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Find video protocols related to scientific articles indexed in Pubmed.
Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs.
Mol. Syst. Biol.
PUBLISHED: 10-19-2014
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Most complex disease-associated genetic variants are located in non-coding regions and are therefore thought to be regulatory in nature. Association mapping of differential allelic expression (AE) is a powerful method to identify SNPs with direct cis-regulatory impact (cis-rSNPs). We used AE mapping to identify cis-rSNPs regulating gene expression in 55 and 63 HapMap lymphoblastoid cell lines from a Caucasian and an African population, respectively, 70 fibroblast cell lines, and 188 purified monocyte samples and found 40-60% of these cis-rSNPs to be shared across cell types. We uncover a new class of cis-rSNPs, which disrupt footprint-derived de novo motifs that are predominantly bound by repressive factors and are implicated in disease susceptibility through overlaps with GWAS SNPs. Finally, we provide the proof-of-principle for a new approach for genome-wide functional validation of transcription factor-SNP interactions. By perturbing NF?B action in lymphoblasts, we identified 489 cis-regulated transcripts with altered AE after NF?B perturbation. Altogether, we perform a comprehensive analysis of cis-variation in four cell populations and provide new tools for the identification of functional variants associated to complex diseases.
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Gray Platelet Syndrome: Pro-inflammatory megakaryocytes and ?-granule loss cause myelofibrosis and confer resistance to cancer metastasis in mice.
Blood
PUBLISHED: 09-27-2014
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NBEAL2 encodes a multidomain scaffolding protein with a putative role in granule ontogeny in human platelets. Mutations in NBEAL2 underlie Gray Platelet Syndrome (GPS), a rare inherited bleeding disorder characterized by a lack of ?-granules within blood platelets and progressive bone marrow fibrosis. We present here a novel Nbeal2(-/-) murine model of GPS and demonstrate that the lack of ?-granules is due to their loss from platelets/mature megakaryocytes, and not by initial impaired formation. We show that the lack of Nbeal2 confers a pro-inflammatory phenotype to the bone marrow megakaryocytes, which in combination with the loss of proteins from ?-granules drives the development of bone marrow fibrosis. In addition, we demonstrate that ?-granule deficiency impairs platelet function beyond their purely hemostatic role and that Nbeal2 deficiency has a protective effect against cancer metastasis.
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Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity.
Science
PUBLISHED: 09-27-2014
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Monocyte differentiation into macrophages represents a cornerstone process for host defense. Concomitantly, immunological imprinting of either tolerance or trained immunity determines the functional fate of macrophages and susceptibility to secondary infections. We characterized the transcriptomes and epigenomes in four primary cell types: monocytes and in vitro-differentiated naïve, tolerized, and trained macrophages. Inflammatory and metabolic pathways were modulated in macrophages, including decreased inflammasome activation, and we identified pathways functionally implicated in trained immunity. ?-glucan training elicits an exclusive epigenetic signature, revealing a complex network of enhancers and promoters. Analysis of transcription factor motifs in deoxyribonuclease I hypersensitive sites at cell-type-specific epigenetic loci unveiled differentiation and treatment-specific repertoires. Altogether, we provide a resource to understand the epigenetic changes that underlie innate immunity in humans.
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Transcriptional diversity during lineage commitment of human blood progenitors.
Science
PUBLISHED: 09-27-2014
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Blood cells derive from hematopoietic stem cells through stepwise fating events. To characterize gene expression programs driving lineage choice, we sequenced RNA from eight primary human hematopoietic progenitor populations representing the major myeloid commitment stages and the main lymphoid stage. We identified extensive cell type-specific expression changes: 6711 genes and 10,724 transcripts, enriched in non-protein-coding elements at early stages of differentiation. In addition, we found 7881 novel splice junctions and 2301 differentially used alternative splicing events, enriched in genes involved in regulatory processes. We demonstrated experimentally cell-specific isoform usage, identifying nuclear factor I/B (NFIB) as a regulator of megakaryocyte maturation-the platelet precursor. Our data highlight the complexity of fating events in closely related progenitor populations, the understanding of which is essential for the advancement of transplantation and regenerative medicine.
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Defining the role of common variation in the genomic and biological architecture of adult human height.
Andrew R Wood, Tonu Esko, Jian Yang, Sailaja Vedantam, Tune H Pers, Stefan Gustafsson, Audrey Y Chu, Karol Estrada, Jian'an Luan, Zoltan Kutalik, Najaf Amin, Martin L Buchkovich, Damien C Croteau-Chonka, Felix R Day, Yanan Duan, Tove Fall, Rudolf Fehrmann, Teresa Ferreira, Anne U Jackson, Juha Karjalainen, Ken Sin Lo, Adam E Locke, Reedik Mägi, Evelin Mihailov, Eleonora Porcu, Joshua C Randall, André Scherag, Anna A E Vinkhuyzen, Harm-Jan Westra, Thomas W Winkler, Tsegaselassie Workalemahu, Jing Hua Zhao, Devin Absher, Eva Albrecht, Denise Anderson, Jeffrey Baron, Marian Beekman, Ayse Demirkan, Georg B Ehret, Bjarke Feenstra, Mary F Feitosa, Krista Fischer, Ross M Fraser, Anuj Goel, Jian Gong, Anne E Justice, Stavroula Kanoni, Marcus E Kleber, Kati Kristiansson, Unhee Lim, Vaneet Lotay, Julian C Lui, Massimo Mangino, Irene Mateo Leach, Carolina Medina-Gomez, Michael A Nalls, Dale R Nyholt, Cameron D Palmer, Dorota Pasko, Sonali Pechlivanis, Inga Prokopenko, Janina S Ried, Stephan Ripke, Dmitry Shungin, Alena Stančáková, Rona J Strawbridge, Yun Ju Sung, Toshiko Tanaka, Alexander Teumer, Stella Trompet, Sander W van der Laan, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Zhaoming Wang, Loïc Yengo, Weihua Zhang, Uzma Afzal, Johan Arnlöv, Gillian M Arscott, Stefania Bandinelli, Amy Barrett, Claire Bellis, Amanda J Bennett, Christian Berne, Matthias Blüher, Jennifer L Bolton, Yvonne Böttcher, Heather A Boyd, Marcel Bruinenberg, Brendan M Buckley, Steven Buyske, Ida H Caspersen, Peter S Chines, Robert Clarke, Simone Claudi-Boehm, Matthew Cooper, E Warwick Daw, Pim A de Jong, Joris Deelen, Graciela Delgado, Josh C Denny, Rosalie Dhonukshe-Rutten, Maria Dimitriou, Alex S F Doney, Marcus Dörr, Niina Eklund, Elodie Eury, Lasse Folkersen, Melissa E Garcia, Frank Geller, Vilmantas Giedraitis, Alan S Go, Harald Grallert, Tanja B Grammer, Jürgen Gräßler, Henrik Grönberg, Lisette C P G M de Groot, Christopher J Groves, Jeffrey Haessler, Per Hall, Toomas Haller, Göran Hallmans, Anke Hannemann, Catharina A Hartman, Maija Hassinen, Caroline Hayward, Nancy L Heard-Costa, Quinta Helmer, Gibran Hemani, Anjali K Henders, Hans L Hillege, Mark A Hlatky, Wolfgang Hoffmann, Per Hoffmann, Oddgeir Holmen, Jeanine J Houwing-Duistermaat, Thomas Illig, Aaron Isaacs, Alan L James, Janina Jeff, Berit Johansen, Asa Johansson, Jennifer Jolley, Thorhildur Juliusdottir, Juhani Junttila, Abel N Kho, Leena Kinnunen, Norman Klopp, Thomas Kocher, Wolfgang Kratzer, Peter Lichtner, Lars Lind, Jaana Lindström, Stéphane Lobbens, Mattias Lorentzon, Yingchang Lu, Valeriya Lyssenko, Patrik K E Magnusson, Anubha Mahajan, Marc Maillard, Wendy L McArdle, Colin A McKenzie, Stela McLachlan, Paul J McLaren, Cristina Menni, Sigrun Merger, Lili Milani, Alireza Moayyeri, Keri L Monda, Mario A Morken, Gabriele Müller, Martina Müller-Nurasyid, Arthur W Musk, Narisu Narisu, Matthias Nauck, Ilja M Nolte, Markus M Nöthen, Laticia Oozageer, Stefan Pilz, Nigel W Rayner, Frida Renstrom, Neil R Robertson, Lynda M Rose, Ronan Roussel, Serena Sanna, Hubert Scharnagl, Salome Scholtens, Fredrick R Schumacher, Heribert Schunkert, Robert A Scott, Joban Sehmi, Thomas Seufferlein, Jianxin Shi, Karri Silventoinen, Johannes H Smit, Albert Vernon Smith, Joanna Smolonska, Alice V Stanton, Kathleen Stirrups, David J Stott, Heather M Stringham, Johan Sundström, Morris A Swertz, Ann-Christine Syvänen, Bamidele O Tayo, Gudmar Thorleifsson, Jonathan P Tyrer, Suzanne van Dijk, Natasja M van Schoor, Nathalie van der Velde, Diana van Heemst, Floor V A van Oort, Sita H Vermeulen, Niek Verweij, Judith M Vonk, Lindsay L Waite, Melanie Waldenberger, Roman Wennauer, Lynne R Wilkens, Christina Willenborg, Tom Wilsgaard, Mary K Wojczynski, Andrew Wong, Alan F Wright, Qunyuan Zhang, Dominique Arveiler, Stephan J L Bakker, John Beilby, Richard N Bergman, Sven Bergmann, Reiner Biffar, John Blangero, Dorret I Boomsma, Stefan R Bornstein, Pascal Bovet, Paolo Brambilla, Morris J Brown, Harry Campbell, Mark J Caulfield, Aravinda Chakravarti, Rory Collins, Francis S Collins, Dana C Crawford, L Adrienne Cupples, John Danesh, Ulf de Faire, Hester M den Ruijter, Raimund Erbel, Jeanette Erdmann, Johan G Eriksson, Martin Farrall, Ele Ferrannini, Jean Ferrières, Ian Ford, Nita G Forouhi, Terrence Forrester, Ron T Gansevoort, Pablo V Gejman, Christian Gieger, Alain Golay, Omri Gottesman, Vilmundur Gudnason, Ulf Gyllensten, David W Haas, Alistair S Hall, Tamara B Harris, Andrew T Hattersley, Andrew C Heath, Christian Hengstenberg, Andrew A Hicks, Lucia A Hindorff, Aroon D Hingorani, Albert Hofman, G Kees Hovingh, Steve E Humphries, Steven C Hunt, Elina Hyppönen, Kevin B Jacobs, Marjo-Riitta Järvelin, Pekka Jousilahti, Antti M Jula, Jaakko Kaprio, John J P Kastelein, Manfred Kayser, Frank Kee, Sirkka M Keinanen-Kiukaanniemi, Lambertus A Kiemeney, Jaspal S Kooner, Charles Kooperberg, Seppo Koskinen, Peter Kovacs, Aldi T Kraja, Meena Kumari, Johanna Kuusisto, Timo A Lakka, Claudia Langenberg, Loic Le Marchand, Terho Lehtimäki, Sara Lupoli, Pamela A F Madden, Satu Mannisto, Paolo Manunta, André Marette, Tara C Matise, Barbara McKnight, Thomas Meitinger, Frans L Moll, Grant W Montgomery, Andrew D Morris, Andrew P Morris, Jeffrey C Murray, Mari Nelis, Claes Ohlsson, Albertine J Oldehinkel, Ken K Ong, Willem H Ouwehand, Gerard Pasterkamp, Annette Peters, Peter P Pramstaller, Jackie F Price, Lu Qi, Olli T Raitakari, Tuomo Rankinen, D C Rao, Treva K Rice, Marylyn Ritchie, Igor Rudan, Veikko Salomaa, Nilesh J Samani, Jouko Saramies, Mark A Sarzynski, Peter E H Schwarz, Sylvain Sebert, Peter Sever, Alan R Shuldiner, Juha Sinisalo, Valgerdur Steinthorsdottir, Ronald P Stolk, Jean-Claude Tardif, Anke Tönjes, Angelo Tremblay, Elena Tremoli, Jarmo Virtamo, Marie-Claude Vohl, , Philippe Amouyel, Folkert W Asselbergs, Themistocles L Assimes, Murielle Bochud, Bernhard O Boehm, Eric Boerwinkle, Erwin P Bottinger, Claude Bouchard, Stéphane Cauchi, John C Chambers, Stephen J Chanock, Richard S Cooper, Paul I W de Bakker, George Dedoussis, Luigi Ferrucci, Paul W Franks, Philippe Froguel, Leif C Groop, Christopher A Haiman, Anders Hamsten, M Geoffrey Hayes, Jennie Hui, David J Hunter, Kristian Hveem, J Wouter Jukema, Robert C Kaplan, Mika Kivimäki, Diana Kuh, Markku Laakso, Yongmei Liu, Nicholas G Martin, Winfried März, Mads Melbye, Susanne Moebus, Patricia B Munroe, Inger Njølstad, Ben A Oostra, Colin N A Palmer, Nancy L Pedersen, Markus Perola, Louis Pérusse, Ulrike Peters, Joseph E Powell, Chris Power, Thomas Quertermous, Rainer Rauramaa, Eva Reinmaa, Paul M Ridker, Fernando Rivadeneira, Jerome I Rotter, Timo E Saaristo, Danish Saleheen, David Schlessinger, P Eline Slagboom, Harold Snieder, Tim D Spector, Konstantin Strauch, Michael Stumvoll, Jaakko Tuomilehto, Matti Uusitupa, Pim van der Harst, Henry Völzke, Mark Walker, Nicholas J Wareham, Hugh Watkins, H-Erich Wichmann, James F Wilson, Pieter Zanen, Panos Deloukas, Iris M Heid, Cecilia M Lindgren, Karen L Mohlke, Elizabeth K Speliotes, Unnur Thorsteinsdottir, Inês Barroso, Caroline S Fox, Kari E North, David P Strachan, Jacques S Beckmann, Sonja I Berndt, Michael Boehnke, Ingrid B Borecki, Mark I McCarthy, Andres Metspalu, Kari Stefansson, André G Uitterlinden, Cornelia M van Duijn, Lude Franke, Cristen J Willer, Alkes L Price, Guillaume Lettre, Ruth J F Loos, Michael N Weedon, Erik Ingelsson, Jeffrey R O'Connell, Gonçalo R Abecasis, Daniel I Chasman, Michael E Goddard, Peter M Visscher, Joel N Hirschhorn, Timothy M Frayling.
Nat. Genet.
PUBLISHED: 08-29-2014
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Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ?2,000, ?3,700 and ?9,500 SNPs explained ?21%, ?24% and ?29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/?-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
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A loss of function screen of identified genome-wide association study Loci reveals new genes controlling hematopoiesis.
PLoS Genet.
PUBLISHED: 07-01-2014
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The formation of mature cells by blood stem cells is very well understood at the cellular level and we know many of the key transcription factors that control fate decisions. However, many upstream signalling and downstream effector processes are only partially understood. Genome wide association studies (GWAS) have been particularly useful in providing new directions to dissect these pathways. A GWAS meta-analysis identified 68 genetic loci controlling platelet size and number. Only a quarter of those genes, however, are known regulators of hematopoiesis. To determine function of the remaining genes we performed a medium-throughput genetic screen in zebrafish using antisense morpholino oligonucleotides (MOs) to knock down protein expression, followed by histological analysis of selected genes using a wide panel of different hematopoietic markers. The information generated by the initial knockdown was used to profile phenotypes and to position candidate genes hierarchically in hematopoiesis. Further analysis of brd3a revealed its essential role in differentiation but not maintenance and survival of thrombocytes. Using the from-GWAS-to-function strategy we have not only identified a series of genes that represent novel regulators of thrombopoiesis and hematopoiesis, but this work also represents, to our knowledge, the first example of a functional genetic screening strategy that is a critical step toward obtaining biologically relevant functional data from GWA study for blood cell traits.
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The INTERVAL trial to determine whether intervals between blood donations can be safely and acceptably decreased to optimise blood supply: study protocol for a randomised controlled trial.
Trials
PUBLISHED: 06-10-2014
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Ageing populations may demand more blood transfusions, but the blood supply could be limited by difficulties in attracting and retaining a decreasing pool of younger donors. One approach to increase blood supply is to collect blood more frequently from existing donors. If more donations could be safely collected in this manner at marginal cost, then it would be of considerable benefit to blood services. National Health Service (NHS) Blood and Transplant in England currently allows men to donate up to every 12 weeks and women to donate up to every 16 weeks. In contrast, some other European countries allow donations as frequently as every 8 weeks for men and every 10 weeks for women. The primary aim of the INTERVAL trial is to determine whether donation intervals can be safely and acceptably decreased to optimise blood supply whilst maintaining the health of donors.
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Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis.
Nat Commun
PUBLISHED: 05-01-2014
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Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (P<5 × 10(-8)) loci, some including known iron-related genes (HFE, SLC40A1, TF, TFR2, TFRC, TMPRSS6) and others novel (ABO, ARNTL, FADS2, NAT2, TEX14). SNPs at ARNTL, TF, and TFR2 affect iron markers in HFE C282Y homozygotes at risk for hemochromatosis. There is substantial overlap between our iron loci and loci affecting erythrocyte and lipid phenotypes. These results will facilitate investigation of the roles of iron in disease.
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DNA methylation and body-mass index: a genome-wide analysis.
Lancet
PUBLISHED: 03-13-2014
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Obesity is a major health problem that is determined by interactions between lifestyle and environmental and genetic factors. Although associations between several genetic variants and body-mass index (BMI) have been identified, little is known about epigenetic changes related to BMI. We undertook a genome-wide analysis of methylation at CpG sites in relation to BMI.
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Single nucleotide polymorphisms with cis-regulatory effects on long non-coding transcripts in human primary monocytes.
PLoS ONE
PUBLISHED: 01-01-2014
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We applied genome-wide allele-specific expression analysis of monocytes from 188 samples. Monocytes were purified from white blood cells of healthy blood donors to detect cis-acting genetic variation that regulates the expression of long non-coding RNAs. We analysed 8929 regions harboring genes for potential long non-coding RNA that were retrieved from data from the ENCODE project. Of these regions, 60% were annotated as intergenic, which implies that they do not overlap with protein-coding genes. Focusing on the intergenic regions, and using stringent analysis of the allele-specific expression data, we detected robust cis-regulatory SNPs in 258 out of 489 informative intergenic regions included in the analysis. The cis-regulatory SNPs that were significantly associated with allele-specific expression of long non-coding RNAs were enriched to enhancer regions marked for active or bivalent, poised chromatin by histone modifications. Out of the lncRNA regions regulated by cis-acting regulatory SNPs, 20% (n?=?52) were co-regulated with the closest protein coding gene. We compared the identified cis-regulatory SNPs with those in the catalog of SNPs identified by genome-wide association studies of human diseases and traits. This comparison identified 32 SNPs in loci from genome-wide association studies that displayed a strong association signal with allele-specific expression of non-coding RNAs in monocytes, with p-values ranging from 6.7×10(-7) to 9.5×10(-89). The identified cis-regulatory SNPs are associated with diseases of the immune system, like multiple sclerosis and rheumatoid arthritis.
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Mutation in KERA identified by linkage analysis and targeted resequencing in a pedigree with premature atherosclerosis.
PLoS ONE
PUBLISHED: 01-01-2014
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Genetic factors explain a proportion of the inter-individual variation in the risk for atherosclerotic events, but the genetic basis of atherosclerosis and atherothrombosis in families with Mendelian forms of premature atherosclerosis is incompletely understood. We set out to unravel the molecular pathology in a large kindred with an autosomal dominant inherited form of premature atherosclerosis.
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Single nucleotide variants in the protein C pathway and mortality in dialysis patients.
PLoS ONE
PUBLISHED: 01-01-2014
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The protein C pathway plays an important role in the maintenance of endothelial barrier function and in the inflammatory and coagulant processes that are characteristic of patients on dialysis. We investigated whether common single nucleotide variants (SNV) in genes encoding protein C pathway components were associated with all-cause 5 years mortality risk in dialysis patients.
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The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data.
Nucleic Acids Res.
PUBLISHED: 11-11-2013
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The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online.
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Expression of a single-chain human leukocyte antigen-DRA/DRB3*01:01 molecule and differential binding of a monoclonal antibody in the presence of specifically bound human platelet antigen-1a peptide.
Transfusion
PUBLISHED: 05-31-2013
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Studies show that 1 in 1200 neonates have a low platelet (PLT) count due to alloimmunization against human PLT antigen (HPA)-1a (?3 -L33). This mainly occurs in HPA-1a-negative mothers who are positive for the human leukocyte antigen (HLA)-DRB3*01:01 allele, but only about one-third of cases will mount an effective alloimmune response. The development of specific treatment modalities requires that the mechanisms driving the maternal alloimmune response against the fetal PLTs be further explored. An antibody reagent that has a different binding affinity to HLA-DRA/DRB3*01:01 with and without the ?3 -L33 peptide would be a valuable reagent to study peptide presentation on maternal antigen-presenting cells.
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Recombinant HPA-1a antibody therapy for treatment of fetomaternal alloimmune thrombocytopenia: proof of principle in human volunteers.
Blood
PUBLISHED: 05-08-2013
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Fetomaternal alloimmune thrombocytopenia, caused by the maternal generation of antibodies against fetal human platelet antigen-1a (HPA-1a), can result in intracranial hemorrhage and intrauterine death. We have developed a therapeutic human recombinant high-affinity HPA-1a antibody (B2G1?nab) that competes for binding to the HPA-1a epitope but carries a modified constant region that does not bind to Fc? receptors. In vitro studies with a range of clinical anti-HPA-1a sera have shown that B2G1?nab blocks monocyte chemiluminescence by >75%. In this first-in-man study, we demonstrate that HPA-1a1b autologous platelets (matching fetal phenotype) sensitized with B2G1?nab have the same intravascular survival as unsensitized platelets (190 hours), while platelets sensitized with a destructive immunoglobulin G1 version of the antibody (B2G1) are cleared from the circulation in 2 hours. Mimicking the situation in fetuses receiving B2G1?nab as therapy, we show that platelets sensitized with a combination of B2G1 (representing destructive HPA-1a antibody) and B2G1?nab survive 3 times as long in circulation compared with platelets sensitized with B2G1 alone. This confirms the therapeutic potential of B2G1?nab. The efficient clearance of platelets sensitized with B2G1 also opens up the opportunity to carry out studies of prophylaxis to prevent alloimmunization in HPA-1a-negative mothers.
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Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci.
Genome Res.
PUBLISHED: 04-09-2013
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Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits.
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Identification of seven loci affecting mean telomere length and their association with disease.
Veryan Codd, Christopher P Nelson, Eva Albrecht, Massimo Mangino, Joris Deelen, Jessica L Buxton, Jouke Jan Hottenga, Krista Fischer, Tonu Esko, Ida Surakka, Linda Broer, Dale R Nyholt, Irene Mateo Leach, Perttu Salo, Sara Hägg, Mary K Matthews, Jutta Palmen, Giuseppe D Norata, Paul F O'Reilly, Danish Saleheen, Najaf Amin, Anthony J Balmforth, Marian Beekman, Rudolf A de Boer, Stefan Böhringer, Peter S Braund, Paul R Burton, Anton J M de Craen, Matthew Denniff, Yanbin Dong, Konstantinos Douroudis, Elena Dubinina, Johan G Eriksson, Katia Garlaschelli, Dehuang Guo, Anna-Liisa Hartikainen, Anjali K Henders, Jeanine J Houwing-Duistermaat, Laura Kananen, Lennart C Karssen, Johannes Kettunen, Norman Klopp, Vasiliki Lagou, Elisabeth M van Leeuwen, Pamela A Madden, Reedik Mägi, Patrik K E Magnusson, Satu Mannisto, Mark I McCarthy, Sarah E Medland, Evelin Mihailov, Grant W Montgomery, Ben A Oostra, Aarno Palotie, Annette Peters, Helen Pollard, Anneli Pouta, Inga Prokopenko, Samuli Ripatti, Veikko Salomaa, H Eka D Suchiman, Ana M Valdes, Niek Verweij, Ana Viñuela, Xiaoling Wang, H-Erich Wichmann, Elisabeth Widén, Gonneke Willemsen, Margaret J Wright, Kai Xia, Xiangjun Xiao, Dirk J van Veldhuisen, Alberico L Catapano, Martin D Tobin, Alistair S Hall, Alexandra I F Blakemore, Wiek H van Gilst, Haidong Zhu, Cardiogram Consortium, Jeanette Erdmann, Muredach P Reilly, Sekar Kathiresan, Heribert Schunkert, Philippa J Talmud, Nancy L Pedersen, Markus Perola, Willem Ouwehand, Jaakko Kaprio, Nicholas G Martin, Cornelia M van Duijn, Iiris Hovatta, Christian Gieger, Andres Metspalu, Dorret I Boomsma, Marjo-Riitta Järvelin, P Eline Slagboom, John R Thompson, Tim D Spector, Pim van der Harst, Nilesh J Samani.
Nat. Genet.
PUBLISHED: 03-29-2013
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Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.
Sonja I Berndt, Stefan Gustafsson, Reedik Mägi, Andrea Ganna, Eleanor Wheeler, Mary F Feitosa, Anne E Justice, Keri L Monda, Damien C Croteau-Chonka, Felix R Day, Tonu Esko, Tove Fall, Teresa Ferreira, Davide Gentilini, Anne U Jackson, Jian'an Luan, Joshua C Randall, Sailaja Vedantam, Cristen J Willer, Thomas W Winkler, Andrew R Wood, Tsegaselassie Workalemahu, Yi-Juan Hu, Sang Hong Lee, Liming Liang, Dan-Yu Lin, Josine L Min, Benjamin M Neale, Gudmar Thorleifsson, Jian Yang, Eva Albrecht, Najaf Amin, Jennifer L Bragg-Gresham, Gemma Cadby, Martin den Heijer, Niina Eklund, Krista Fischer, Anuj Goel, Jouke-Jan Hottenga, Jennifer E Huffman, Ivonne Jarick, Asa Johansson, Toby Johnson, Stavroula Kanoni, Marcus E Kleber, Inke R König, Kati Kristiansson, Zoltan Kutalik, Claudia Lamina, Cécile Lecoeur, Guo Li, Massimo Mangino, Wendy L McArdle, Carolina Medina-Gomez, Martina Müller-Nurasyid, Julius S Ngwa, Ilja M Nolte, Lavinia Paternoster, Sonali Pechlivanis, Markus Perola, Marjolein J Peters, Michael Preuss, Lynda M Rose, Jianxin Shi, Dmitry Shungin, Albert Vernon Smith, Rona J Strawbridge, Ida Surakka, Alexander Teumer, Mieke D Trip, Jonathan Tyrer, Jana V van Vliet-Ostaptchouk, Liesbeth Vandenput, Lindsay L Waite, Jing Hua Zhao, Devin Absher, Folkert W Asselbergs, Mustafa Atalay, Antony P Attwood, Anthony J Balmforth, Hanneke Basart, John Beilby, Lori L Bonnycastle, Paolo Brambilla, Marcel Bruinenberg, Harry Campbell, Daniel I Chasman, Peter S Chines, Francis S Collins, John M Connell, William O Cookson, Ulf de Faire, Femmie de Vegt, Mariano Dei, Maria Dimitriou, Sarah Edkins, Karol Estrada, David M Evans, Martin Farrall, Marco M Ferrario, Jean Ferrières, Lude Franke, Francesca Frau, Pablo V Gejman, Harald Grallert, Henrik Grönberg, Vilmundur Gudnason, Alistair S Hall, Per Hall, Anna-Liisa Hartikainen, Caroline Hayward, Nancy L Heard-Costa, Andrew C Heath, Johannes Hebebrand, Georg Homuth, Frank B Hu, Sarah E Hunt, Elina Hyppönen, Carlos Iribarren, Kevin B Jacobs, John-Olov Jansson, Antti Jula, Mika Kähönen, Sekar Kathiresan, Frank Kee, Kay-Tee Khaw, Mika Kivimäki, Wolfgang Koenig, Aldi T Kraja, Meena Kumari, Kari Kuulasmaa, Johanna Kuusisto, Jaana H Laitinen, Timo A Lakka, Claudia Langenberg, Lenore J Launer, Lars Lind, Jaana Lindström, Jianjun Liu, Antonio Liuzzi, Marja-Liisa Lokki, Mattias Lorentzon, Pamela A Madden, Patrik K Magnusson, Paolo Manunta, Diana Marek, Winfried März, Irene Mateo Leach, Barbara McKnight, Sarah E Medland, Evelin Mihailov, Lili Milani, Grant W Montgomery, Vincent Mooser, Thomas W Mühleisen, Patricia B Munroe, Arthur W Musk, Narisu Narisu, Gerjan Navis, George Nicholson, Ellen A Nohr, Ken K Ong, Ben A Oostra, Colin N A Palmer, Aarno Palotie, John F Peden, Nancy Pedersen, Annette Peters, Ozren Polašek, Anneli Pouta, Peter P Pramstaller, Inga Prokopenko, Carolin Pütter, Aparna Radhakrishnan, Olli Raitakari, Augusto Rendon, Fernando Rivadeneira, Igor Rudan, Timo E Saaristo, Jennifer G Sambrook, Alan R Sanders, Serena Sanna, Jouko Saramies, Sabine Schipf, Stefan Schreiber, Heribert Schunkert, So-Youn Shin, Stefano Signorini, Juha Sinisalo, Boris Skrobek, Nicole Soranzo, Alena Stančáková, Klaus Stark, Jonathan C Stephens, Kathleen Stirrups, Ronald P Stolk, Michael Stumvoll, Amy J Swift, Eirini V Theodoraki, Barbara Thorand, David-Alexandre Trégouët, Elena Tremoli, Melanie M van der Klauw, Joyce B J van Meurs, Sita H Vermeulen, Jorma Viikari, Jarmo Virtamo, Veronique Vitart, Gérard Waeber, Zhaoming Wang, Elisabeth Widén, Sarah H Wild, Gonneke Willemsen, Bernhard R Winkelmann, Jacqueline C M Witteman, Bruce H R Wolffenbuttel, Andrew Wong, Alan F Wright, M Carola Zillikens, Philippe Amouyel, Bernhard O Boehm, Eric Boerwinkle, Dorret I Boomsma, Mark J Caulfield, Stephen J Chanock, L Adrienne Cupples, Daniele Cusi, George V Dedoussis, Jeanette Erdmann, Johan G Eriksson, Paul W Franks, Philippe Froguel, Christian Gieger, Ulf Gyllensten, Anders Hamsten, Tamara B Harris, Christian Hengstenberg, Andrew A Hicks, Aroon Hingorani, Anke Hinney, Albert Hofman, Kees G Hovingh, Kristian Hveem, Thomas Illig, Marjo-Riitta Järvelin, Karl-Heinz Jöckel, Sirkka M Keinanen-Kiukaanniemi, Lambertus A Kiemeney, Diana Kuh, Markku Laakso, Terho Lehtimäki, Douglas F Levinson, Nicholas G Martin, Andres Metspalu, Andrew D Morris, Markku S Nieminen, Inger Njølstad, Claes Ohlsson, Albertine J Oldehinkel, Willem H Ouwehand, Lyle J Palmer, Brenda Penninx, Chris Power, Michael A Province, Bruce M Psaty, Lu Qi, Rainer Rauramaa, Paul M Ridker, Samuli Ripatti, Veikko Salomaa, Nilesh J Samani, Harold Snieder, Thorkild I A Sørensen, Timothy D Spector, Kari Stefansson, Anke Tönjes, Jaakko Tuomilehto, André G Uitterlinden, Matti Uusitupa, Pim van der Harst, Peter Vollenweider, Henri Wallaschofski, Nicholas J Wareham, Hugh Watkins, H-Erich Wichmann, James F Wilson, Gonçalo R Abecasis, Themistocles L Assimes, Inês Barroso, Michael Boehnke, Ingrid B Borecki, Panos Deloukas, Caroline S Fox, Timothy Frayling, Leif C Groop, Talin Haritunian, Iris M Heid, David Hunter, Robert C Kaplan, Fredrik Karpe, Miriam F Moffatt, Karen L Mohlke, Jeffrey R O'Connell, Yudi Pawitan, Eric E Schadt, David Schlessinger, Valgerdur Steinthorsdottir, David P Strachan, Unnur Thorsteinsdottir, Cornelia M van Duijn, Peter M Visscher, Anna Maria Di Blasio, Joel N Hirschhorn, Cecilia M Lindgren, Andrew P Morris, David Meyre, André Scherag, Mark I McCarthy, Elizabeth K Speliotes, Kari E North, Ruth J F Loos, Erik Ingelsson.
Nat. Genet.
PUBLISHED: 03-14-2013
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Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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SMIM1 underlies the Vel blood group and influences red blood cell traits.
Nat. Genet.
PUBLISHED: 03-08-2013
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The blood group Vel was discovered 60 years ago, but the underlying gene is unknown. Individuals negative for the Vel antigen are rare and are required for the safe transfusion of patients with antibodies to Vel. To identify the responsible gene, we sequenced the exomes of five individuals negative for the Vel antigen and found that four were homozygous and one was heterozygous for a low-frequency 17-nucleotide frameshift deletion in the gene encoding the 78-amino-acid transmembrane protein SMIM1. A follow-up study showing that 59 of 64 Vel-negative individuals were homozygous for the same deletion and expression of the Vel antigen on SMIM1-transfected cells confirm SMIM1 as the gene underlying the Vel blood group. An expression quantitative trait locus (eQTL), the common SNP rs1175550 contributes to variable expression of the Vel antigen (P = 0.003) and influences the mean hemoglobin concentration of red blood cells (RBCs; P = 8.6 × 10(-15)). In vivo, zebrafish with smim1 knockdown showed a mild reduction in the number of RBCs, identifying SMIM1 as a new regulator of RBC formation. Our findings are of immediate relevance, as the homozygous presence of the deletion allows the unequivocal identification of Vel-negative blood donors.
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New insights into the genetic basis of TAR (thrombocytopenia-absent radii) syndrome.
Curr. Opin. Genet. Dev.
PUBLISHED: 02-15-2013
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Thrombocytopenia with absent radii (TAR) syndrome is a rare disorder combining specific skeletal abnormalities with a reduced platelet count. Rare proximal microdeletions of 1q21.1 are found in the majority of patients but are also found in unaffected parents. Recently it was shown that TAR syndrome is caused by the compound inheritance of a low-frequency noncoding SNP and a rare null allele in RBM8A, a gene encoding the exon-junction complex subunit member Y14 located in the deleted region. This finding provides new insight into the complex inheritance pattern and new clues to the molecular mechanisms underlying TAR syndrome. We discuss TAR syndrome in the context of abnormal phenotypes associated with proximal and distal 1q21.1 microdeletion and microduplications with incomplete penetrance and variable expressivity.
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Common genetic variants do not associate with CAD in familial hypercholesterolemia.
Eur. J. Hum. Genet.
PUBLISHED: 02-11-2013
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In recent years, multiple loci dispersed on the genome have been shown to be associated with coronary artery disease (CAD). We investigated whether these common genetic variants also hold value for CAD prediction in a large cohort of patients with familial hypercholesterolemia (FH). We genotyped a total of 41 single-nucleotide polymorphisms (SNPs) in 1701 FH patients, of whom 482 patients (28.3%) had at least one coronary event during an average follow up of 66 years. The association of each SNP with event-free survival time was calculated with a Cox proportional hazard model. In the cardiovascular disease risk factor adjusted analysis, the most significant SNP was rs1122608:G>T in the SMARCA4 gene near the LDL-receptor (LDLR) gene, with a hazard ratio for CAD risk of 0.74 (95% CI 0.49-0.99; P-value 0.021). However, none of the SNPs reached the Bonferroni threshold. Of all the known CAD loci analyzed, the SMARCA4 locus near the LDLR had the strongest negative association with CAD in this high-risk FH cohort. The effect is contrary to what was expected. None of the other loci showed association with CAD.European Journal of Human Genetics advance online publication, 13 November 2013; doi:10.1038/ejhg.2013.242.
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Genome-wide haplotype analysis of cis expression quantitative trait loci in monocytes.
PLoS Genet.
PUBLISHED: 01-31-2013
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In order to assess whether gene expression variability could be influenced by several SNPs acting in cis, either through additive or more complex haplotype effects, a systematic genome-wide search for cis haplotype expression quantitative trait loci (eQTL) was conducted in a sample of 758 individuals, part of the Cardiogenics Transcriptomic Study, for which genome-wide monocyte expression and GWAS data were available. 19,805 RNA probes were assessed for cis haplotypic regulation through investigation of ~2,1 × 10(9) haplotypic combinations. 2,650 probes demonstrated haplotypic p-values >10(4)-fold smaller than the best single SNP p-value. Replication of significant haplotype effects were tested for 412 probes for which SNPs (or proxies) that defined the detected haplotypes were available in the Gutenberg Health Study composed of 1,374 individuals. At the Bonferroni correction level of 1.2 × 10(-4) (~0.05/412), 193 haplotypic signals replicated. 1000 G imputation was then conducted, and 105 haplotypic signals still remained more informative than imputed SNPs. In-depth analysis of these 105 cis eQTL revealed that at 76 loci genetic associations were compatible with additive effects of several SNPs, while for the 29 remaining regions data could be compatible with a more complex haplotypic pattern. As 24 of the 105 cis eQTL have previously been reported to be disease-associated loci, this work highlights the need for conducting haplotype-based and 1000 G imputed cis eQTL analysis before commencing functional studies at disease-associated loci.
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Loci influencing blood pressure identified using a cardiovascular gene-centric array.
Santhi K Ganesh, Vinicius Tragante, Wei Guo, Yiran Guo, Matthew B Lanktree, Erin N Smith, Toby Johnson, Berta Almoguera Castillo, John Barnard, Jens Baumert, Yen-Pei Christy Chang, Clara C Elbers, Martin Farrall, Mary E Fischer, Nora Franceschini, Tom R Gaunt, Johannes M I H Gho, Christian Gieger, Yan Gong, Aaron Isaacs, Marcus E Kleber, Irene Mateo Leach, Caitrin W McDonough, Matthijs F L Meijs, Olle Mellander, Cliona M Molony, Ilja M Nolte, Sandosh Padmanabhan, Tom S Price, Ramakrishnan Rajagopalan, Jonathan Shaffer, Sonia Shah, Haiqing Shen, Nicole Soranzo, Peter J van der Most, Erik P A van Iperen, Jessica van Setten, Jessic A Van Setten, Judith M Vonk, Li Zhang, Amber L Beitelshees, Gerald S Berenson, Deepak L Bhatt, Jolanda M A Boer, Eric Boerwinkle, Ben Burkley, Amber Burt, Aravinda Chakravarti, Wei Chen, Rhonda M Cooper-DeHoff, Sean P Curtis, Albert Dreisbach, David Duggan, Georg B Ehret, Richard R Fabsitz, Myriam Fornage, Ervin Fox, Clement E Furlong, Ron T Gansevoort, Marten H Hofker, G Kees Hovingh, Susan A Kirkland, Kandice Kottke-Marchant, Abdullah Kutlar, Andrea Z LaCroix, Taimour Y Langaee, Yun R Li, Honghuang Lin, Kiang Liu, Steffi Maiwald, Rainer Malik, , Gurunathan Murugesan, Christopher Newton-Cheh, Jeffery R O'Connell, N Charlotte Onland-Moret, Willem H Ouwehand, Walter Palmas, Brenda W Penninx, Carl J Pepine, Mary Pettinger, Joseph F Polak, Vasan S Ramachandran, Jane Ranchalis, Susan Redline, Paul M Ridker, Lynda M Rose, Hubert Scharnag, Nicholas J Schork, Daichi Shimbo, Alan R Shuldiner, Sathanur R Srinivasan, Ronald P Stolk, Herman A Taylor, Barbara Thorand, Mieke D Trip, Cornelia M van Duijn, W Monique Verschuren, Cisca Wijmenga, Bernhard R Winkelmann, Sharon Wyatt, J Hunter Young, Bernhard O Boehm, Mark J Caulfield, Daniel I Chasman, Karina W Davidson, Pieter A Doevendans, Garret A FitzGerald, John G Gums, Hakon Hakonarson, Hans L Hillege, Thomas Illig, Gail P Jarvik, Julie A Johnson, John J P Kastelein, Wolfgang Koenig, Winfried März, Braxton D Mitchell, Sarah S Murray, Albertine J Oldehinkel, Daniel J Rader, Muredach P Reilly, Alex P Reiner, Eric E Schadt, Roy L Silverstein, Harold Snieder, Alice V Stanton, André G Uitterlinden, Pim van der Harst, Yvonne T van der Schouw, Nilesh J Samani, Andrew D Johnson, Patricia B Munroe, Paul I W de Bakker, Xiaofeng Zhu, Daniel Levy, Brendan J Keating, Folkert W Asselbergs.
Hum. Mol. Genet.
PUBLISHED: 01-08-2013
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Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ?50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ?2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
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New gene functions in megakaryopoiesis and platelet formation.
Christian Gieger, Aparna Radhakrishnan, Ana Cvejic, Weihong Tang, Eleonora Porcu, Giorgio Pistis, Jovana Serbanovic-Canic, Ulrich Elling, Alison H Goodall, Yann Labrune, Lorna M Lopez, Reedik Mägi, Stuart Meacham, Yukinori Okada, Nicola Pirastu, Rossella Sorice, Alexander Teumer, Katrin Voss, Weihua Zhang, Ramiro Ramirez-Solis, Joshua C Bis, David Ellinghaus, Martin Gögele, Jouke-Jan Hottenga, Claudia Langenberg, Peter Kovacs, Paul F O'Reilly, So-Youn Shin, Tonu Esko, Jaana Hartiala, Stavroula Kanoni, Federico Murgia, Afshin Parsa, Jonathan Stephens, Pim van der Harst, C Ellen van der Schoot, Hooman Allayee, Antony Attwood, Beverley Balkau, François Bastardot, Saonli Basu, Sebastian E Baumeister, Ginevra Biino, Lorenzo Bomba, Amélie Bonnefond, Francois Cambien, John C Chambers, Francesco Cucca, Pio D'Adamo, Gail Davies, Rudolf A de Boer, Eco J C de Geus, Angela Döring, Paul Elliott, Jeanette Erdmann, David M Evans, Mario Falchi, Wei Feng, Aaron R Folsom, Ian H Frazer, Quince D Gibson, Nicole L Glazer, Chris Hammond, Anna-Liisa Hartikainen, Susan R Heckbert, Christian Hengstenberg, Micha Hersch, Thomas Illig, Ruth J F Loos, Jennifer Jolley, Kay Tee Khaw, Brigitte Kühnel, Marie-Christine Kyrtsonis, Vasiliki Lagou, Heather Lloyd-Jones, Thomas Lumley, Massimo Mangino, Andrea Maschio, Irene Mateo Leach, Barbara McKnight, Yasin Memari, Braxton D Mitchell, Grant W Montgomery, Yusuke Nakamura, Matthias Nauck, Gerjan Navis, Ute Nöthlings, Ilja M Nolte, David J Porteous, Anneli Pouta, Peter P Pramstaller, Janne Pullat, Susan M Ring, Jerome I Rotter, Daniela Ruggiero, Aimo Ruokonen, Cinzia Sala, Nilesh J Samani, Jennifer Sambrook, David Schlessinger, Stefan Schreiber, Heribert Schunkert, James Scott, Nicholas L Smith, Harold Snieder, John M Starr, Michael Stumvoll, Atsushi Takahashi, W H Wilson Tang, Kent Taylor, Albert Tenesa, Swee Lay Thein, Anke Tönjes, Manuela Uda, Sheila Ulivi, Dirk J van Veldhuisen, Peter M Visscher, Uwe Völker, H-Erich Wichmann, Kerri L Wiggins, Gonneke Willemsen, Tsun-Po Yang, Jing Hua Zhao, Paavo Zitting, John R Bradley, George V Dedoussis, Paolo Gasparini, Stanley L Hazen, Andres Metspalu, Mario Pirastu, Alan R Shuldiner, L Joost van Pelt, Jaap-Jan Zwaginga, Dorret I Boomsma, Ian J Deary, Andre Franke, Philippe Froguel, Santhi K Ganesh, Marjo-Riitta Järvelin, Nicholas G Martin, Christa Meisinger, Bruce M Psaty, Timothy D Spector, Nicholas J Wareham, Jan-Willem N Akkerman, Marina Ciullo, Panos Deloukas, Andreas Greinacher, Steve Jupe, Naoyuki Kamatani, Jyoti Khadake, Jaspal S Kooner, Josef Penninger, Inga Prokopenko, Derek Stemple, Daniela Toniolo, Lorenz Wernisch, Serena Sanna, Andrew A Hicks, Augusto Rendon, Manuel A Ferreira, Willem H Ouwehand, Nicole Soranzo.
Nature
PUBLISHED: 10-21-2011
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Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.
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Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene.
Hum. Mol. Genet.
PUBLISHED: 10-11-2011
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The chromosome 16p13 region has been associated with several autoimmune diseases, including type 1 diabetes (T1D) and multiple sclerosis (MS). CLEC16A has been reported as the most likely candidate gene in the region, since it contains the most disease-associated single-nucleotide polymorphisms (SNPs), as well as an imunoreceptor tyrosine-based activation motif. However, here we report that intron 19 of CLEC16A, containing the most autoimmune disease-associated SNPs, appears to behave as a regulatory sequence, affecting the expression of a neighbouring gene, DEXI. The CLEC16A alleles that are protective from T1D and MS are associated with increased expression of DEXI, and no other genes in the region, in two independent monocyte gene expression data sets. Critically, using chromosome conformation capture (3C), we identified physical proximity between the DEXI promoter region and intron 19 of CLEC16A, separated by a loop of >150 kb. In reciprocal experiments, a 20 kb fragment of intron 19 of CLEC16A, containing SNPs associated with T1D and MS, as well as with DEXI expression, interacted with the promotor region of DEXI but not with candidate DNA fragments containing other potential causal genes in the region, including CLEC16A. Intron 19 of CLEC16A is highly enriched for transcription-factor-binding events and markers associated with enhancer activity. Taken together, these data indicate that although the causal variants in the 16p13 region lie within CLEC16A, DEXI is an unappreciated autoimmune disease candidate gene, and illustrate the power of the 3C approach in progressing from genome-wide association studies results to candidate causal genes.
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Identification of candidate genes linking systemic inflammation to atherosclerosis; results of a human in vivo LPS infusion study.
BMC Med Genomics
PUBLISHED: 08-10-2011
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It is widely accepted that atherosclerosis and inflammation are intimately linked. Monocytes play a key role in both of these processes and we hypothesized that activation of inflammatory pathways in monocytes would lead to, among others, proatherogenic changes in the monocyte transcriptome. Such differentially expressed genes in circulating monocytes would be strong candidates for further investigation in disease association studies.
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Silencing of RhoA nucleotide exchange factor, ARHGEF3, reveals its unexpected role in iron uptake.
Blood
PUBLISHED: 06-28-2011
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Genomewide association meta-analysis studies have identified > 100 independent genetic loci associated with blood cell indices, including volume and count of platelets and erythrocytes. Although several of these loci encode known regulators of hematopoiesis, the mechanism by which most sequence variants exert their effect on blood cell formation remains elusive. An example is the Rho guanine nucleotide exchange factor, ARHGEF3, which was previously implicated by genomewide association meta-analysis studies in bone cell biology. Here, we report on the unexpected role of ARHGEF3 in regulation of iron uptake and erythroid cell maturation. Although early erythroid differentiation progressed normally, silencing of arhgef3 in Danio rerio resulted in microcytic and hypochromic anemia. This was rescued by intracellular supplementation of iron, showing that arhgef3-depleted erythroid cells are fully capable of hemoglobinization. Disruption of the arhgef3 target, RhoA, also produced severe anemia, which was, again, corrected by iron injection. Moreover, silencing of ARHGEF3 in erythromyeloblastoid cells K562 showed that the uptake of transferrin was severely impaired. Taken together, this is the first study to provide evidence for ARHGEF3 being a regulator of transferrin uptake in erythroid cells, through activation of RHOA.
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Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans.
PLoS Genet.
PUBLISHED: 06-27-2011
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One major expectation from the transcriptome in humans is to characterize the biological basis of associations identified by genome-wide association studies. So far, few cis expression quantitative trait loci (eQTLs) have been reliably related to disease susceptibility. Trans-regulating mechanisms may play a more prominent role in disease susceptibility. We analyzed 12,808 genes detected in at least 5% of circulating monocyte samples from a population-based sample of 1,490 European unrelated subjects. We applied a method of extraction of expression patterns-independent component analysis-to identify sets of co-regulated genes. These patterns were then related to 675,350 SNPs to identify major trans-acting regulators. We detected three genomic regions significantly associated with co-regulated gene modules. Association of these loci with multiple expression traits was replicated in Cardiogenics, an independent study in which expression profiles of monocytes were available in 758 subjects. The locus 12q13 (lead SNP rs11171739), previously identified as a type 1 diabetes locus, was associated with a pattern including two cis eQTLs, RPS26 and SUOX, and 5 trans eQTLs, one of which (MADCAM1) is a potential candidate for mediating T1D susceptibility. The locus 12q24 (lead SNP rs653178), which has demonstrated extensive disease pleiotropy, including type 1 diabetes, hypertension, and celiac disease, was associated to a pattern strongly correlating to blood pressure level. The strongest trans eQTL in this pattern was CRIP1, a known marker of cellular proliferation in cancer. The locus 12q15 (lead SNP rs11177644) was associated with a pattern driven by two cis eQTLs, LYZ and YEATS4, and including 34 trans eQTLs, several of them tumor-related genes. This study shows that a method exploiting the structure of co-expressions among genes can help identify genomic regions involved in trans regulation of sets of genes and can provide clues for understanding the mechanisms linking genome-wide association loci to disease.
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Blood pressure loci identified with a gene-centric array.
Toby Johnson, Tom R Gaunt, Stephen J Newhouse, Sandosh Padmanabhan, Maciej Tomaszewski, Meena Kumari, Richard W Morris, Ioanna Tzoulaki, Eoin T O'Brien, Neil R Poulter, Peter Sever, Denis C Shields, Simon Thom, Sasiwarang G Wannamethee, Peter H Whincup, Morris J Brown, John M Connell, Richard J Dobson, Philip J Howard, Charles A Mein, Abiodun Onipinla, Sue Shaw-Hawkins, Yun Zhang, George Davey Smith, Ian N M Day, Debbie A Lawlor, Alison H Goodall, , F Gerald Fowkes, Gonçalo R Abecasis, Paul Elliott, Vesela Gateva, Peter S Braund, Paul R Burton, Christopher P Nelson, Martin D Tobin, Pim van der Harst, Nicola Glorioso, Hani Neuvrith, Erika Salvi, Jan A Staessen, Andrea Stucchi, Nabila Devos, Xavier Jeunemaitre, Pierre-Francois Plouin, Jean Tichet, Peeter Juhanson, Elin Org, Margus Putku, Siim Sõber, Gudrun Veldre, Margus Viigimaa, Anna Levinsson, Annika Rosengren, Dag S Thelle, Claire E Hastie, Thomas Hedner, Wai K Lee, Olle Melander, Björn Wahlstrand, Rebecca Hardy, Andrew Wong, Jackie A Cooper, Jutta Palmen, Li Chen, Alexandre F R Stewart, George A Wells, Harm-Jan Westra, Marcel G M Wolfs, Robert Clarke, Maria Grazia Franzosi, Anuj Goel, Anders Hamsten, Mark Lathrop, John F Peden, Udo Seedorf, Hugh Watkins, Willem H Ouwehand, Jennifer Sambrook, Jonathan Stephens, Juan-Pablo Casas, Fotios Drenos, Michael V Holmes, Mika Kivimäki, Sonia Shah, Tina Shah, Philippa J Talmud, John Whittaker, Chris Wallace, Christian Delles, Maris Laan, Diana Kuh, Steve E Humphries, Fredrik Nyberg, Daniele Cusi, Robert Roberts, Christopher Newton-Cheh, Lude Franke, Alice V Stanton, Anna F Dominiczak, Martin Farrall, Aroon D Hingorani, Nilesh J Samani, Mark J Caulfield, Patricia B Munroe.
Am. J. Hum. Genet.
PUBLISHED: 06-15-2011
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Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.
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Multiple loci are associated with white blood cell phenotypes.
Michael A Nalls, David J Couper, Toshiko Tanaka, Frank J A van Rooij, Ming-Huei Chen, Albert V Smith, Daniela Toniolo, Neil A Zakai, Qiong Yang, Andreas Greinacher, Andrew R Wood, Melissa Garcia, Paolo Gasparini, Yongmei Liu, Thomas Lumley, Aaron R Folsom, Alex P Reiner, Christian Gieger, Vasiliki Lagou, Janine F Felix, Henry Völzke, Natalia A Gouskova, Alessandro Biffi, Angela Döring, Uwe Völker, Sean Chong, Kerri L Wiggins, Augusto Rendon, Abbas Dehghan, Matt Moore, Kent Taylor, James G Wilson, Guillaume Lettre, Albert Hofman, Joshua C Bis, Nicola Pirastu, Caroline S Fox, Christa Meisinger, Jennifer Sambrook, Sampath Arepalli, Matthias Nauck, Holger Prokisch, Jonathan Stephens, Nicole L Glazer, L Adrienne Cupples, Yukinori Okada, Atsushi Takahashi, Yoichiro Kamatani, Koichi Matsuda, Tatsuhiko Tsunoda, Toshihiro Tanaka, Michiaki Kubo, Yusuke Nakamura, Kazuhiko Yamamoto, Naoyuki Kamatani, Michael Stumvoll, Anke Tönjes, Inga Prokopenko, Thomas Illig, Kushang V Patel, Stephen F Garner, Brigitte Kühnel, Massimo Mangino, Ben A Oostra, Swee Lay Thein, Josef Coresh, H-Erich Wichmann, Stephan Menzel, Jingping Lin, Giorgio Pistis, André G Uitterlinden, Tim D Spector, Alexander Teumer, Gudny Eiriksdottir, Vilmundur Gudnason, Stefania Bandinelli, Timothy M Frayling, Aravinda Chakravarti, Cornelia M van Duijn, David Melzer, Willem H Ouwehand, Daniel Levy, Eric Boerwinkle, Andrew B Singleton, Dena G Hernandez, Dan L Longo, Nicole Soranzo, Jacqueline C M Witteman, Bruce M Psaty, Luigi Ferrucci, Tamara B Harris, Christopher J O'Donnell, Santhi K Ganesh.
PLoS Genet.
PUBLISHED: 04-17-2011
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White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.
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Association between walking speed and age in healthy, free-living individuals using mobile accelerometry--a cross-sectional study.
PLoS ONE
PUBLISHED: 04-11-2011
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Walking speed is a fundamental parameter of human motion and is increasingly considered as an important indicator of individuals health status.
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Inherited variation in vitamin D genes is associated with predisposition to autoimmune disease type 1 diabetes.
Diabetes
PUBLISHED: 03-25-2011
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Vitamin D deficiency (25-hydroxyvitamin D [25(OH)D] <50 nmol/L) is commonly reported in both children and adults worldwide, and growing evidence indicates that vitamin D deficiency is associated with many extraskeletal chronic disorders, including the autoimmune diseases type 1 diabetes and multiple sclerosis.
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Cross-domain inhibition of TACE ectodomain.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 03-17-2011
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Proteolytic release from the cell surface is an essential activation event for many growth factors and cytokines. TNF-? converting enzyme (TACE) is a membrane-bound metalloprotease responsible for solubilizing many pathologically significant membrane substrates and is an attractive therapeutic target for the treatment of cancer and arthritis. Prior attempts to antagonize cell-surface TACE activity have focused on small-molecule inhibition of the metalloprotease active site. Given the highly conserved nature of metalloprotease active sites, this paradigm has failed to produce a truly specific TACE inhibitor and continues to obstruct the clinical investigation of TACE activity. We report the bespoke development of a specific TACE inhibitory human antibody using "two-step" phage display. This approach combines calculated selection conditions with antibody variable-domain exchange to direct individual antibody variable domains to desired epitopes. The resulting "cross-domain" human antibody is a previously undescribed selective TACE antagonist and provides a unique alternative to small-molecule metalloprotease inhibition.
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Genome-wide analysis of simultaneous GATA1/2, RUNX1, FLI1, and SCL binding in megakaryocytes identifies hematopoietic regulators.
Dev. Cell
PUBLISHED: 02-28-2011
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Hematopoietic differentiation critically depends on combinations of transcriptional regulators controlling the development of individual lineages. Here, we report the genome-wide binding sites for the five key hematopoietic transcription factors--GATA1, GATA2, RUNX1, FLI1, and TAL1/SCL--in primary human megakaryocytes. Statistical analysis of the 17,263 regions bound by at least one factor demonstrated that simultaneous binding by all five factors was the most enriched pattern and often occurred near known hematopoietic regulators. Eight genes not previously appreciated to function in hematopoiesis that were bound by all five factors were shown to be essential for thrombocyte and/or erythroid development in zebrafish. Moreover, one of these genes encoding the PDZK1IP1 protein shared transcriptional enhancer elements with the blood stem cell regulator TAL1/SCL. Multifactor ChIP-Seq analysis in primary human cells coupled with a high-throughput in vivo perturbation screen therefore offers a powerful strategy to identify essential regulators of complex mammalian differentiation processes.
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Exome sequencing identifies NBEAL2 as the causative gene for gray platelet syndrome.
Nat. Genet.
PUBLISHED: 02-23-2011
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Gray platelet syndrome (GPS) is a predominantly recessive platelet disorder that is characterized by mild thrombocytopenia with large platelets and a paucity of ?-granules; these abnormalities cause mostly moderate but in rare cases severe bleeding. We sequenced the exomes of four unrelated individuals and identified NBEAL2 as the causative gene; it has no previously known function but is a member of a gene family that is involved in granule development. Silencing of nbeal2 in zebrafish abrogated thrombocyte formation.
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Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease.
Heribert Schunkert, Inke R König, Sekar Kathiresan, Muredach P Reilly, Themistocles L Assimes, Hilma Holm, Michael Preuss, Alexandre F R Stewart, Maja Barbalic, Christian Gieger, Devin Absher, Zouhair Aherrahrou, Hooman Allayee, David Altshuler, Sonia S Anand, Karl Andersen, Jeffrey L Anderson, Diego Ardissino, Stephen G Ball, Anthony J Balmforth, Timothy A Barnes, Diane M Becker, Lewis C Becker, Klaus Berger, Joshua C Bis, S Matthijs Boekholdt, Eric Boerwinkle, Peter S Braund, Morris J Brown, Mary Susan Burnett, Ian Buysschaert, , John F Carlquist, Li Chen, Sven Cichon, Veryan Codd, Robert W Davies, George Dedoussis, Abbas Dehghan, Serkalem Demissie, Joseph M Devaney, Patrick Diemert, Ron Do, Angela Doering, Sandra Eifert, Nour Eddine El Mokhtari, Stephen G Ellis, Roberto Elosua, James C Engert, Stephen E Epstein, Ulf de Faire, Marcus Fischer, Aaron R Folsom, Jennifer Freyer, Bruna Gigante, Domenico Girelli, Solveig Gretarsdottir, Vilmundur Gudnason, Jeffrey R Gulcher, Eran Halperin, Naomi Hammond, Stanley L Hazen, Albert Hofman, Benjamin D Horne, Thomas Illig, Carlos Iribarren, Gregory T Jones, J Wouter Jukema, Michael A Kaiser, Lee M Kaplan, John J P Kastelein, Kay-Tee Khaw, Joshua W Knowles, Genovefa Kolovou, Augustine Kong, Reijo Laaksonen, Diether Lambrechts, Karin Leander, Guillaume Lettre, Mingyao Li, Wolfgang Lieb, Christina Loley, Andrew J Lotery, Pier M Mannucci, Seraya Maouche, Nicola Martinelli, Pascal P McKeown, Christa Meisinger, Thomas Meitinger, Olle Melander, Pier Angelica Merlini, Vincent Mooser, Thomas Morgan, Thomas W Mühleisen, Joseph B Muhlestein, Thomas Münzel, Kiran Musunuru, Janja Nahrstaedt, Christopher P Nelson, Markus M Nöthen, Oliviero Olivieri, Riyaz S Patel, Chris C Patterson, Annette Peters, Flora Peyvandi, Liming Qu, Arshed A Quyyumi, Daniel J Rader, Loukianos S Rallidis, Catherine Rice, Frits R Rosendaal, Diana Rubin, Veikko Salomaa, M Lourdes Sampietro, Manj S Sandhu, Eric Schadt, Arne Schäfer, Arne Schillert, Stefan Schreiber, Jürgen Schrezenmeir, Stephen M Schwartz, David S Siscovick, Mohan Sivananthan, Suthesh Sivapalaratnam, Albert Smith, Tamara B Smith, Jaapjan D Snoep, Nicole Soranzo, John A Spertus, Klaus Stark, Kathy Stirrups, Monika Stoll, W H Wilson Tang, Stephanie Tennstedt, Gudmundur Thorgeirsson, Gudmar Thorleifsson, Maciej Tomaszewski, André G Uitterlinden, Andre M van Rij, Benjamin F Voight, Nick J Wareham, George A Wells, H-Erich Wichmann, Philipp S Wild, Christina Willenborg, Jaqueline C M Witteman, Benjamin J Wright, Shu Ye, Tanja Zeller, Andreas Ziegler, Francois Cambien, Alison H Goodall, L Adrienne Cupples, Thomas Quertermous, Winfried März, Christian Hengstenberg, Stefan Blankenberg, Willem H Ouwehand, Alistair S Hall, Panos Deloukas, John R Thompson, Kari Stefansson, Robert Roberts, Unnur Thorsteinsdottir, Christopher J O'Donnell, Ruth McPherson, Jeanette Erdmann, Nilesh J Samani.
Nat. Genet.
PUBLISHED: 02-10-2011
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We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 × 10?? and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
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Maps of open chromatin guide the functional follow-up of genome-wide association signals: application to hematological traits.
PLoS Genet.
PUBLISHED: 01-26-2011
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Turning genetic discoveries identified in genome-wide association (GWA) studies into biological mechanisms is an important challenge in human genetics. Many GWA signals map outside exons, suggesting that the associated variants may lie within regulatory regions. We applied the formaldehyde-assisted isolation of regulatory elements (FAIRE) method in a megakaryocytic and an erythroblastoid cell line to map active regulatory elements at known loci associated with hematological quantitative traits, coronary artery disease, and myocardial infarction. We showed that the two cell types exhibit distinct patterns of open chromatin and that cell-specific open chromatin can guide the finding of functional variants. We identified an open chromatin region at chromosome 7q22.3 in megakaryocytes but not erythroblasts, which harbors the common non-coding sequence variant rs342293 known to be associated with platelet volume and function. Resequencing of this open chromatin region in 643 individuals provided strong evidence that rs342293 is the only putative causative variant in this region. We demonstrated that the C- and G-alleles differentially bind the transcription factor EVI1 affecting PIK3CG gene expression in platelets and macrophages. A protein-protein interaction network including up- and down-regulated genes in Pik3cg knockout mice indicated that PIK3CG is associated with gene pathways with an established role in platelet membrane biogenesis and thrombus formation. Thus, rs342293 is the functional common variant at this locus; to the best of our knowledge this is the first such variant to be elucidated among the known platelet quantitative trait loci (QTLs). Our data suggested a molecular mechanism by which a non-coding GWA index SNP modulates platelet phenotype.
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Detection of human platelet antigen-1a alloantibodies in cases of fetomaternal alloimmune thrombocytopenia using recombinant ?3 integrin fragments coupled to fluorescently labeled beads.
Transfusion
PUBLISHED: 12-16-2010
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Testing for alloantibodies against human platelet antigens (HPAs) is essential for the clinical diagnosis of fetomaternal alloimmune thrombocytopenia (FMAIT), posttransfusion purpura, and platelet (PLT) refractoriness. Most of the methods currently used for HPA alloantibody detection rely on the availability of panels of HPA-typed PLTs and some rely on validated monoclonal antibodies (MoAbs) against the PLT glycoproteins. Recombinant ?3 integrins displaying the HPA-1a (rHPA-1a) or HPA-1b (rHPA-1b) epitopes have been produced as an alternative source of antigen. The suitability of these integrin fragments was evaluated for the development of an HPA-1a alloantibody screening assay, using Luminex xMAP technology.
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The role of meis1 in primitive and definitive hematopoiesis during zebrafish development.
Haematologica
PUBLISHED: 11-03-2010
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The Meis1 protein represents an important cofactor for Hox and Pbx1 and is implicated in human and murine leukemias. Though much is known about the role of meis1 in leukemogenesis, its function in normal hematopoiesis remains largely unclear. Here we characterized the role of the proto-oncogene, meis1, during zebrafish primitive and definitive hematopoiesis.
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Dindel: accurate indel calls from short-read data.
Genome Res.
PUBLISHED: 10-27-2010
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Small insertions and deletions (indels) are a common and functionally important type of sequence polymorphism. Most of the focus of studies of sequence variation is on single nucleotide variants (SNVs) and large structural variants. In principle, high-throughput sequencing studies should allow identification of indels just as SNVs. However, inference of indels from next-generation sequence data is challenging, and so far methods for identifying indels lag behind methods for calling SNVs in terms of sensitivity and specificity. We propose a Bayesian method to call indels from short-read sequence data in individuals and populations by realigning reads to candidate haplotypes that represent alternative sequence to the reference. The candidate haplotypes are formed by combining candidate indels and SNVs identified by the read mapper, while allowing for known sequence variants or candidates from other methods to be included. In our probabilistic realignment model we account for base-calling errors, mapping errors, and also, importantly, for increased sequencing error indel rates in long homopolymer runs. We show that our method is sensitive and achieves low false discovery rates on simulated and real data sets, although challenges remain. The algorithm is implemented in the program Dindel, which has been used in the 1000 Genomes Project call sets.
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Transcription profiling in human platelets reveals LRRFIP1 as a novel protein regulating platelet function.
Blood
PUBLISHED: 09-10-2010
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Within the healthy population, there is substantial, heritable, and interindividual variability in the platelet response. We explored whether a proportion of this variability could be accounted for by interindividual variation in gene expression. Through a correlative analysis of genome-wide platelet RNA expression data from 37 subjects representing the normal range of platelet responsiveness within a cohort of 500 subjects, we identified 63 genes in which transcript levels correlated with variation in the platelet response to adenosine diphosphate and/or the collagen-mimetic peptide, cross-linked collagen-related peptide. Many of these encode proteins with no reported function in platelets. An association study of 6 of the 63 genes in 4235 cases and 6379 controls showed a putative association with myocardial infarction for COMMD7 (COMM domain-containing protein 7) and a major deviation from the null hypo thesis for LRRFIP1 [leucine-rich repeat (in FLII) interacting protein 1]. Morpholino-based silencing in Danio rerio identified a modest role for commd7 and a significant effect for lrrfip1 as positive regulators of thrombus formation. Proteomic analysis of human platelet LRRFIP1-interacting proteins indicated that LRRFIP1 functions as a component of the platelet cytoskeleton, where it interacts with the actin-remodeling proteins Flightless-1 and Drebrin. Taken together, these data reveal novel proteins regulating the platelet response.
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A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk.
Nature
PUBLISHED: 07-28-2010
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Combined analyses of gene networks and DNA sequence variation can provide new insights into the aetiology of common diseases that may not be apparent from genome-wide association studies alone. Recent advances in rat genomics are facilitating systems-genetics approaches. Here we report the use of integrated genome-wide approaches across seven rat tissues to identify gene networks and the loci underlying their regulation. We defined an interferon regulatory factor 7 (IRF7)-driven inflammatory network (IDIN) enriched for viral response genes, which represents a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. We show that Epstein-Barr virus induced gene 2 (Ebi2, also known as Gpr183), which lies at this locus and controls B lymphocyte migration, is expressed in macrophages and regulates the IDIN. The human orthologous locus on chromosome 13q32 controlled the human equivalent of the IDIN, which was conserved in monocytes. IDIN genes were more likely to associate with susceptibility to type 1 diabetes (T1D)-a macrophage-associated autoimmune disease-than randomly selected immune response genes (P = 8.85?×?10(-6)). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P = 7.0?×?10(-10); odds ratio, 1.15), which was one of five single nucleotide polymorphisms in this region associated with EBI2 (GPR183) expression. These data implicate IRF7 network genes and their regulatory locus in the pathogenesis of T1D.
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Complex exon-intron marking by histone modifications is not determined solely by nucleosome distribution.
PLoS ONE
PUBLISHED: 07-14-2010
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It has recently been shown that nucleosome distribution, histone modifications and RNA polymerase II (Pol II) occupancy show preferential association with exons ("exon-intron marking"), linking chromatin structure and function to co-transcriptional splicing in a variety of eukaryotes. Previous ChIP-sequencing studies suggested that these marking patterns reflect the nucleosomal landscape. By analyzing ChIP-chip datasets across the human genome in three cell types, we have found that this marking system is far more complex than previously observed. We show here that a range of histone modifications and Pol II are preferentially associated with exons. However, there is noticeable cell-type specificity in the degree of exon marking by histone modifications and, surprisingly, this is also reflected in some histone modifications patterns showing biases towards introns. Exon-intron marking is laid down in the absence of transcription on silent genes, with some marking biases changing or becoming reversed for genes expressed at different levels. Furthermore, the relationship of this marking system with splicing is not simple, with only some histone modifications reflecting exon usage/inclusion, while others mirror patterns of exon exclusion. By examining nucleosomal distributions in all three cell types, we demonstrate that these histone modification patterns cannot solely be accounted for by differences in nucleosome levels between exons and introns. In addition, because of inherent differences between ChIP-chip array and ChIP-sequencing approaches, these platforms report different nucleosome distribution patterns across the human genome. Our findings confound existing views and point to active cellular mechanisms which dynamically regulate histone modification levels and account for exon-intron marking. We believe that these histone modification patterns provide links between chromatin accessibility, Pol II movement and co-transcriptional splicing.
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Lack of association between the Trp719Arg polymorphism in kinesin-like protein-6 and coronary artery disease in 19 case-control studies.
Themistocles L Assimes, Hilma Holm, Sekar Kathiresan, Muredach P Reilly, Gudmar Thorleifsson, Benjamin F Voight, Jeanette Erdmann, Christina Willenborg, Dhananjay Vaidya, Changchun Xie, Chris C Patterson, Thomas M Morgan, Mary Susan Burnett, Mingyao Li, Mark A Hlatky, Joshua W Knowles, John R Thompson, Devin Absher, Carlos Iribarren, Alan Go, Stephen P Fortmann, Stephen Sidney, Neil Risch, Hua Tang, Richard M Myers, Klaus Berger, Monika Stoll, Svati H Shah, Gudmundur Thorgeirsson, Karl Andersen, Aki S Havulinna, J Enrique Herrera, Nauder Faraday, Yoonhee Kim, Brian G Kral, Rasika A Mathias, Ingo Ruczinski, Bhoom Suktitipat, Alexander F Wilson, Lisa R Yanek, Lewis C Becker, Patrick Linsel-Nitschke, Wolfgang Lieb, Inke R König, Christian Hengstenberg, Marcus Fischer, Klaus Stark, Wibke Reinhard, Janina Winogradow, Martina Grassl, Anika Grosshennig, Michael Preuss, Stefan Schreiber, H-Erich Wichmann, Christa Meisinger, Jean Yee, Yechiel Friedlander, Ron Do, James B Meigs, Gordon Williams, David M Nathan, Calum A MacRae, Liming Qu, Robert L Wilensky, William H Matthai, Atif N Qasim, Hakon Hakonarson, Augusto D Pichard, Kenneth M Kent, Lowell Satler, Joseph M Lindsay, Ron Waksman, Christopher W Knouff, Dawn M Waterworth, Max C Walker, Vincent E Mooser, Jaume Marrugat, Gavin Lucas, Isaac Subirana, Joan Sala, Rafael Ramos, Nicola Martinelli, Oliviero Olivieri, Elisabetta Trabetti, Giovanni Malerba, Pier Franco Pignatti, Candace Guiducci, Daniel Mirel, Melissa Parkin, Joel N Hirschhorn, Rosanna Asselta, Stefano Duga, Kiran Musunuru, Mark J Daly, Shaun Purcell, Sandra Eifert, Peter S Braund, Benjamin J Wright, Anthony J Balmforth, Stephen G Ball, , Willem H Ouwehand, Panos Deloukas, Michael Scholz, Francois Cambien, Andreas Huge, Thomas Scheffold, Veikko Salomaa, Domenico Girelli, Christopher B Granger, Leena Peltonen, Pascal P McKeown, David Altshuler, Olle Melander, Joseph M Devaney, Stephen E Epstein, Daniel J Rader, Roberto Elosua, James C Engert, Sonia S Anand, Alistair S Hall, Andreas Ziegler, Christopher J O'Donnell, John A Spertus, David Siscovick, Stephen M Schwartz, Diane Becker, Unnur Thorsteinsdottir, Kari Stefansson, Heribert Schunkert, Nilesh J Samani, Thomas Quertermous.
J. Am. Coll. Cardiol.
PUBLISHED: 06-14-2010
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We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD).
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index.
Elizabeth K Speliotes, Cristen J Willer, Sonja I Berndt, Keri L Monda, Gudmar Thorleifsson, Anne U Jackson, Hana Lango Allen, Cecilia M Lindgren, Jian'an Luan, Reedik Mägi, Joshua C Randall, Sailaja Vedantam, Thomas W Winkler, Lu Qi, Tsegaselassie Workalemahu, Iris M Heid, Valgerdur Steinthorsdottir, Heather M Stringham, Michael N Weedon, Eleanor Wheeler, Andrew R Wood, Teresa Ferreira, Robert J Weyant, Ayellet V Segrè, Karol Estrada, Liming Liang, James Nemesh, Ju-Hyun Park, Stefan Gustafsson, Tuomas O Kilpeläinen, Jian Yang, Nabila Bouatia-Naji, Tonu Esko, Mary F Feitosa, Zoltan Kutalik, Massimo Mangino, Soumya Raychaudhuri, André Scherag, Albert Vernon Smith, Ryan Welch, Jing Hua Zhao, Katja K Aben, Devin M Absher, Najaf Amin, Anna L Dixon, Eva Fisher, Nicole L Glazer, Michael E Goddard, Nancy L Heard-Costa, Volker Hoesel, Jouke-Jan Hottenga, Asa Johansson, Toby Johnson, Shamika Ketkar, Claudia Lamina, Shengxu Li, Miriam F Moffatt, Richard H Myers, Narisu Narisu, John R B Perry, Marjolein J Peters, Michael Preuss, Samuli Ripatti, Fernando Rivadeneira, Camilla Sandholt, Laura J Scott, Nicholas J Timpson, Jonathan P Tyrer, Sophie van Wingerden, Richard M Watanabe, Charles C White, Fredrik Wiklund, Christina Barlassina, Daniel I Chasman, Matthew N Cooper, John-Olov Jansson, Robert W Lawrence, Niina Pellikka, Inga Prokopenko, Jianxin Shi, Elisabeth Thiering, Helene Alavere, Maria T S Alibrandi, Peter Almgren, Alice M Arnold, Thor Aspelund, Larry D Atwood, Beverley Balkau, Anthony J Balmforth, Amanda J Bennett, Yoav Ben-Shlomo, Richard N Bergman, Sven Bergmann, Heike Biebermann, Alexandra I F Blakemore, Tanja Boes, Lori L Bonnycastle, Stefan R Bornstein, Morris J Brown, Thomas A Buchanan, Fabio Busonero, Harry Campbell, Francesco P Cappuccio, Christine Cavalcanti-Proença, Yii-Der Ida Chen, Chih-Mei Chen, Peter S Chines, Robert Clarke, Lachlan Coin, John Connell, Ian N M Day, Martin den Heijer, Jubao Duan, Shah Ebrahim, Paul Elliott, Roberto Elosua, Gudny Eiriksdottir, Michael R Erdos, Johan G Eriksson, Maurizio F Facheris, Stephan B Felix, Pamela Fischer-Posovszky, Aaron R Folsom, Nele Friedrich, Nelson B Freimer, Mao Fu, Stefan Gaget, Pablo V Gejman, Eco J C Geus, Christian Gieger, Anette P Gjesing, Anuj Goel, Philippe Goyette, Harald Grallert, Jürgen Gräßler, Danielle M Greenawalt, Christopher J Groves, Vilmundur Gudnason, Candace Guiducci, Anna-Liisa Hartikainen, Neelam Hassanali, Alistair S Hall, Aki S Havulinna, Caroline Hayward, Andrew C Heath, Christian Hengstenberg, Andrew A Hicks, Anke Hinney, Albert Hofman, Georg Homuth, Jennie Hui, Wilmar Igl, Carlos Iribarren, Bo Isomaa, Kevin B Jacobs, Ivonne Jarick, Elizabeth Jewell, Ulrich John, Torben Jørgensen, Pekka Jousilahti, Antti Jula, Marika Kaakinen, Eero Kajantie, Lee M Kaplan, Sekar Kathiresan, Johannes Kettunen, Leena Kinnunen, Joshua W Knowles, Ivana Kolčić, Inke R König, Seppo Koskinen, Peter Kovacs, Johanna Kuusisto, Peter Kraft, Kirsti Kvaløy, Jaana Laitinen, Olivier Lantieri, Chiara Lanzani, Lenore J Launer, Cécile Lecoeur, Terho Lehtimäki, Guillaume Lettre, Jianjun Liu, Marja-Liisa Lokki, Mattias Lorentzon, Robert N Luben, Barbara Ludwig, , Paolo Manunta, Diana Marek, Michel Marre, Nicholas G Martin, Wendy L McArdle, Anne McCarthy, Barbara McKnight, Thomas Meitinger, Olle Melander, David Meyre, Kristian Midthjell, Grant W Montgomery, Mario A Morken, Andrew P Morris, Rosanda Mulić, Julius S Ngwa, Mari Nelis, Matt J Neville, Dale R Nyholt, Christopher J O'Donnell, Stephen O'Rahilly, Ken K Ong, Ben Oostra, Guillaume Paré, Alex N Parker, Markus Perola, Irene Pichler, Kirsi H Pietiläinen, Carl G P Platou, Ozren Polašek, Anneli Pouta, Suzanne Rafelt, Olli Raitakari, Nigel W Rayner, Martin Ridderstråle, Winfried Rief, Aimo Ruokonen, Neil R Robertson, Peter Rzehak, Veikko Salomaa, Alan R Sanders, Manjinder S Sandhu, Serena Sanna, Jouko Saramies, Markku J Savolainen, Susann Scherag, Sabine Schipf, Stefan Schreiber, Heribert Schunkert, Kaisa Silander, Juha Sinisalo, David S Siscovick, Jan H Smit, Nicole Soranzo, Ulla Sovio, Jonathan Stephens, Ida Surakka, Amy J Swift, Mari-Liis Tammesoo, Jean-Claude Tardif, Maris Teder-Laving, Tanya M Teslovich, John R Thompson, Brian Thomson, Anke Tönjes, Tiinamaija Tuomi, Joyce B J van Meurs, Gert-Jan van Ommen, Vincent Vatin, Jorma Viikari, Sophie Visvikis-Siest, Veronique Vitart, Carla I G Vogel, Benjamin F Voight, Lindsay L Waite, Henri Wallaschofski, G Bragi Walters, Elisabeth Widén, Susanna Wiegand, Sarah H Wild, Gonneke Willemsen, Daniel R Witte, Jacqueline C Witteman, Jianfeng Xu, Qunyuan Zhang, Lina Zgaga, Andreas Ziegler, Paavo Zitting, John P Beilby, I Sadaf Farooqi, Johannes Hebebrand, Heikki V Huikuri, Alan L James, Mika Kähönen, Douglas F Levinson, Fabio Macciardi, Markku S Nieminen, Claes Ohlsson, Lyle J Palmer, Paul M Ridker, Michael Stumvoll, Jacques S Beckmann, Heiner Boeing, Eric Boerwinkle, Dorret I Boomsma, Mark J Caulfield, Stephen J Chanock, Francis S Collins, L Adrienne Cupples, George Davey Smith, Jeanette Erdmann, Philippe Froguel, Henrik Grönberg, Ulf Gyllensten, Per Hall, Torben Hansen, Tamara B Harris, Andrew T Hattersley, Richard B Hayes, Joachim Heinrich, Frank B Hu, Kristian Hveem, Thomas Illig, Marjo-Riitta Järvelin, Jaakko Kaprio, Fredrik Karpe, Kay-Tee Khaw, Lambertus A Kiemeney, Heiko Krude, Markku Laakso, Debbie A Lawlor, Andres Metspalu, Patricia B Munroe, Willem H Ouwehand, Oluf Pedersen, Brenda W Penninx, Annette Peters, Peter P Pramstaller, Thomas Quertermous, Thomas Reinehr, Aila Rissanen, Igor Rudan, Nilesh J Samani, Peter E H Schwarz, Alan R Shuldiner, Timothy D Spector, Jaakko Tuomilehto, Manuela Uda, André Uitterlinden, Timo T Valle, Martin Wabitsch, Gérard Waeber, Nicholas J Wareham, Hugh Watkins, James F Wilson, Alan F Wright, M Carola Zillikens, Nilanjan Chatterjee, Steven A McCarroll, Shaun Purcell, Eric E Schadt, Peter M Visscher, Themistocles L Assimes, Ingrid B Borecki, Panos Deloukas, Caroline S Fox, Leif C Groop, Talin Haritunians, David J Hunter, Robert C Kaplan, Karen L Mohlke, Jeffrey R O'Connell, Leena Peltonen, David Schlessinger, David P Strachan, Cornelia M van Duijn, H-Erich Wichmann, Timothy M Frayling, Unnur Thorsteinsdottir, Gonçalo R Abecasis, Inês Barroso, Michael Boehnke, Kari Stefansson, Kari E North, Mark I McCarthy, Joel N Hirschhorn, Erik Ingelsson, Ruth J F Loos.
Nat. Genet.
PUBLISHED: 05-13-2010
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Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ? 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10??), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies.
Lancet
PUBLISHED: 05-11-2010
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Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality.
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
Hana Lango Allen, Karol Estrada, Guillaume Lettre, Sonja I Berndt, Michael N Weedon, Fernando Rivadeneira, Cristen J Willer, Anne U Jackson, Sailaja Vedantam, Soumya Raychaudhuri, Teresa Ferreira, Andrew R Wood, Robert J Weyant, Ayellet V Segrè, Elizabeth K Speliotes, Eleanor Wheeler, Nicole Soranzo, Ju-Hyun Park, Jian Yang, Daniel Gudbjartsson, Nancy L Heard-Costa, Joshua C Randall, Lu Qi, Albert Vernon Smith, Reedik Mägi, Tomi Pastinen, Liming Liang, Iris M Heid, Jian'an Luan, Gudmar Thorleifsson, Thomas W Winkler, Michael E Goddard, Ken Sin Lo, Cameron Palmer, Tsegaselassie Workalemahu, Yurii S Aulchenko, Asa Johansson, M Carola Zillikens, Mary F Feitosa, Tonu Esko, Toby Johnson, Shamika Ketkar, Peter Kraft, Massimo Mangino, Inga Prokopenko, Devin Absher, Eva Albrecht, Florian Ernst, Nicole L Glazer, Caroline Hayward, Jouke-Jan Hottenga, Kevin B Jacobs, Joshua W Knowles, Zoltan Kutalik, Keri L Monda, Ozren Polašek, Michael Preuss, Nigel W Rayner, Neil R Robertson, Valgerdur Steinthorsdottir, Jonathan P Tyrer, Benjamin F Voight, Fredrik Wiklund, Jianfeng Xu, Jing Hua Zhao, Dale R Nyholt, Niina Pellikka, Markus Perola, John R B Perry, Ida Surakka, Mari-Liis Tammesoo, Elizabeth L Altmaier, Najaf Amin, Thor Aspelund, Tushar Bhangale, Gabrielle Boucher, Daniel I Chasman, Constance Chen, Lachlan Coin, Matthew N Cooper, Anna L Dixon, Quince Gibson, Elin Grundberg, Ke Hao, M Juhani Junttila, Lee M Kaplan, Johannes Kettunen, Inke R König, Tony Kwan, Robert W Lawrence, Douglas F Levinson, Mattias Lorentzon, Barbara McKnight, Andrew P Morris, Martina Müller, Julius Suh Ngwa, Shaun Purcell, Suzanne Rafelt, Rany M Salem, Erika Salvi, Serena Sanna, Jianxin Shi, Ulla Sovio, John R Thompson, Michael C Turchin, Liesbeth Vandenput, Dominique J Verlaan, Veronique Vitart, Charles C White, Andreas Ziegler, Peter Almgren, Anthony J Balmforth, Harry Campbell, Lorena Citterio, Alessandro De Grandi, Anna Dominiczak, Jubao Duan, Paul Elliott, Roberto Elosua, Johan G Eriksson, Nelson B Freimer, Eco J C Geus, Nicola Glorioso, Shen Haiqing, Anna-Liisa Hartikainen, Aki S Havulinna, Andrew A Hicks, Jennie Hui, Wilmar Igl, Thomas Illig, Antti Jula, Eero Kajantie, Tuomas O Kilpeläinen, Markku Koiranen, Ivana Kolčić, Seppo Koskinen, Peter Kovacs, Jaana Laitinen, Jianjun Liu, Marja-Liisa Lokki, Ana Marušić, Andrea Maschio, Thomas Meitinger, Antonella Mulas, Guillaume Paré, Alex N Parker, John F Peden, Astrid Petersmann, Irene Pichler, Kirsi H Pietiläinen, Anneli Pouta, Martin Ridderstråle, Jerome I Rotter, Jennifer G Sambrook, Alan R Sanders, Carsten Oliver Schmidt, Juha Sinisalo, Jan H Smit, Heather M Stringham, G Bragi Walters, Elisabeth Widén, Sarah H Wild, Gonneke Willemsen, Laura Zagato, Lina Zgaga, Paavo Zitting, Helene Alavere, Martin Farrall, Wendy L McArdle, Mari Nelis, Marjolein J Peters, Samuli Ripatti, Joyce B J van Meurs, Katja K Aben, Kristin G Ardlie, Jacques S Beckmann, John P Beilby, Richard N Bergman, Sven Bergmann, Francis S Collins, Daniele Cusi, Martin den Heijer, Gudny Eiriksdottir, Pablo V Gejman, Alistair S Hall, Anders Hamsten, Heikki V Huikuri, Carlos Iribarren, Mika Kähönen, Jaakko Kaprio, Sekar Kathiresan, Lambertus Kiemeney, Thomas Kocher, Lenore J Launer, Terho Lehtimäki, Olle Melander, Tom H Mosley, Arthur W Musk, Markku S Nieminen, Christopher J O'Donnell, Claes Ohlsson, Ben Oostra, Lyle J Palmer, Olli Raitakari, Paul M Ridker, John D Rioux, Aila Rissanen, Carlo Rivolta, Heribert Schunkert, Alan R Shuldiner, David S Siscovick, Michael Stumvoll, Anke Tönjes, Jaakko Tuomilehto, Gert-Jan van Ommen, Jorma Viikari, Andrew C Heath, Nicholas G Martin, Grant W Montgomery, Michael A Province, Manfred Kayser, Alice M Arnold, Larry D Atwood, Eric Boerwinkle, Stephen J Chanock, Panos Deloukas, Christian Gieger, Henrik Grönberg, Per Hall, Andrew T Hattersley, Christian Hengstenberg, Wolfgang Hoffman, G Mark Lathrop, Veikko Salomaa, Stefan Schreiber, Manuela Uda, Dawn Waterworth, Alan F Wright, Themistocles L Assimes, Inês Barroso, Albert Hofman, Karen L Mohlke, Dorret I Boomsma, Mark J Caulfield, L Adrienne Cupples, Jeanette Erdmann, Caroline S Fox, Vilmundur Gudnason, Ulf Gyllensten, Tamara B Harris, Richard B Hayes, Marjo-Riitta Järvelin, Vincent Mooser, Patricia B Munroe, Willem H Ouwehand, Brenda W Penninx, Peter P Pramstaller, Thomas Quertermous, Igor Rudan, Nilesh J Samani, Timothy D Spector, Henry Völzke, Hugh Watkins, James F Wilson, Leif C Groop, Talin Haritunians, Frank B Hu, Robert C Kaplan, Andres Metspalu, Kari E North, David Schlessinger, Nicholas J Wareham, David J Hunter, Jeffrey R O'Connell, David P Strachan, H-Erich Wichmann, Ingrid B Borecki, Cornelia M van Duijn, Eric E Schadt, Unnur Thorsteinsdottir, Leena Peltonen, André G Uitterlinden, Peter M Visscher, Nilanjan Chatterjee, Ruth J F Loos, Michael Boehnke, Mark I McCarthy, Erik Ingelsson, Cecilia M Lindgren, Gonçalo R Abecasis, Kari Stefansson, Timothy M Frayling, Joel N Hirschhorn.
Nature
PUBLISHED: 04-23-2010
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Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P?
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Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulators.
Cell Stem Cell
PUBLISHED: 03-13-2010
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Combinatorial transcription factor (TF) interactions control cellular phenotypes and, therefore, underpin stem cell formation, maintenance, and differentiation. Here, we report the genome-wide binding patterns and combinatorial interactions for ten key regulators of blood stem/progenitor cells (SCL/TAL1, LYL1, LMO2, GATA2, RUNX1, MEIS1, PU.1, ERG, FLI-1, and GFI1B), thus providing the most comprehensive TF data set for any adult stem/progenitor cell type to date. Genome-wide computational analysis of complex binding patterns, followed by functional validation, revealed the following: first, a previously unrecognized combinatorial interaction between a heptad of TFs (SCL, LYL1, LMO2, GATA2, RUNX1, ERG, and FLI-1). Second, we implicate direct protein-protein interactions between four key regulators (RUNX1, GATA2, SCL, and ERG) in stabilizing complex binding to DNA. Third, Runx1(+/-)::Gata2(+/-) compound heterozygous mice are not viable with severe hematopoietic defects at midgestation. Taken together, this study demonstrates the power of genome-wide analysis in generating novel functional insights into the transcriptional control of stem and progenitor cells.
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Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls.
, Nick Craddock, Matthew E Hurles, Niall Cardin, Richard D Pearson, Vincent Plagnol, Samuel Robson, Damjan Vukcevic, Chris Barnes, Donald F Conrad, Eleni Giannoulatou, Chris Holmes, Jonathan L Marchini, Kathy Stirrups, Martin D Tobin, Louise V Wain, Chris Yau, Jan Aerts, Tariq Ahmad, T Daniel Andrews, Hazel Arbury, Anthony Attwood, Adam Auton, Stephen G Ball, Anthony J Balmforth, Jeffrey C Barrett, Inês Barroso, Anne Barton, Amanda J Bennett, Sanjeev Bhaskar, Katarzyna Blaszczyk, John Bowes, Oliver J Brand, Peter S Braund, Francesca Bredin, Gerome Breen, Morris J Brown, Ian N Bruce, Jaswinder Bull, Oliver S Burren, John Burton, Jake Byrnes, Sian Caesar, Chris M Clee, Alison J Coffey, John M C Connell, Jason D Cooper, Anna F Dominiczak, Kate Downes, Hazel E Drummond, Darshna Dudakia, Andrew Dunham, Bernadette Ebbs, Diana Eccles, Sarah Edkins, Cathryn Edwards, Anna Elliot, Paul Emery, David M Evans, Gareth Evans, Steve Eyre, Anne Farmer, I Nicol Ferrier, Lars Feuk, Tomas Fitzgerald, Edward Flynn, Alistair Forbes, Liz Forty, Jayne A Franklyn, Rachel M Freathy, Polly Gibbs, Paul Gilbert, Omer Gokumen, Katherine Gordon-Smith, Emma Gray, Elaine Green, Chris J Groves, Detelina Grozeva, Rhian Gwilliam, Anita Hall, Naomi Hammond, Matt Hardy, Pile Harrison, Neelam Hassanali, Husam Hebaishi, Sarah Hines, Anne Hinks, Graham A Hitman, Lynne Hocking, Eleanor Howard, Philip Howard, Joanna M M Howson, Debbie Hughes, Sarah Hunt, John D Isaacs, Mahim Jain, Derek P Jewell, Toby Johnson, Jennifer D Jolley, Ian R Jones, Lisa A Jones, George Kirov, Cordelia F Langford, Hana Lango-Allen, G Mark Lathrop, James Lee, Kate L Lee, Charlie Lees, Kevin Lewis, Cecilia M Lindgren, Meeta Maisuria-Armer, Julian Maller, John Mansfield, Paul Martin, Dunecan C O Massey, Wendy L McArdle, Peter McGuffin, Kirsten E McLay, Alex Mentzer, Michael L Mimmack, Ann E Morgan, Andrew P Morris, Craig Mowat, Simon Myers, William Newman, Elaine R Nimmo, Michael C O'Donovan, Abiodun Onipinla, Ifejinelo Onyiah, Nigel R Ovington, Michael J Owen, Kimmo Palin, Kirstie Parnell, David Pernet, John R B Perry, Anne Phillips, Dalila Pinto, Natalie J Prescott, Inga Prokopenko, Michael A Quail, Suzanne Rafelt, Nigel W Rayner, Richard Redon, David M Reid, Renwick, Susan M Ring, Neil Robertson, Ellie Russell, David St Clair, Jennifer G Sambrook, Jeremy D Sanderson, Helen Schuilenburg, Carol E Scott, Richard Scott, Sheila Seal, Sue Shaw-Hawkins, Beverley M Shields, Matthew J Simmonds, Debbie J Smyth, Elilan Somaskantharajah, Katarina Spanova, Sophia Steer, Jonathan Stephens, Helen E Stevens, Millicent A Stone, Zhan Su, Deborah P M Symmons, John R Thompson, Wendy Thomson, Mary E Travers, Clare Turnbull, Armand Valsesia, Mark Walker, Neil M Walker, Chris Wallace, Margaret Warren-Perry, Nicholas A Watkins, John Webster, Michael N Weedon, Anthony G Wilson, Matthew Woodburn, B Paul Wordsworth, Allan H Young, Eleftheria Zeggini, Nigel P Carter, Timothy M Frayling, Charles Lee, Gil McVean, Patricia B Munroe, Aarno Palotie, Stephen J Sawcer, Stephen W Scherer, David P Strachan, Chris Tyler-Smith, Matthew A Brown, Paul R Burton, Mark J Caulfield, Alastair Compston, Martin Farrall, Stephen C L Gough, Alistair S Hall, Andrew T Hattersley, Adrian V S Hill, Christopher G Mathew, Marcus Pembrey, Jack Satsangi, Michael R Stratton, Jane Worthington, Panos Deloukas, Audrey Duncanson, Dominic P Kwiatkowski, Mark I McCarthy, Willem Ouwehand, Miles Parkes, Nazneen Rahman, John A Todd, Nilesh J Samani, Peter Donnelly.
Nature
PUBLISHED: 03-05-2010
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Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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Common variants near TERC are associated with mean telomere length.
Nat. Genet.
PUBLISHED: 01-12-2010
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We conducted genome-wide association analyses of mean leukocyte telomere length in 2,917 individuals, with follow-up replication in 9,492 individuals. We identified an association with telomere length on 3q26 (rs12696304, combined P = 3.72 x 10(-14)) at a locus that includes TERC, which encodes the telomerase RNA component. Each copy of the minor allele of rs12696304 was associated with an approximately 75-base-pair reduction in mean telomere length, equivalent to approximately 3.6 years of age-related telomere-length attrition.
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Platelets release novel thiol isomerase enzymes which are recruited to the cell surface following activation.
Br. J. Haematol.
PUBLISHED: 12-08-2009
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The thiol isomerase enzymes protein disulphide isomerase (PDI) and endoplasmic reticulum protein 5 (ERp5) are released by resting and activated platelets. These re-associate with the cell surface where they modulate a range of platelet responses including adhesion, secretion and aggregation. Recent studies suggest the existence of yet uncharacterised platelet thiol isomerase proteins. This study aimed to identify which other thiol isomerase enzymes are present in human platelets. Through the use of immunoblotting, flow cytometry, cell-surface biotinylation and gene array analysis, we report the presence of five additional thiol isomerases in human and mouse platelets and megakaryocytes, namely; ERp57, ERp72, ERp44, ERp29 and TMX3. ERp72, ERp57, ERp44 and ERp29 are released by platelets and relocate to the cell surface following platelet activation. The transmembrane thiol isomerase TMX3 was also detected on the platelet surface but does not increase following activation. Extracellular PDI is also implicated in the regulation of coagulation by the modulation of tissue factor activity. ERp57 was identified within platelet-derived microparticle fractions, suggesting that ERp57 may also be involved in the regulation of coagulation as well as platelet function. These data collectively implicate the expanding family of platelet-surface thiol isomerases in the regulation of haemostasis.
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Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region.
Nat. Genet.
PUBLISHED: 08-17-2009
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Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P < 1 x 10(-5) were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 x 10(-17)), 16q22 (CDH1 and CDH3; P = 2.8 x 10(-8)) and 7q31 (LAMB1; P = 3.0 x 10(-8)). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis.
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Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium.
Nat. Genet.
PUBLISHED: 08-07-2009
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Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.
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PECAM-1 expression and activity negatively regulate multiple platelet signaling pathways.
FEBS Lett.
PUBLISHED: 06-11-2009
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Platelet endothelial cell adhesion molecule-1 (PECAM-1) inhibits platelet response to collagen and may also inhibit two other major platelet agonists ADP and thrombin although this has been less well explored. We hypothesized that the combined effect of inhibiting these three platelet activating pathways may act to significantly inhibit thrombus formation. We demonstrate a negative relationship between PECAM-1 surface expression and platelet response to cross-linked collagen related peptide (CRP-XL) and ADP, and an inhibitory effect of PECAM-1 clustering on platelet response to CRP-XL, ADP and thrombin. This combined inhibition of multiple signaling pathways results in a marked reduction in thrombus formation.
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Functional genomics in zebrafish permits rapid characterization of novel platelet membrane proteins.
Blood
PUBLISHED: 06-10-2009
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In this study, we demonstrate the suitability of the vertebrate Danio rerio (zebrafish) for functional screening of novel platelet genes in vivo by reverse genetics. Comparative transcript analysis of platelets and their precursor cell, the megakaryocyte, together with nucleated blood cell elements, endothelial cells, and erythroblasts, identified novel platelet membrane proteins with hitherto unknown roles in thrombus formation. We determined the phenotype induced by antisense morpholino oligonucleotide (MO)-based knockdown of 5 of these genes in a laser-induced arterial thrombosis model. To validate the model, the genes for platelet glycoprotein (GP) IIb and the coagulation protein factor VIII were targeted. MO-injected fish showed normal thrombus initiation but severely impaired thrombus growth, consistent with the mouse knockout phenotypes, and concomitant knockdown of both resulted in spontaneous bleeding. Knockdown of 4 of the 5 novel platelet proteins altered arterial thrombosis, as demonstrated by modified kinetics of thrombus initiation and/or development. We identified a putative role for BAMBI and LRRC32 in promotion and DCBLD2 and ESAM in inhibition of thrombus formation. We conclude that phenotypic analysis of MO-injected zebrafish is a fast and powerful method for initial screening of novel platelet proteins for function in thrombosis.
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Alloantibodies against low-frequency human platelet antigens do not account for a significant proportion of cases of fetomaternal alloimmune thrombocytopenia: evidence from 1054 cases.
Transfusion
PUBLISHED: 06-04-2009
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Maternal alloantibodies against the five common human platelet antigen (HPA) systems (HPA-1 to -3, -5, and -15) are found in only 20% of cases referred for fetal and neonatal thrombocytopenia (FMAIT) investigations. The question asked was whether mismatches for the remaining 11 low-frequency HPAs (HPA-4 and -6bw to -17bw) might in part explain the remaining 80% of cases.
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Single domain antibodies against the collagen signalling receptor glycoprotein VI are inhibitors of collagen induced thrombus formation.
Platelets
PUBLISHED: 05-22-2009
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Human Domain Antibodies (dAbs) that bind to and inhibit the function of platelet glycoprotein VI (GPVI) have been isolated from phage display libraries and their efficacy demonstrated using in vitro models of platelet activation. Here we describe the properties of one such antibody, BLO8-1, which has been shown to specifically inhibit the binding of recombinant human GPVI to cross-linked collagen related peptide (CRP-XL) in vitro. BLO8-1 specifically binds to the platelet cell surface and prevents CRP-XL induced platelet aggregation in platelet-rich plasma, as well as inhibiting thrombus formation in whole blood under arterial shear conditions. Using a series of mutant GPVI molecules, BLO8-1 was shown to recognize an epitope within the collagen binding domain of GPVI, therefore the anti-thrombotic effect of this dAb is predicted to be due to direct blocking of the collagen-GPVI interaction. These data, together with the desirable properties of Domain Antibodies, show that dAbs could potentially be used to generate novel biopharmaceuticals with anti-thrombotic properties.
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A functional genomics approach reveals novel quantitative trait loci associated with platelet signaling pathways.
Blood
PUBLISHED: 05-08-2009
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Platelet response to activation varies widely between individuals but shows interindividual consistency and strong heritability. The genetic basis of this variation has not been properly explored. We therefore systematically measured the effect on function of sequence variation in 97 candidate genes in the collagen and adenosine-diphosphate (ADP) signaling pathways. Resequencing of the genes in 48 European DNA samples nearly doubled the number of known single nucleotide polymorphisms (SNPs) and informed the selection of 1327 SNPs for genotyping in 500 healthy Northern European subjects with known platelet responses to collagen-related peptide (CRP-XL) and ADP. This identified 17 novel associations with platelet function (P < .005) accounting for approximately 46% of the variation in response. Further investigations with platelets of known genotype explored the mechanisms behind some of the associations. SNPs in PEAR1 associated with increased platelet response to CRP-XL and increased PEAR1 protein expression after platelet degranulation. The minor allele of a 3 untranslated region (UTR) SNP (rs2769668) in VAV3 was associated with higher protein expression (P = .03) and increased P-selectin exposure after ADP activation (P = .004). Furthermore the minor allele of the intronic SNP rs17786144 in ITPR1 modified Ca(2+) levels after activation with ADP (P < .004). These data provide novel insights into key hubs within platelet signaling networks.
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Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource.
Nat. Genet.
PUBLISHED: 04-15-2009
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Genome-wide association studies (GWAS) have identified over 300 regions associated with more than 70 common diseases. However, identifying causal genes within an associated region remains a major challenge. One approach to resolving causal genes is through the dissection of gene-phenotype correlations. Here we use polychromatic flow cytometry to show that differences in surface expression of the human interleukin-2 (IL-2) receptor alpha (IL2RA, or CD25) protein are restricted to particular immune cell types and correlate with several haplotypes in the IL2RA region that have previously been associated with two autoimmune diseases, type 1 diabetes (T1D) and multiple sclerosis. We confirm our strongest gene-phenotype correlation at the RNA level by allele-specific expression (ASE). We also define key parameters for the design and implementation of post-GWAS gene-phenotype investigations and demonstrate the usefulness of a large bioresource of genotype-selectable normal donors from whom fresh, primary cells can be analyzed.
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Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data.
Diabetes
PUBLISHED: 04-01-2009
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This study examined how differences in the BMI distribution of type 2 diabetic case subjects affected genome-wide patterns of type 2 diabetes association and considered the implications for the etiological heterogeneity of type 2 diabetes.
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Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size.
PLoS Genet.
PUBLISHED: 03-04-2009
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Recent genome-wide (GW) scans have identified several independent loci affecting human stature, but their contribution through the different skeletal components of height is still poorly understood. We carried out a genome-wide scan in 12,611 participants, followed by replication in an additional 7,187 individuals, and identified 17 genomic regions with GW-significant association with height. Of these, two are entirely novel (rs11809207 in CATSPER4, combined P-value = 6.1x10(-8) and rs910316 in TMED10, P-value = 1.4x10(-7)) and two had previously been described with weak statistical support (rs10472828 in NPR3, P-value = 3x10(-7) and rs849141 in JAZF1, P-value = 3.2x10(-11)). One locus (rs1182188 at GNA12) identifies the first height eQTL. We also assessed the contribution of height loci to the upper- (trunk) and lower-body (hip axis and femur) skeletal components of height. We find evidence for several loci associated with trunk length (including rs6570507 in GPR126, P-value = 4x10(-5) and rs6817306 in LCORL, P-value = 4x10(-4)), hip axis length (including rs6830062 at LCORL, P-value = 4.8x10(-4) and rs4911494 at UQCC, P-value = 1.9x10(-4)), and femur length (including rs710841 at PRKG2, P-value = 2.4x10(-5) and rs10946808 at HIST1H1D, P-value = 6.4x10(-6)). Finally, we used conditional analyses to explore a possible differential contribution of the height loci to these different skeletal size measurements. In addition to validating four novel loci controlling adult stature, our study represents the first effort to assess the contribution of genetic loci to three skeletal components of height. Further statistical tests in larger numbers of individuals will be required to verify if the height loci affect height preferentially through these subcomponents of height.
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Investigation of Crohns disease risk loci in ulcerative colitis further defines their molecular relationship.
Gastroenterology
PUBLISHED: 03-03-2009
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Identifying shared and disease-specific susceptibility loci for Crohns disease (CD) and ulcerative colitis (UC) would help define the biologic relationship between the inflammatory bowel diseases. More than 30 CD susceptibility loci have been identified. These represent important candidate susceptibility loci for UC. Loci discovered by the index genome scans in CD have previously been tested for association with UC, but those identified in the recent meta-analysis await such investigation. Furthermore, the recently identified UC locus at ECM1 requires formal testing for association with CD.
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A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium.
Nat. Genet.
PUBLISHED: 02-24-2009
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The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.
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A HaemAtlas: characterizing gene expression in differentiated human blood cells.
Blood
PUBLISHED: 02-19-2009
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Hematopoiesis is a carefully controlled process that is regulated by complex networks of transcription factors that are, in part, controlled by signals resulting from ligand binding to cell-surface receptors. To further understand hematopoiesis, we have compared gene expression profiles of human erythroblasts, megakaryocytes, B cells, cytotoxic and helper T cells, natural killer cells, granulocytes, and monocytes using whole genome microarrays. A bioinformatics analysis of these data was performed focusing on transcription factors, immunoglobulin superfamily members, and lineage-specific transcripts. We observed that the numbers of lineage-specific genes varies by 2 orders of magnitude, ranging from 5 for cytotoxic T cells to 878 for granulocytes. In addition, we have identified novel coexpression patterns for key transcription factors involved in hematopoiesis (eg, GATA3-GFI1 and GATA2-KLF1). This study represents the most comprehensive analysis of gene expression in hematopoietic cells to date and has identified genes that play key roles in lineage commitment and cell function. The data, which are freely accessible, will be invaluable for future studies on hematopoiesis and the role of specific genes and will also aid the understanding of the recent genome-wide association studies.
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A novel variant on chromosome 7q22.3 associated with mean platelet volume, counts, and function.
Blood
PUBLISHED: 02-12-2009
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Mean platelet volume (MPV) and platelet count (PLT) are highly heritable and tightly regulated traits. We performed a genome-wide association study for MPV and identified one SNP, rs342293, as having highly significant and reproducible association with MPV (per-G allele effect 0.016 +/- 0.001 log fL; P < 1.08 x 10(-24)) and PLT (per-G effect -4.55 +/- 0.80 10(9)/L; P < 7.19 x 10(-8)) in 8586 healthy subjects. Whole-genome expression analysis in the 1-MB region showed a significant association with platelet transcript levels for PIK3CG (n = 35; P = .047). The G allele at rs342293 was also associated with decreased binding of annexin V to platelets activated with collagen-related peptide (n = 84; P = .003). The region 7q22.3 identifies the first QTL influencing platelet volume, counts, and function in healthy subjects. Notably, the association signal maps to a chromosome region implicated in myeloid malignancies, indicating this site as an important regulatory site for hematopoiesis. The identification of loci regulating MPV by this and other studies will increase our insight in the processes of megakaryopoiesis and proplatelet formation, and it may aid the identification of genes that are somatically mutated in essential thrombocytosis.
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New susceptibility locus for coronary artery disease on chromosome 3q22.3.
Nat. Genet.
PUBLISHED: 02-08-2009
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We present a three-stage analysis of genome-wide SNP data in 1,222 German individuals with myocardial infarction and 1,298 controls, in silico replication in three additional genome-wide datasets of coronary artery disease (CAD) and subsequent replication in approximately 25,000 subjects. We identified one new CAD risk locus on 3q22.3 in MRAS (P = 7.44 x 10(-13); OR = 1.15, 95% CI = 1.11-1.19), and suggestive association with a locus on 12q24.31 near HNF1A-C12orf43 (P = 4.81 x 10(-7); OR = 1.08, 95% CI = 1.05-1.11).
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.