B., Lund, E., Martinez, C., Bingham, S., Rasmuson, T., Hainaut, P., Riboli, E., Ahrens, W., Benhamou, S., Lagiou, P., Trichopoulos, D., Holcátová, I., Merletti, F., Kjaerheim, K., Agudo, A., MacFarlane, G., Talamini, R., Simonato, L., Lowry, R., Conway, D.I., Znaor, A., Healy, C., Zelenika, D., Boland, A., Delepine, M., Foglio, M., Lechner, D., Matsuda, F., Blanche, H., Gut, I., Heath, S., Lathrop, M., Brennan, P., Savelli, Bruno, Masaryk Memorial Cancer Institute, Masaryk Memorial Cancer Institute (RECAMO), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), and Universita degli Studi di Padova
Subjects: Lung Neoplasms, Genotype, Locus (genetics), [SDV.CAN]Life Sciences [q-bio]/Cancer, Receptors, Nicotinic, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Odds Ratio, medicine, Humans, Genetic Predisposition to Disease, ddc:610, nicotinic acetylcholine receptor, Lung cancer, 030304 developmental biology, Chromosomes, Human, Pair 15, 0303 health sciences, Multidisciplinary, CHRNA5, Respiratory disease, Cancer, medicine.disease, Lung cancer susceptibility, 3. Good health, Europe, Protein Subunits, lung cancer, Nicotinic acetylcholine receptor, Nicotinic agonist, 030220 oncology & carcinogenesis, Immunology, biology.protein
Abstract: Letter; International audience; Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually1. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 × 10$^{-10}$). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 × 10$^{-20}$ overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N′-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets
Published: 2008
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49. Exploration of associations between phospholipase A2 gene family polymorphisms and AIDS progression using the SNPlex method

Author: Sigrid Leclerc, Simon Heath, Sophie Limou, Mario Foglio, Jean-François Zagury, Cédric Coulonges, Thomas Hirtzig, Jean-Louis Spadoni, Gérard Lambeau, Gora Diop, Amu Therwath, Ivo Gut, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Chaire de Bioinformatique, Conservatoire National des Arts et Métiers [CNAM] (CNAM), Laboratoire d'Oncologie Moléculaire, Université Paris Diderot - Paris 7 (UPD7), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), ACV Development Foundation and Neovacs SA, Centre National de la Recherche Scientifique (CNRS), Association pour la Recherche sur le Cancer (ARC), French Ministry of Education, Technology and Research, HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), and Université Nice Sophia Antipolis (1965 - 2019) (UNS)
Subjects: Protein family, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, White People, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Genotype, Gene family, Humans, Genetic Predisposition to Disease, Typing, Gene, MESH: Phospholipases A2, MESH: Cohort Studies, Alleles, 030304 developmental biology, Genetic association, Pharmacology, Genetics, MESH: Acquired Immunodeficiency Syndrome, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Acquired Immunodeficiency Syndrome, MESH: Humans, biology, MESH: Alleles, MESH: Polymorphism, Single Nucleotide, MESH: Genomics, MESH: Genetic Predisposition to Disease, General Medicine, MESH: European Continental Ancestry Group, MESH: Haplotypes, Genomics, biology.organism_classification, 3. Good health, MESH: France, Phospholipases A2, Haplotypes, 030220 oncology & carcinogenesis, Lentivirus, Disease Progression, MESH: Disease Progression, France
Abstract: Members of the secreted phospholipase A2 (PLA2) protein family can inhibit HIV-1 virus replication in vitro. To evaluate the impact of PLA2 gene polymorphisms on AIDS disease development, we studied 12 family members using SNPlextrade mark technology that permitted simultaneous typing of 70 tagging Single Nucleotide Polymorphisms (tagSNPs). The study utilized HIV-1 seropositive donors with slow progressor (n=168) or rapid progressor (n=54) status, plus 355 control subjects. All donors were Caucasian (total 577 individuals). Genetic associations yielded mainly 0.01p0.05, but lower p-values were obtained for four tagSNPs and seven haplotype alleles. These stronger associations corresponded to both secreted (PLA2G2A, PLA2G2D and PLA2G3) and cytosolic (PLA2G4A and PLA2G6) PLA2 genes, including three (PLA2G2A, PLA2G2D and PLA2G4A) implicated in the pathogenesis of other diseases. Our results suggest that the PLA2 gene family may represent genes of interest for a larger study targeting all the known tagSNPs in the PLA2 genes. The data presented in this study will have to be confirmed in other AIDS cohorts and will also be useful for studies undertaken on the PLA2 gene family in other disease cohorts.
Published: 2007
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50. Newly identified loci that influence lipid concentrations and risk of coronary artery disease

Author: Richard N. Bergman, Derrick A Bennett, Cristen J. Willer, Richard M. Watanabe, Nicholas J. Timpson, Karen L. Mohlke, Robert Clarke, Francis S. Collins, Laura J. Scott, Antonio Cao, Angelo Scuteri, Alan R. Shuldiner, Antonella Mulas, G. Mark Lathrop, Andrea Maschio, Samer S. Najjar, Diana Zelenika, Serena Sanna, William L. Duren, Michael Boehnke, Jaakko Tuomilehto, Pilar Galan, James B. Strait, Heather M. Stringham, Debbie A Lawlor, Rory Collins, Ramaiah Nagaraja, Anne U. Jackson, Yun Li, Jouko Sundvall, Sarah Parish, Manuela Uda, George Davey-Smith, Giuseppe Albai, Paul Scheet, Shah Ebrahim, Haiqing Shen, David Schlessinger, Pierre Meneton, Lori L. Bonnycastle, Simon Heath, Gonçalo R. Abecasis, Mario A. Morken, Wei-Min Chen, Edward G. Lakatta, Amy J. Swift, Yoav Ben-Shlomo, Narisu Narisu, Fabio Busonero, and Serge Hercberg
Subjects: medicine.medical_specialty, Apolipoprotein B, Coronary Artery Disease, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Article, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Gene Frequency, Risk Factors, Internal medicine, Genetics, medicine, Humans, Computer Simulation, Allele frequency, Alleles, Triglycerides, 030304 developmental biology, Probability, 0303 health sciences, Likelihood Functions, biology, Cholesterol, Genome, Human, PCSK9, Haplotype, Cholesterol, HDL, Genetic Variation, Cholesterol, LDL, Lipids, Markov Chains, 3. Good health, Endocrinology, chemistry, Haplotypes, ABCA1, Case-Control Studies, LDL receptor, biology.protein, lipids (amino acids, peptides, and proteins), Lipoprotein
Abstract: To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.
Published: 2007

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