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201. Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

Author: Cristina Cereda, Jurjen J. Luykx, Sandra Meier, Derek W. Morris, Douglas M. Ruderfer, Mythily Subramaniam, Paul Cormican, Lyudmila Georgieva, John Landers, Silvana Penco, Marian L. Hamshere, Frank Dudbridge, Mari Nelis, Dick Schijven, Jimmy Lee, Sarah E. Bergen, Alessandro Padovani, Nicholas W. Wood, Meraida Polak, Hannelore Ehrenreich, Nancy G. Buccola, Noa Carrera, Stefan Herms, Panos Roussos, Marion Friedl, Teimuraz Silagadze, Jim van Os, Annette M. Hartmann, Ole A. Andreassen, R. Jeroen Pasterkamp, Sibylle G. Schwab, Aleksey Shatunov, Eli A. Stahl, David A. Collier, Farooq Amin, Michael Conlon O'Donovan, Guiqing Cai, Kung-Yee Liang, Denis C. Bauer, Charles Curtis, Brion S. Maher, Ashley R. Jones, Sara L. Pulit, Sarah Tosato, Milan Macek, Vivianna M. Van Deerlin, Vincenzo Silani, Pietro Fratta, Bettina Konte, Rosanna Tortelli, Dan Rujescu, T. Scott Stroup, Elizabeth Bevilacqua, Christian Lunetta, Bradley T. Webb, Christophe Tzourio, Patrick Vourc'h, Joel N. Hirschhorn, Gilbert Bensimon, Timothy G. Dinan, Thomas G. Schulze, Richard A. Belliveau, Daniel R. Weinberger, Andrew McQuillin, Qingqin S. Li, Orla Hardiman, Claudine Laurent, Masashi Ikeda, Tim Kahlke, Rodney J. Scott, Frans Henskens, Tune H. Pers, Wolfgang Lieb, Christian Hammer, Elvira Bramon, Hana Kuzelova-Ptackova, Raquelle I. Mesholam-Gately, Ingrid Melle, Nadine Cohen, David Cohen, Nazli Basak, Elisabeth Stögmann, Nelson B. Freimer, Peter Eichhammer, J. Mallet, Preben Bo Mortensen, Robert H. Brown, Wouter van Rheenen, Roberto Del Bo, Dai Wang, Laurent Essioux, Larry J. Seidman, Hreinn Stefansson, Erik G. Jönsson, Mads V. Hollegaard, Raymond C.K. Chan, Susana Pinto, Alexander Richards, Jubao Duan, Peter Holmans, George Kirov, Pablo V. Gejman, Philippe Amouyel, Stephanie Godard, Dieter B. Wildenauer, Martina Wiedau-Pazos, Stacy Steinberg, Ole Mors, Andres Metspalu, Rolf Adolfsson, Shaun Purcell, Hugh Gurling, Joseph I. Friedman, Erik Söderman, Mark Weiser, Giacomo P. Comi, James A. Knowles, Peter M. Andersen, Brien P. Riley, Nakao Iwata, Jeremy M. Silverman, Mark J. Daly, Elena Parkhomenko, Digby Quested, Srinivas Thirumalai, Ulrich Schall, Jan Lubinski, Dragan M. Svrakic, Aaron R. Wolen, S. Hong Lee, Andrew Pocklington, Bernard Lerer, Vahram Haroutunian, Matthew C. Kiernan, Kenneth L. Davis, Assen Jablensky, William Byerley, Karol Estrada, Aarno Palotie, Cinzia Tiloca, Eadbhard O'Callaghan, Perry T.C. van Doormaal, Colm McDonald, Federico Casale, Thomas Meitinger, Robert Freedman, Gerome Breen, Milena Blagojevic-Radivojkov, Ian P. Blair, Ann E. Pulver, Jan H. Veldink, Giancarlo Logroscino, Miaoxin Li, Abraham Reichenberg, Esben Agerbo, Siddharthan Chandran, Patrik K. E. Magnusson, Andrew M. McIntosh, Gianni Sorarù, Maura Brunetti, Xuebin Zheng, Madeline Alexander, James L. Kennedy, Douglas Blackwood, Menachem Fromer, Martilias S. Farrell, Alan R. Sanders, Dominic B. Rowe, Alexis Brice, Jonathan Pimm, Emily H. M. Wong, Jana Strohmaier, André G. Uitterlinden, Andrea Calvo, Carsten Drepper, John Q. Trojanowski, Marcella Rietschel, Siow Ann Chong, Karen E. Morrison, Sang-Yun Oh, Laura Nisenbaum, Margaret O'Brien, Alkes L. Price, Carin J. Meijer, Michael Davidson, John Powell, Petr Slominsky, Wiepke Cahn, Cinzia Gellera, Vihra Milanova, Peter M. Visscher, Patricia T. Michie, Dimitris Dikeos, Jianxin Shi, Veikko Salomaa, Philip Van Damme, James J. Crowley, Younes Mokrab, Valentina Escott-Price, Jesus S. Mora, Stanley V. Catts, David St Clair, Bernhard Landwehrmeyer, John Hardy, Kristin K. Nicodemus, Dominique Campion, Juha Veijola, Wim Robberecht, Thomas Meyer, Peter Lichtner, Christos Pantelis, Markus Weber, Nilo Riva, Jin P. Szatkiewicz, Michele T. Pato, Cinzia Bertolin, Frank P. Diekstra, Simon Arcuti, Bryan J. Mowry, Hon-Cheong So, Adriano Chiò, Viviana Pensato, Yunjung Kim, Jean-François Dartigues, Zita Ausrele Kucinskiene, Inez Myin-Germeys, Jaana Suvisaari, Sophie E. Legge, Roel A. Ophoff, Philippe Corcia, Gerald Nestadt, Stephan Ripke, Kuang Lin, Paola Giusti-Rodríguez, Michael John Owen, Chris C. A. Spencer, Safa Saker-Delye, Robert W. McCarley, Kimberley D. Chambert, Brandon Wormley, Isabella Fogh, Mamede de Carvalho, Pamela J. Shaw, Tõnu Esko, Ronald Y. L. Chan, Jianjun Liu, Tim B. Bigdeli, Christian R. Andres, David M. Hougaard, Michael Gill, Ammar Al-Chalabi, Colm O'Dushlaine, Rick A.A. van der Spek, Gary Donohoe, Tao Li, Jonathan D. Glass, Christopher Shaw, Draga Toncheva, Leonard H. van den Berg, Liene Nikitina-Zake, Morten Mattingsdal, François Salachas, Andrey Khrunin, Line Olsen, Jochen H. Weishaupt, Jo Knight, Katie Sidle, Filip Eftimov, Massimiliano Filosto, Russell L. McLaughlin, Pak C. Sham, Joshua L. Roffman, Thomas Hansen, Naser Durmishi, Deborah A. Nertney, Juha Karjalainen, Robert Swingler, Ditte Demontis, Vaidutis Kučinskas, Jennifer L. Moran, Leo McCluskey, Donald W. Black, Eric F.C. Cheung, Qiang Wang, Olli Pietilainen, Vera Golimbet, Anna K. Kähler, Clement C. Zai, Nigel Williams, Annelie Nordin, Wolfgang Maier, Bradley N. Smith, Ettore Beghi, Rosa Capozzo, Garth A. Nicholson, Markus M. Nöuthen, Jordan W. Smoller, Eric Y.H. Chen, Joseph D. Buxbaum, Letizia Mazzini, Andrea Malaspina, Antonio Julià, Stephanie Williams, Tracey L. Petryshen, Christine Payan, Johan G. Eriksson, Carmel M. Loughland, Elodie Drapeau, Lieuwe de Haan, Martin Begemann, Lukas Tittmann, Franziska Degenhardt, Mark Reimers, Jurgen Del Favero, Jacqueline I. Goldstein, Annelot M. Dekker, Sergi Papiol, Svetlana A. Limborska, René S. Kahn, Shuna Colville, Kelly L. Williams, Pamela Sklar, Diana O. Perkins, Lili Milani, Ayman H. Fanous, Nicola Ticozzi, Fernando Rivadeneira, Marianne de Visser, P. Nigel Leigh, James T.R. Walters, Josef Frank, Aiden Corvin, Silviu Alin Bacanu, John L. Waddington, Stephanie H. Witt, Tiina Paunio, Margot Albus, Catherine Lomen-Hoerth, Sara Marsal, Per Hoffmann, David Curtis, Cindy Maurel, Todd Lencz, Orietta Pansarasa, Manuel Mattheisen, Anneke J. van der Kooi, A. Hofman, Dermot Walsh, Hailiang Huang, Ann Olincy, Anders D. Børglum, Ricardo Rojas-García, William Sproviero, Albert C. Ludolph, Edward M. Scolnick, Danielle Posthuma, George N. Papadimitriou, Michael A. van Es, Fritz Zimprich, F. Anthony O'Neill, Lude Franke, Jouko Lönnqvist, Daniel G. Bradley, Sven Cichon, Susanna Abdulla, Kristel R. van Eijk, Ingrid Agartz, Elisabetta Pupillo, Milica Pejovic-Milovancevic, Antonia Ratti, Henrik B. Rasmussen, Kari Stefansson, Brendan Bulik-Sullivan, Béla Melegh, Stéphanie Millecamps, Janis Klovins, Enrico Domenici, Michael Sendtner, Kai-How Farh, Randy L. Buckner, Albert Hofman, Benjamin M. Neale, Naomi R. Wray, An Goris, Kang Sim, Lauren Elman, Giulio Genovese, Jens R. Wendland, Rita M. Cantor, Ariel Darvasi, Christina M. Hultman, Sandra D'Alfonso, Cristina Moglia, Carlos N. Pato, Sena Karachanak-Yankova, Nicholas John Craddock, Richard W. Orrell, Richard Bruggeman, Kenneth S. Kendler, Alan M. Pittman, Robin M. Murray, Richard E. Straub, Cathryn M. Lewis, Srdjan Djurovic, Vincent Meininger, Jeffrey A. Lieberman, Bertram Müller-Myhsok, Phil Lee, David J. Kavanagh, Srihari Gopal, Igor Nenadic, Matthew C. Keller, Christian R. Schubert, Jacob Gratten, Alexandra Durr, Roger Pamphlett, Douglas F. Levinson, Luba Kalaydjieva, Chiara Zecca, Anil K. Malhotra, Andre Franke, Vaughan J. Carr, Steven A. McCarroll, C. Robert Cloninger, Judit Bene, Ina Giegling, Wei Cheng, Hualin Simon Xi, Thomas Werge, Eric Strengman, Susanne Petri, Engilbert Sigurdsson, Mark Hansen, Patrick F. Sullivan, Kieran C. Murphy, Inge Joa, Complex Trait Genetics, McLaughlin, Russell L, Schijven, Dick, Van Rheenen, Wouter, Van Eijk, Kristel R, O'Brien, Margaret, Kahn, René S, Ophoff, Roel A, Goris, An, Bradley, Daniel G, Al-Chalabi, Ammar, Van Den Berg, Leonard H, Luykx, Jurjen J, Hardiman, Orla, Veldink, Jan H, Lee, S Hong, Project MinE GWAS Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Kučinskas, Vaidutis, Kučinskienė, Zita Aušrelė, Other departments, Neurology, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Adult Psychiatry, Schizophrenia Working Group of the Psychiatric Genomics Consortiumz, Germeys, Inez, Robberecht, Wim, and Van Damme, Philip
Subjects: 0301 basic medicine, Oncology, Genetics and Molecular Biology (all), Linkage disequilibrium, Multifactorial Inheritance, General Physics and Astronomy, Genome-wide association study, Comorbidity, VARIANTS, Neurodegenerative, Biochemistry, DISEASE, 3124 Neurology and psychiatry, Linkage Disequilibrium, Cohort Studies, 0302 clinical medicine, Genetics research, Odds Ratio, 2.1 Biological and endogenous factors, Amyotrophic lateral sclerosis, Aetiology, ARCHITECTURE, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Multidisciplinary, Chemistry (all), Motor neuron disease, Schizophrenia, BIPOLAR DISORDER, Single Nucleotide, Serious Mental Illness, 3. Good health, Mental Health, RC0346, motor neuron disease, Project MinE GWAS Consortium, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Science, European Continental Ancestry Group, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, White People, 03 medical and health sciences, Physics and Astronomy (all), Rare Diseases, SDG 3 - Good Health and Well-being, Clinical Research, Internal medicine, MD Multidisciplinary, mental disorders, medicine, Genetics, Journal Article, Humans, Genetic Predisposition to Disease, Family, Bipolar disorder, GENOME-WIDE ASSOCIATION, Polymorphism, Biology, METAANALYSIS, business.industry, Amyotrophic Lateral Sclerosis, Human Genome, Case-control study, 3112 Neurosciences, Neurosciences, General Chemistry, Odds ratio, medicine.disease, R1, Brain Disorders, 030104 developmental biology, genetics research, Case-Control Studies, RC0321, Linear Models, PLEIOTROPY, Human medicine, 3111 Biomedicine, Biochemistry, Genetics and Molecular Biology (all), ALS, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6; P=1 × 10−4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10−7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies., Relatives of patients with amyotrophic lateral sclerosis have an unexpectedly high incidence of schizophrenia. Here, the authors show a genetic link between the two conditions, suggesting shared neurobiological mechanisms.
Published: 2017
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202. An epigenome-wide association study of educational attainment (n = 10,767)

Author: George Davey Smith, Sara Hägg, Antti Latvala, Khadeeja Ismail, Cisca Wijmenga, Karen A. Mather, Laura Baglietto, Miina Ollikainen, Allison M. Hodge, Jari Lahti, Ian J. Deary, Andrew J Simpkin, Nicholas G. Martin, Ilkka Seppälä, Annette Peters, Silva Kasela, Riccardo E. Marioni, Mikko Hurme, Lisette Stolk, Pooja R. Mandaviya, Tõnu Esko, Kirsi Auro, Gianluca Severi, Jadwiga Buchwald, Silvia Polidoro, Yunzhang Wang, Neil M Davies, Pauliina Karell, Danielle Posthuma, Paolo Vineis, Roger L. Milne, Clemens Baumbach, Magnus Johannesson, Erdogan Taskesen, Richard Karlsson Linnér, Steve Horvath, Jaakko Kaprio, André G. Uitterlinden, Kyoko Watanabe, Christian Gieger, John M. Starr, Anni Joensuu, Melanie Waldenberger, Alison Pattie, Cornelius A. Rietveld, Pekka Jousilahti, Nicola J. Armstrong, Giovanni Fiorito, Sarah E. Medland, Lude Franke, Joyce B. C van Meurs, Graham G. Giles, Mika Kähönen, Andres Metspalu, Marc Jan Bonder, Lili Milani, Margaret J. Wright, Caroline L Relton, Terho Lehtimäki, Philipp Koellinger, Nancy L. Pedersen, Markus Perola, Elisabeth B. Binder, Allan F. McRae, Stella Iurato, Katri Räikkönen, Daniel J. Benjamin, Sarah E. Harris, Johan G. Eriksson, Perminder S. Sachdev, and Olli T. Raitakari
Subjects: Genetics, 0303 health sciences, Epigenome, Biology, Bioinformatics, Educational attainment, 03 medical and health sciences, 0302 clinical medicine, CpG site, DNA methylation, 030212 general & internal medicine, Epigenetics, Association (psychology), Body mass index, 030304 developmental biology, Cohort study
Abstract: The epigenome has been shown to be influenced by biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption, and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here, we provide evidence on the associations between epigenetic modifications—in our case, CpG methylation—and educational attainment (EA), a biologically distal environmental factor that is arguably among of the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10,767 individuals. While we find that 9 CpG probes are significantly associated with EA, only two remain associated when we restrict the sample to never-smokers. These two are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, their effect sizes on EA are far smaller than the known associations between CpG probes and biologically proximal environmental factors. Two analyses that combine the effects of many probes—polygenic methylation score and epigenetic-clock analyses—both suggest small associations with EA. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.
Published: 2017
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203. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Author: Lilia Maria de Azevedo Moreira, Joris A. Veltman, Anne Destree, Ercan Mihci, Banu Güzel Nur, Charles Marques Lourenço, Eva Rossier, Simon E. Fisher, Julie S. Cohen, Julie Hoover-Fong, Viviane Borges Ferreira, Mariana Aracena, Aida Telegrafi, Kátia Maria da Rocha, Alexander Hoischen, Julie McGaughran, Hülya Kayserili, Anthony Vandersteen, Lindsday A. Lambie, Bert B.A. de Vries, Sarah A. Graham, Heiko Reutter, Alessandra Baumer, Pelagia Deriziotis, Andreas Dufke, Maria Luisa Giovannucci Uzielli, Robert Smigiel, Theresa A. Grebe, Albert Schinzel, Christian Gilissen, Bregje W.M. van Bon, Careni Spencer, Marloes Steehouwer, Martin Smitka, Alice S. Brooks, Umut Altunoglu, Elisabetta Lapi, Charu Deshpande, Aleksandra Jezela-Stanek, Dafne Dain Gandelman Horovitz, Nataliya Di Donato, Ali Fatemi, Gwenaelle Andre, Lude Franke, Rocio Acuna-Hidalgo, Sipko van Dam, Clinical Genetics, Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Acuna-Hidalgo, Rocio, Deriziotis, Pelagia, Steehouwer, Marloes, Gilissen, Christian, Graham, Sarah, Dam, Sipko van, Hoover-Fong, Julie, Telegrafi, Aida, Destree, Anne, Smigiel, Robert, Lambie, Lindsday, Altunoglu, Umut, Lapi, Elisabetta, Uzielli, Maria Luisa, Aracena, Mariana, Nur, Banu G., Mihci, Ercan, Moreira, Lilia M. A., Borges Ferreira, Viviane, Horovitz, Dafne D. G., Rocha, Katia M. da, Jezela-Stanek, Aleksandra, Brooks, Alice S., Reutter, Heiko, Cohen, Julie S., Fatemi, Ali, Smitka, Martin, Grebe, Theresa A., Donato, Nataliya Di, Deshpande, Charu, Vandersteen, Anthony, Lourenço, Charles Marques, Dufke, Andreas, Rossier, Eva, Andre, Gwenaelle, Baumer, Alessandra, Spencer, Careni, McGaughran, Julie, Franke, Lude, Veltman, Joris A., Vries, Bert B. A. de, Schinzel, Albert, Fisher, Simon E., Hoischen, Alexander, Bon, Bregje W. van, School of Medicine, Department of Genetics, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: 0301 basic medicine, Male, Cancer Research, Somatic cell, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Gene Identification and Analysis, Gene Expression, medicine.disease_cause, Biochemistry, Germline, Hematologic Cancers and Related Disorders, Craniofacial Abnormalities, Exon, Database and Informatics Methods, Animal Cells, Medicine and Health Sciences, Nuclear protein, Child, Genetics (clinical), ATYPICAL CML, MYELODYSPLASTIC SYNDROME, Connective Tissue Cells, Genetics, Medicine, Nuclear Proteins, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], CLONAL HEMATOPOIESIS, Hematology, CHRONIC NEUTROPHILIC LEUKEMIA, Germline Mutation, Phenotype, 3. Good health, Cell Transformation, Neoplastic, Oncology, Connective Tissue, Child, Preschool, Hematologic Neoplasms, Female, Cellular Types, Anatomy, Neurodevelopmental disorders Radboud Institute for Molecular Life Sciences [Radboudumc 7], Hand Deformities, Congenital, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Research Article, Neuroinformatics, lcsh:QH426-470, Blotting, Western, Nails, Malformed, Protein degradation, Biology, Research and Analysis Methods, Cell Line, PROGRESSIVE BRAIN ATROPHY, 03 medical and health sciences, Germline mutation, Intellectual Disability, Leukemias, medicine, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, JUVENILE MYELOMONOCYTIC LEUKEMIA, CHRONIC MYELOID-LEUKEMIA, Protein Interactions, Molecular Biology, Mutation Detection, Ecology, Evolution, Behavior and Systematics, Genetic Association Studies, Germ-Line Mutation, Cell Proliferation, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], CHILDHOOD-CANCER, Gene Expression Profiling, DISEASE PROGRESSION, Infant, Newborn, Biology and Life Sciences, Cancers and Neoplasms, Proteins, Infant, CSF3R T618I, Cell Biology, Fibroblasts, Chronic neutrophilic leukemia, Chronic myeloid-leukemia, Juvenile myelomonocytic leukemia, Progressive brain atrophy, Myelodysplastic syndrome, Clonal hematopoiesis, Disease progression, Childhood-cancer, Atypical cml, Csf3r T618i, lcsh:Genetics, 030104 developmental biology, Biological Tissue, Biological Databases, HEK293 Cells, Mutation, Mutation Databases, Cancer research, Somatic Mutation, Carcinogenesis, Carrier Proteins
Abstract: Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients ( including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype., Radboud University Medical Center; Max Planck Society; European Research Council (ERC); VIDI; Netherlands Organization for Scientific Research (NWO); Netherlands Organization for Scientific Research
Published: 2017

204. Controlling bias and inflation in epigenome- and transcriptome-wide association studies using the empirical null distribution

Author: Peter Van ‘t Hof, Erik W. van Zwet, Matthijs Moed, Jeroen van Rooij, Joris Deelen, Freerk van Dijk, Nico Lakenberg, Cisca Wijmenga, André G. Uitterlinden, Rick Jansen, Maarten van Iterson, Dasha V. Zhernakova, Szymon M. Kielbasa, Martijn Vermaat, Marleen J. van Greevenbroek, Hailiang Mei, Cornelia M. van Duijn, René Pool, Jan Bot, Lude Franke, Sasha Zhernakova, Michiel van Galen, H. Eka D. Suchiman, Morris A. Swertz, Marc Jan Bonder, Bert A. Hofman, Wibowo Arindrarto, Joyce B. J. van Meurs, Jouke J. Hottenga, Coen D.A. Stehouwer, Jenny van Dongen, Michael M. P. J. Verbiest, René Luijk, P. Eline Slagboom, Patrick Deelen, Dorret I. Boomsma, Jan H. Veldink, Leonard H. van den Berg, Diana van Heemst, Aaron Isaacs, Marijn Verkerk, Peter A C 't Hoen, Ruud van der Breggen, Casper G. Schalkwijk, Ettje F. Tigchelaar, Peter Bram 't Hoen, Marian Beekman, Carla J.H. van der Kallen, Bastiaan T. Heijmans, P. Mila Jhamai, Irene Nooren, Biological Psychology, APH - Mental Health, APH - Methodology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, and Laboratory Medicine
Subjects: Epigenomics, 0301 basic medicine, Inflation, Netherlands Twin Register (NTR), Epigenome-and transcriptome-wide association studies, media_common.quotation_subject, Bayesian probability, Method, Empirical null distribution, Biology, Epigenesis, Genetic, 03 medical and health sciences, symbols.namesake, Bayes' theorem, Meta-Analysis as Topic, SDG 3 - Good Health and Well-being, Bias, Gibbs sampler, Econometrics, Null distribution, Epigenome- and transcriptome-wide association studies, Humans, Spurious relationship, Statistical hypothesis testing, media_common, Genetics, Smoking, Age Factors, Bayes Theorem, Meta-analysis, 030104 developmental biology, symbols, False positive rate, Transcriptome, Genome-Wide Association Study, Gibbs sampling
Abstract: We show that epigenome- and transcriptome-wide association studies (EWAS and TWAS) are prone to significant inflation and bias of test statistics, an unrecognized phenomenon introducing spurious findings if left unaddressed. Neither GWAS-based methodology nor state-of-the-art confounder adjustment methods completely remove bias and inflation. We propose a Bayesian method to control bias and inflation in EWAS and TWAS based on estimation of the empirical null distribution. Using simulations and real data, we demonstrate that our method maximizes power while properly controlling the false positive rate. We illustrate the utility of our method in large-scale EWAS and TWAS meta-analyses of age and smoking. Electronic supplementary material The online version of this article (doi:10.1186/s13059-016-1131-9) contains supplementary material, which is available to authorized users.
Published: 2017
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205. GAVIN

Author: Lude Franke, Tom J. de Koning, Eddy N. de Boer, Richard J. Sinke, Cisca Wijmenga, Alain Knopperts, Kristin M. Abbott, Birgit Sikkema-Raddatz, K. Joeri van der Velde, Cleo C. van Diemen, Morris A. Swertz, Rolf H. Sijmons, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Movement Disorder (MD)
Subjects: 0301 basic medicine, Computer science, DATABASE, Method, Automated protocol, Computational biology, Biology, DISEASE, 03 medical and health sciences, Gene Frequency, SCORE, Humans, Allele frequency, Gene, Genetic Association Studies, 030304 developmental biology, Genetics, 0303 health sciences, Clinical next-generation sequencing, Interpretation (logic), NONCODING VARIANTS, MUTATIONS, Gene sets, 030305 genetics & heredity, Computational Biology, Genetic Variation, computer.file_format, Pathogenicity, Molecular diagnostics, Gene-specific calibration, GENOME, MODEL, 030104 developmental biology, Open source, Variant classification, Executable, Protein impact, Pathogenicity prediction, computer, Software, PATHOGENICITY, Genome-Wide Association Study
Abstract: Here, we present GAVIN, a new method that delivers accurate classification of variants for next-generation sequencing molecular diagnostics. It is based on gene-specific calibrations of allele frequencies (from the ExAC database), effect impact (using SnpEff) and estimated deleteriousness (CADD scores) for >3,000 genes. In a benchmark on 18 clinical gene sets, we achieved a sensitivity of 91.6%, with a specificity of 78.2%. This accuracy was unmatched by 12 other tools we tested. We provide GAVIN as an online MOLGENIS service to annotate VCF files, and as open source executable for use in bioinformatic pipelines. It can be found athttp://molgenis.org/gavin.
Published: 2017
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206. Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia

Author: Esther A. R. Nibbeling, Monique H.M. Vlak, Cleo J. L. M. Smeets, Bart P.C. van de Warrenburg, Cleo C. van Diemen, Berry Kremer, Corien C. Verschuuren-Bemelmans, Anna Duarri, Lude Franke, Richard J. Sinke, Juha Karjalainen, Dineke S. Verbeek, Giovana B Bampi, Noam Adir, Elly F. Ippel, Cisca Wijmenga, Gerben van der Vries, Dennis Dooijes, Michiel R. Fokkens, Ewout R. Brunt, Jelkje J. de Boer-Bergsma, Molecular Neuroscience and Ageing Research (MOLAR), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Department of Health and Life Sciences, Movement Disorder (MD), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: 0301 basic medicine, MISSENSE MUTATIONS, Male, ALPHA-SYNUCLEIN, Gene regulatory network, POLYGLUTAMINE EXPANSIONS, Kinesins, whole exome sequencing, ACTIN DYNAMICS, 0302 clinical medicine, spinocerebellar ataxia, MOTOR DYSFUNCTION, Chlorocebus aethiops, Missense mutation, Exome, Gene Regulatory Networks, Exome sequencing, Genetics, Reverse Transcriptase Polymerase Chain Reaction, EPISODIC ATAXIA, neurodegeneration, DOMINANT CEREBELLAR ATAXIAS, Kinesin, Cadherins, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Pedigree, CALCIUM-CHANNEL, COS Cells, Spinocerebellar ataxia, PROTOCADHERIN FAT1, Female, Sequence Analysis, Plasmids, congenital, hereditary, and neonatal diseases and abnormalities, Biology, Real-Time Polymerase Chain Reaction, Transfection, HUMAN CANCERS, Cercopithecus aethiops, 03 medical and health sciences, Journal Article, medicine, Phospholipase D, synaptic transmission, Animals, Humans, Spinocerebellar Ataxias, EP300, Episodic ataxia, genetic network, DNA, Sequence Analysis, DNA, medicine.disease, nervous system diseases, 030104 developmental biology, HEK293 Cells, nervous system, Neurology (clinical), Candidate Disease Gene, E1A-Associated p300 Protein, 030217 neurology & neurosurgery
Abstract: Item does not contain fulltext The autosomal dominant cerebellar ataxias, referred to as spinocerebellar ataxias in genetic nomenclature, are a rare group of progressive neurodegenerative disorders characterized by loss of balance and coordination. Despite the identification of numerous disease genes, a substantial number of cases still remain without a genetic diagnosis. Here, we report five novel spinocerebellar ataxia genes, FAT2, PLD3, KIF26B, EP300, and FAT1, identified through a combination of exome sequencing in genetically undiagnosed families and targeted resequencing of exome candidates in a cohort of singletons. We validated almost all genes genetically, assessed damaging effects of the gene variants in cell models and further consolidated a role for several of these genes in the aetiology of spinocerebellar ataxia through network analysis. Our work links spinocerebellar ataxia to alterations in synaptic transmission and transcription regulation, and identifies these as the main shared mechanisms underlying the genetically diverse spinocerebellar ataxia types.
Published: 2017

207. Disease variants alter transcription factor levels and methylation of their binding sites

Author: Cornelia M. van Duijn, H. Eka D. Suchiman, Hailiang Mei, Bastiaan T. Heijmans, Michiel van Galen, Wibowo Arindrarto, Daria V. Zhernakova, Peter A C 't Hoen, Coen D.A. Stehouwer, Cisca Wijmenga, Erik W. van Zwet, Peter van ‘t Hof, Albert Hofman, Yang Li, Marian Beekman, Carla J.H. van der Kallen, P. Eline Slagboom, Joris Deelen, Szymon M. Kielbasa, Jouke J. Hottenga, Alexandra Zhernakova, René Luijk, Aaron Isaacs, Diana van Heemst, Jeroen van Rooij, P. Mila Jhamai, Irene Nooren, Iris Jonkers, Leonard H. van den Berg, René Pool, André G. Uitterlinden, Jenny van Dongen, Casper G. Schalkwijk, Lude Franke, Morris A. Swertz, Marc Jan Bonder, Nico Lakenberg, Marijn Verkerk, Rick Jansen, Michael Verbiest, Patrick Deelen, Mathieu Lemire, Ettje F. Tigchelaar, Thomas J. Hudson, Martijn Vermaat, Matthijs Moed, Jan H. Veldink, Roderick C. Slieker, Marleen M.J. van Greevenbroek, Jan Bot, Joyce B. J. van Meurs, Ruud van der Breggen, Maarten van Iterson, Dorret I. Boomsma, Freerk van Dijk, MUMC+: HVC Pieken Maastricht Studie (9), MUMC+: MA Interne Geneeskunde (3), RS: CARIM - R3.01 - Vascular complications of diabetes and the metabolic syndrome, Interne Geneeskunde, Biochemie, RS: FHML MaCSBio, RS: CARIM - R1.01 - Blood proteins & engineering, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, APH - Aging & Later Life, Epidemiology and Data Science, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL), Internal Medicine, and Epidemiology
Subjects: 0301 basic medicine, Male, Netherlands Twin Register (NTR), SUSCEPTIBILITY LOCI, PROTEINS, Quantitative Trait Loci, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Cohort Studies, 03 medical and health sciences, Epigenetics of physical exercise, SDG 3 - Good Health and Well-being, Genetics, Journal Article, Humans, Disease, Epigenetics, GENOME-WIDE ASSOCIATION, RNA-Directed DNA Methylation, Transcription factor, Epigenomics, 030304 developmental biology, GENE-EXPRESSION, 0303 health sciences, ARCHITECTURE, Binding Sites, Genome, Human, 030305 genetics & heredity, Epigenome, Methylation, DNA, DNA Methylation, Middle Aged, FAMILY, 030104 developmental biology, Phenotype, CpG site, Gene Expression Regulation, CTCF, Expression quantitative trait loci, DNA methylation, Illumina Methylation Assay, Female, Genome-Wide Association Study, Transcription Factors
Abstract: Most disease associated genetic risk factors are non-coding, making it challenging to design experiments to understand their functional consequences. Identification of expression quantitative trait loci (eQTLs) has been a powerful approach to infer downstream effects of disease variants but the large majority remains unexplained.. The analysis of DNA methylation, a key component of the epigenome, offers highly complementary data on the regulatory potential of genomic regions. However, a large-scale, combined analysis of methylome and transcriptome data to infer downstream effects of disease variants is lacking. Here, we show that disease variants have wide-spread effects on DNA methylation in trans that likely reflect the downstream effects on binding sites of cis-regulated transcription factors. Using data on 3,841 Dutch samples, we detected 272,037 independent cis-meQTLs (FDR < 0.05) and identified 1,907 trait-associated SNPs that affect methylation levels of 10,141 different CpG sites in trans (FDR < 0.05), an eight-fold increase in the number of downstream effects that was known from trans-eQTL studies. Trans-meQTL CpG sites are enriched for active regulatory regions, being correlated with gene expression and overlap with Hi-C determined interchromosomal contacts. We detected many trans-meQTL SNPs that affect expression levels of nearby transcription factors (including NFKB1, CTCF and NKX2-3), while the corresponding trans-meQTL CpG sites frequently coincide with its respective binding site. Trans-meQTL mapping therefore provides a strategy for identifying and better understanding downstream functional effects of many disease-associated variants.
Published: 2017
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208. Identification of context-dependent expression quantitative trait loci in whole blood

Author: Leonard H. van den Berg, Dorret I. Boomsma, Rick Jansen, Harm-Jan Westra, Daria V. Zhernakova, Peter A C 't Hoen, Albert Hofman, P. Mila Jhamai, Patrick Deelen, Jan Bot, Cisca Wijmenga, Irene Nooren, Yang I. Li, Szymon M. Kielbasa, Maarten van Iterson, Coen D.A. Stehouwer, Michiel van Galen, Freerk van Dijk, Jan H. Veldink, Marleen M.J. van Greevenbroek, Marian Beekman, Casper G. Schalkwijk, Hailiang Mei, Alexandra Zhernakova, Carla J.H. van der Kallen, Jouke J. Hottenga, Wibowo Arindrarto, Peter van ‘t Hof, René Pool, P. Eline Slagboom, André G. Uitterlinden, Diana van Heemst, Marijn Verkerk, Niek de Klein, Bastiaan T. Heijmans, Aaron Isaacs, Matthijs Moed, Lude Franke, Cornelia M. van Duijn, Ettje F. Tigchelaar, Marc Jan Bonder, Joyce B. J. van Meurs, Joris Deelen, Martijn Vermaat, Jenny van Dongen, Jeroen van Rooij, Morris A. Swertz, MUMC+: HVC Pieken Maastricht Studie (9), MUMC+: MA Interne Geneeskunde (3), RS: CARIM - R3.01 - Vascular complications of diabetes and the metabolic syndrome, Interne Geneeskunde, Biochemie, RS: FHML MaCSBio, RS: CARIM - R1.01 - Blood proteins & engineering, Laboratory Medicine, Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Complex Trait Genetics, Biological Psychology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL), Internal Medicine, and Epidemiology
Subjects: 0301 basic medicine, False discovery rate, Male, Netherlands Twin Register (NTR), Quantitative Trait Loci, Single-nucleotide polymorphism, Context (language use), Biology, Regulatory Sequences, Nucleic Acid, VARIANTS, Genome, Polymorphism, Single Nucleotide, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, DISEASE ASSOCIATIONS, INFECTION, Genetics, Journal Article, Humans, Cell Lineage, Genetic Predisposition to Disease, RNA, Messenger, CELL, Allele, Gene, GENE-EXPRESSION, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, HUMAN NEUTROPHILS, Blood Proteins, Middle Aged, ALLELES, Gene expression profiling, GENOME, 030104 developmental biology, OBESITY, Expression quantitative trait loci, Female, ENRICHMENT, 030217 neurology & neurosurgery
Abstract: Genetic risk factors often localize to noncoding regions of the genome with unknown effects on disease etiology. Expression quantitative trait loci (eQTLs) help to explain the regulatory mechanisms underlying these genetic associations. Knowledge of the context that determines the nature and strength of eQTLs may help identify cell types relevant to pathophysiology and the regulatory networks underlying disease. Here we generated peripheral blood RNA-seq data from 2,116 unrelated individuals and systematically identified context-dependent eQTLs using a hypothesis-free strategy that does not require previous knowledge of the identity of the modifiers. Of the 23,060 significant cis-regulated genes (false discovery rate (FDR) ≤ 0.05), 2,743 (12%) showed context-dependent eQTL effects. The majority of these effects were influenced by cell type composition. A set of 145 cis-eQTLs depended on type I interferon signaling. Others were modulated by specific transcription factors binding to the eQTL SNPs.
Published: 2017
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209. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Author: Emmi Tikkanen, Pascal Guénel, Rico Rueedi, Hamdi Mbarek, Gerardo Heiss, Hilary K. Finucane, Jing Hua Zhao, Peter K. Joshi, Mark I. McCarthy, Frank B. Hu, Stephen J. Chanock, Manjeet K. Bolla, Sandosh Padmanabhan, Vilmundur Gudnason, Chunyan He, Aarno Palotie, Reedik Mägi, Joe Dennis, Nicholas G. Martin, Behrooz Z. Alizadeh, Elisabeth Widen, Caroline Hayward, Penelope A. Lind, Magdalena Zoledziewska, Ayellet V. Segrè, Fergus J. Couch, Massimo Mangino, Melissa C. Southey, Immaculata De Vivo, Yongmei Liu, Ute Hamann, Angela Cox, Maartje J. Hooning, Iffat Rahman, Mitul Shah, Eric Boerwinkle, Matthias W. Beckmann, Catharina A. Hartman, Tanguy Corre, Kathryn L. Lunetta, Thérèse Truong, Anna Marie Mulligan, Caterina Barbieri, Robert Winqvist, Lili Milani, Cristina Menni, Frits R. Rosendaal, Pau Navarro, Christian Gieger, Ken K. Ong, Stig E. Bojesen, Susan M. Ring, Marjanka K. Schmidt, George McMahon, Deborah J. Thompson, Robert Karlsson, Nicholas J. Timpson, M. Arfan Ikram, Alexander Teumer, Jingmei Li, Christa Meisinger, Diana L. Cousminer, Doris Stöckl, Heli Nevanlinna, Teresa Nutile, Tim D. Spector, Eva Albrecht, Murielle Bochud, Linda Broer, Felix R. Day, Sven Bergmann, Renée de Mutsert, Nicholas J. Wareham, Marjo-Riitta Järvelin, Marzyeh Amini, Elisabeth Altmaier, Isabel dos-Santos-Silva, Peter Vollenweider, Douglas F. Easton, Tamara B. Harris, Ellen A. Nohr, Paul D.P. Pharoah, David J. Porteous, Jenny A. Visser, Ilja M. Nolte, Genevieve Lachance, Thomas Meitinger, Archie Campbell, Thomas Brüning, Graham G. Giles, Johan G. Eriksson, Nancy L. Pedersen, George Davey Smith, Gonneke Willemsen, Joanne M. Murabito, Francesco Cucca, Daniel I. Chasman, Eleonora Porcu, Nora Franceschini, Thibaud Boutin, Ulla Sovio, Roger L. Milne, Annette Peters, Lisette Stolk, Paul M. Ridker, Claudia Langenberg, Patrick Sulem, Toshiko Tanaka, Marike Gabrielson, Judith S. Brand, Unnur Thorsteindottir, Alison M. Dunning, Marina Ciullo, Julie E. Buring, Harold Snieder, Lude Franke, Meir J. Stampfer, Po-Ru Loh, Julian Peto, Ellen W. Demerath, Sheila Ulivi, Ivana Kolcic, Maristella Steri, Jouke J. Hottenga, Amanda B. Spurdle, Tõnu Esko, Katherine S. Pollard, Eulalia Catamo, Anneli Pouta, Kyriaki Michailidou, Dieter Flesch-Janys, James F. Wilson, Kamila Czene, Sean Whalen, Diether Lambrechts, Abhishek Sarkar, Laura Crisponi, Jonathan Tyrer, Antonietta Robino, Sara Lindström, Harald Grallert, Stefania Lenarduzzi, Peter Kraft, Patrik K. E. Magnusson, Lavinia Paternoster, Digna R. Velez Edwards, Mike A. Nalls, Per Hall, Joyce Y. Tung, Cinzia Sala, Lindsay Fernández-Rhodes, Ayush Giri, Hiltrud Brauch, André G. Uitterlinden, Alkes L. Price, Tracy A. O'Mara, Lynda M. Rose, John L. Hopper, David A. Hinds, Katherine S. Ruth, Arto Mannermaa, Uwe Völker, Rossella Sorice, Zoltán Kutalik, Debbie A Lawlor, Georgia Chenevix-Trench, Anna Murray, Albertine J. Oldehinkel, Bruce H. R. Wolffenbuttel, Hae Kyung Im, Dale R. Nyholt, Lenore J. Launer, Andres Metspalu, Irene L. Andrulis, Konstantin Strauch, Albert V. Smith, Daniela Toniolo, Eco J. C. de Geus, Jenny Chang-Claude, Marek Zygmunt, Dorret I. Boomsma, Harry Campbell, Peter Devilee, Henry Völzke, Daniela Ruggiero, Dennis O. Mook-Kanamori, John R. B. Perry, Javier Benitez, Grant W. Montgomery, David J. Hunter, David Karasik, Luigi Ferrucci, Emily Hallberg, Stefania Bandinelli, Hermann Brenner, Raymond Noordam, Sarah E. Medland, Peter A. Fasching, Qin Wang, Ilaria Gandin, Manolis Kellis, Hannes Helgason, Igor Rudan, Paolo Radice, Michela Traglia, Jian'an Luan, Robert A. Scott, Brumat Marco, Veronique Vitart, Kari Stefansson, Katharina E. Schraut, Ko Willems van Dijk, Ozren Polasek, Daniel F. Gudbjartsson, Natalia Perjakova, Joop S.E. Laven, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Mental Health, APH - Methodology, Art and Culture, History, Antiquity, Day, Felix R., Thompson, Deborah J., Helgason, Hanne, Chasman, Daniel I., Finucane, Hilary, Sulem, Patrick, Ruth, Katherine S., Whalen, Sean, Sarkar, Abhishek K., Albrecht, Eva, Altmaier, Elisabeth, Amini, Marzyeh, Barbieri, CATERINA MARIA, Boutin, Thibaud, Campbell, Archie, Demerath, Ellen, Giri, Ayush, He, Chunyan, Hottenga, Jouke J., Karlsson, Robert, Kolcic, Ivana, Loh, Po Ru, Lunetta, Kathryn L., Mangino, Massimo, Brumat, Marco, Mcmahon, George, Medland, Sarah E., Nolte, Ilja M., Noordam, Raymond, Nutile, Teresa, Paternoster, Lavinia, Perjakova, Natalia, Porcu, Eleonora, Rose, Lynda M., Schraut, Katharina E., Segrã¨, Ayellet V., Smith, Albert V., Stolk, Lisette, Teumer, Alexander, Andrulis, Irene L., Bandinelli, Stefania, Beckmann, Matthias W., Benitez, Javier, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E., Bolla, Manjeet K., Brand, Judith S., Brauch, Hiltrud, Brenner, Hermann, Broer, Linda, Brã¼ning, Thoma, Buring, Julie E., Campbell, Harry, Catamo, Eulalia, Chanock, Stephen, Chenevix Trench, Georgia, Corre, Tanguy, Couch, Fergus J., Cousminer, Diana L., Cox, Angela, Crisponi, Laura, Czene, Kamila, Davey Smith, George, De Geus, Eco J. C. N., De Mutsert, Renã©e, De Vivo, Immaculata, Dennis, Joe, Devilee, Peter, Dos Santos Silva, Isabel, Dunning, Alison M., Eriksson, Johan G., Fasching, Peter A., FernÃ¡ndez Rhodes, Lindsay, Ferrucci, Luigi, Flesch Janys, Dieter, Franke, Lude, Gabrielson, Marike, Gandin, Ilaria, Giles, Graham G., Grallert, Harald, Gudbjartsson, Daniel F., Guã©nel, Pascal, Hall, Per, Hallberg, Emily, Hamann, Ute, Harris, Tamara B., Hartman, Catharina A., Heiss, Gerardo, Hooning, Maartje J., Hopper, John L., Hu, Frank, Hunter, David J., Ikram, M. Arfan, Im, Hae Kyung, Jã¤rvelin, Marjo Riitta, Joshi, Peter K., Karasik, David, Kellis, Manoli, Kutalik, Zoltan, Lachance, Genevieve, Lambrechts, Diether, Langenberg, Claudia, Launer, Lenore J., Laven, Joop S. E., Lenarduzzi, Stefania, Li, Jingmei, Lind, Penelope A., Lindstrom, Sara, Liu, Yongmei, Luan, Jian'An, Mã¤gi, Reedik, Mannermaa, Arto, Mbarek, Hamdi, Mccarthy, Mark I., Meisinger, Christa, Meitinger, Thoma, Menni, Cristina, Metspalu, Andre, Michailidou, Kyriaki, Milani, Lili, Milne, Roger L., Montgomery, Grant W., Mulligan, Anna M., Nalls, Mike A., Navarro, Pau, Nevanlinna, Heli, Nyholt, Dale R., Oldehinkel, Albertine J., O'Mara, Tracy A., Padmanabhan, Sandosh, Palotie, Aarno, Pedersen, Nancy, Peters, Annette, Peto, Julian, Pharoah, Paul D. P., Pouta, Anneli, Radice, Paolo, Rahman, Iffat, Ring, Susan M., Robino, Antonietta, Rosendaal, Frits R., Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Sala, Cinzia F., Schmidt, Marjanka K., Scott, Robert A., Shah, Mitul, Sorice, Rossella, Southey, Melissa C., Sovio, Ulla, Stampfer, Meir, Steri, Maristella, Strauch, Konstantin, Tanaka, Toshiko, Tikkanen, Emmi, Timpson, Nicholas J., Traglia, Michela, Truong, Thã©rã¨se, Tyrer, Jonathan P., Uitterlinden, AndrÃ© G., Edwards, Digna R. Velez, Vitart, Veronique, Vã¶lker, Uwe, Vollenweider, Peter, Wang, Qin, Widen, Elisabeth, Van Dijk, Ko Willem, Willemsen, Gonneke, Winqvist, Robert, Wolffenbuttel, Bruce H. R., Zhao, Jing Hua, Zoledziewska, Magdalena, Zygmunt, Marek, Alizadeh, Behrooz Z., Boomsma, Dorret I., Ciullo, Marina, Cucca, Francesco, Esko, Tãµnu, Franceschini, Nora, Gieger, Christian, Gudnason, Vilmundur, Hayward, Caroline, Kraft, Peter, Lawlor, Debbie A., Magnusson, Patrik K. E., Martin, Nicholas G., Mook Kanamori, Dennis O., Nohr, Ellen A., Polasek, Ozren, Porteous, David, Price, Alkes L., Ridker, Paul M., Snieder, Harold, Spector, Tim D., Stã¶ckl, Dori, Toniolo, Daniela, Ulivi, Sheila, Visser, Jenny A., Vã¶lzke, Henry, Wareham, Nicholas J., Wilson, James F., LifeLines Cohort, Study, Interact, Consortium, Kconfab/aocs, Investigator, Endometrial Cancer Association, Consortium, Ovarian Cancer Association, Consortium, Practical, Consortium, Spurdle, Amanda B., Thorsteindottir, Unnur, Pollard, Katherine S., Easton, Douglas F., Tung, Joyce Y., Chang Claude, Jenny, Hinds, David, Murray, Anna, Murabito, Joanne M., Stefansson, Kari, Ong, Ken K., Perry, John R. B., Internal Medicine, Erasmus MC other, Medical Oncology, Epidemiology, Obstetrics & Gynecology, Day, Felix [0000-0003-3789-7651], Thompson, Deborah [0000-0003-1465-5799], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Langenberg, Claudia [0000-0002-5017-7344], Luan, Jian'an [0000-0003-3137-6337], Pharoah, Paul [0000-0001-8494-732X], Sovio, Ulla [0000-0002-0799-1105], Tyrer, Jonathan [0000-0003-3724-4757], Zhao, Jing Hua [0000-0003-4930-3582], Wareham, Nicholas [0000-0003-1422-2993], Easton, Douglas [0000-0003-2444-3247], Ong, Kenneth [0000-0003-4689-7530], Perry, John [0000-0001-6483-3771], Apollo - University of Cambridge Repository, Massachusetts Institute of Technology. Department of Mathematics, and Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Subjects: 0301 basic medicine, Male, Netherlands Twin Register (NTR), Ovarian Cancer Association Consortium, LOCI, Genome-wide association study, cancer risk, Menarche/genetics, Bioinformatics, GWAS, menarche, puberty, Body Mass Index, Risk Factors, Neoplasms, Databases, Genetic, WIDE ASSOCIATION, Endometrial Cancer Association Consortium, Ribonucleoproteins/genetics, 2. Zero hunger, Genetics, Age Factors, Genetics GWAS menarche, reproductive disorders, Neoplasms/genetics, 3. Good health, Ribonucleoproteins, Menarche, MENDELIAN RANDOMIZATION, Intercellular Signaling Peptides and Proteins, GROWTH, Female, TRAITS, Population variance, Intercellular Signaling Peptides and Proteins/genetics, Adolescent, Ubiquitin-Protein Ligases, kConFab/AOCS Investigators, Quantitative Trait Loci, Quantitative trait locus, Biology, METABOLISM, INHERITANCE, Polymorphism, Single Nucleotide, PRACTICAL consortium, 03 medical and health sciences, Genomic Imprinting, SDG 3 - Good Health and Well-being, Mendelian randomization, REGRESSION, medicine, Journal Article, Humans, cancer, Genetic Predisposition to Disease, 1000 Genomes Project, Membrane Proteins/genetics, METAANALYSIS, Puberty, Calcium-Binding Proteins, Membrane Proteins, Cancer, InterAct Consortium, Heritability, medicine.disease, BODY-MASS INDEX, 030104 developmental biology, genome-wide association studies, Puberty/genetics, LifeLines Cohort Study, Genome-Wide Association Study
Abstract: The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to similar to 370,000 women, we identify 389 independent signals (P
Published: 2017
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210. A genetic variant in granzyme B is associated with progression of joint destruction in rheumatoid arthritis

Author: Tore Saxne, M. K. Leijsma, Elisabet Lindqvist, Elisabeth Brouwer, Lude Franke, M. P. M. van der Linden, D. P. C. de Rooy, T. W. J. Huizinga, René E. M. Toes, Rachel Knevel, Nina A. Daha, Jeanine J. Houwing-Duistermaat, A. Krabben, A.H.M. van der Helm-van Mil, Harm-Jan Westra, Alexandra Zhernakova, S. Tsonaka, Anthony G. Wilson, Faculteit Medische Wetenschappen/UMCG, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: Adult, Male, Candidate gene, Genotype, PROTEOGLYCAN, Quantitative Trait Loci, Immunology, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Severity of Illness Index, Granzymes, Linkage Disequilibrium, GZMB, Arthritis, Rheumatoid, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, CARTILAGE, Humans, Immunology and Allergy, SNP, Medicine, COHORT, Pharmacology (medical), RNA, Messenger, Aged, 030304 developmental biology, 030203 arthritis & rheumatology, 0303 health sciences, RADIOGRAPHIC DAMAGE, business.industry, CHONDROCYTES, Genetic Variation, Middle Aged, medicine.disease, KILLER, 3. Good health, Minor allele frequency, Granzyme B, SEVERITY, Rheumatoid arthritis, Expression quantitative trait loci, Disease Progression, Female, Joints, business
Abstract: Objective Genetic factors account for an estimated 4558% of the variance in joint destruction in rheumatoid arthritis (RA). The serine proteinase granzyme B induces target cell apoptosis, and several in vitro studies suggest that granzyme B is involved in apoptosis of chondrocytes. Serum levels of granzyme B are increased in RA and are also associated with radiographic erosions. The aim of this study was to investigate GZMB as a candidate gene accounting for the severity of joint destruction in RA. Methods A total of 1,418 patients with 4,885 radiograph sets of the hands and feet from 4 independent cohorts were studied. First, explorative analyses were performed in 600 RA patients in the Leiden Early Arthritis Clinic cohort. Fifteen single-nucleotide polymorphisms (SNPs) tagging GZMB were tested. Significantly associated SNPs were genotyped in data sets representing patients from the Groningen, Sheffield, and Lund cohorts. In each data set, the relative increase in the annual rate of progression in the presence of a genotype was assessed. Data were summarized in a meta-analysis. The association of GZMB with the RNA expression level of the GZMB genomic region was tested by mapping expression quantitative trait loci (QTLs) on 1,469 whole blood samples. Results SNP rs8192916 was significantly associated with the rate of joint destruction in the first cohort and in the meta-analysis of all data sets. Patients homozygous for the minor allele of rs8192916 had a higher rate of joint destruction per year compared with other patients (P = 7.8 x 104). Expression QTL of GZMB identified higher expression in the presence of the minor allele of rs8192916 (P = 2.27 x 105). Conclusion SNP rs8192916 located in GZMB is associated with the progression of joint destruction in RA as well as with RNA expression in whole blood.
Published: 2013
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211. Genetic variants linked to education predict longevity

Author: Chris Power, Gail Davies, Ilaria Gandin, Panagiotis Deloukas, Jennifer E. Huffman, Pascal Timshel, Albert V. Smith, A. Kong, Paul Lichtenstein, Joseph K. Pickrell, Philipp Koellinger, P. L. De Jager, Reedik Mägi, G. B. Chen, Neil Pendleton, B. V. Halldórsson, George Dedoussis, Antti-Pekka Sarin, Natalia Pervjakova, Veikko Salomaa, Simona Vaccargiu, Ozren Polasek, K. H. Jöckel, Elisabeth Steinhagen-Thiessen, Y. Milaneschi, Jessica D. Faul, Patricia A. Boyle, Patrik K. E. Magnusson, Igor Rudan, Christopher P. Nelson, Vilmundur Gudnason, John Attia, Jürgen Wellmann, Kristi Läll, Konstantin Strauch, Stuart J. Ritchie, Markus Perola, Nicola Pirastu, Klaus Bønnelykke, Robert Karlsson, R. de Vlaming, Liisa Keltigangas-Jarvinen, Thomas Meitinger, Riccardo E. Marioni, Anu Loukola, Barbera Franke, Reinhold Schmidt, Maël Lebreton, Sven Oskarsson, E. Mihailov, Harm-Jan Westra, David R. Weir, Aldi T. Kraja, Niek Verweij, Peter M. Visscher, Hans-Jörgen Grabe, Johannes H. Brandsma, Mark Adams, R. J. Scott, G. Thorleifsson, Tõnu Esko, Mika Kähönen, Saskia P. Hagenaars, Patrick Turley, Johannes Waage, Peter Lichtner, Dragana Vuckovic, Antonietta Robino, Henry Völzke, Lydia Quaye, C. de Leeuw, Marika Kaakinen, Wei Zhao, Abdel Abdellaoui, Reka Nagy, Pedro Marques-Vidal, Johan G. Eriksson, Alan F. Wright, Andres Metspalu, Lavinia Paternoster, Momoko Horikoshi, Jan A. Staessen, Tarunveer S. Ahluwalia, Tian Liu, Martin Kroh, Aldo Rustichini, Giorgia Girotto, Cristina Venturini, Lili Milani, Jennifer A. Smith, Ginevra Biino, Tessel E. Galesloot, Michael A. Horan, Gerardus A. Meddens, James F. Wilson, Francesco Cucca, Peter Vollenweider, Erika Salvi, P. J. van der Most, Jari Lahti, Campbell A, David Laibson, Andrew Bakshi, Wolfgang Hoffmann, Tomi Mäki-Opas, Andreas J. Forstner, C M van Duijn, Nicholas G. Martin, Jonathan Marten, Ute Bültmann, Olli T. Raitakari, David A. Bennett, A.G. Uitterlinden, J. E. De Neve, Ingrid B. Borecki, WD Hill, Bo Jacobsson, Antti Latvala, Katri Räikkönen, Michael B. Miller, Jonathan P. Beauchamp, S. J. van der Lee, Ilja Demuth, Stavroula Kanoni, Veronique Vitart, Elina Hyppönen, N. Eklund, Francesco P. Cappuccio, Robert F. Krueger, Maria Pina Concas, Jaime Derringer, F. J.A. Van Rooij, Helena Schmidt, Patrick J. F. Groenen, Valur Emilsson, Rico Rueedi, Aysu Okbay, Georg Homuth, Edith Hofer, W. E. R. Ollier, Hannah Campbell, Paolo Gasparini, Mark Alan Fontana, Magnus Johannesson, Seppo Koskinen, Christopher F. Chabris, Jouke-Jan Hottenga, Christine Meisinger, Kari Stefansson, Jun Ding, Tia Sorensen, Brenda W.J.H. Penninx, Michelle N. Meyer, James J. Lee, Diego Vozzi, Gonneke Willemsen, K. Petrovic, Sarah E. Medland, Mary F. Feitosa, Henning Tiemeier, L. J. Launer, William G. Iacono, Massimo Mangino, Tune H. Pers, S. E. Baumeister, Christopher Oldmeadow, Grant W. Montgomery, Marjo-Riitta Järvelin, Jaakko Kaprio, Catharine R. Gale, S.F.W. Meddens, Kevin Thom, Klaus Berger, Pablo V. Gejman, Lude Franke, Gyda Bjornsdottir, Daniel J. Benjamin, Steven F. Lehrer, Krista Fischer, Alan R. Sanders, S. Ulivi, Katharina E. Schraut, Tim D. Spector, Amy Hofman, Matt McGue, Terho Lehtimäki, D. C. Liewald, Hans Bisgaard, L. Eisele, Astanand Jugessur, George Davey Smith, T.B. Harris, A.R. Thurik, Cornelius A. Rietveld, David Schlessinger, Z. Kutalik, David J. Porteous, Lynne J. Hocking, N J Timpson, A. Palotie, Lambertus A. Kiemeney, Ian J. Deary, Sharon L.R. Kardia, Peter K. Joshi, Nilesh J. Samani, Michael A. Province, Börge Schmidt, Richa Gupta, Carmen Amador, Erin B. Ware, Joyce Y. Tung, Ioanna-Panagiota Kalafati, Lars Bertram, Caroline Hayward, P. van der Harst, Penelope A. Lind, Kadri Kaasik, N.A. Furlotte, Sarah E. Harris, B. St Pourcain, Susan M. Ring, Zhihong Zhu, Alexander Teumer, Behrooz Z. Alizadeh, Judith M. Vonk, Blair H. Smith, A Payton, Wouter J. Peyrot, Jacob Gratten, Douglas F. Levinson, C Gieger, Leanne M. Hall, Andrew Heath, Mario Pirastu, Peter Eibich, Nancy L. Pedersen, Ronny Myhre, Antonio Terracciano, David M. Evans, Raymond A. Poot, Uwe Völker, Dorret I. Boomsma, Clemens Baumbach, Unnur Thorsteinsdottir, Ivana Kolcic, Jia-Shu Yang, Dalton Conley, A. A. Vinkhuyzen, Danielle Posthuma, Karl-Oskar Lindgren, Olga Rostapshova, Jonas Bacelis, Daniele Cusi, Yong Qian, Bjarni Gunnarsson, George McMahon, Elizabeth G. Holliday, Pamela A. F. Madden, David A. Hinds, David Cesarini, Jianxin Shi, Najaf Amin, Dale R. Nyholt, Applied Economics, Epidemiology, Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Aletta Jacobs School of Public Health, Public Health Research (PHR), Stem Cell Aging Leukemia and Lymphoma (SALL), Cardiovascular Centre (CVC), Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, EMGO - Mental health, Complex Trait Genetics, Biological Psychology, Marioni, RE, Ritchie, SJ, Joshi, PK, Hagenaars, SP, Hypponen, E, Benjamin, DJ, Social Science Genetic Association Consortium, Marioni, Re, Ritchie, Sj, Joshi, Pk, Hagenaars, Sp, Okbay, A, Fischer, K, Adams, Mj, Hill, Wd, Davies, G, Nagy, R, Amador, C, Läll, K, Metspalu, A, Liewald, Dc, Campbell, A, Wilson, Jf, Hayward, C, Esko, T, Porteous, Dj, Gale, Cr, Deary, Ij, Beauchamp, Jp, Fontana, Ma, Lee, Jj, Pers, Th, Rietveld, Ca, Turley, P, Chen, Gb, Emilsson, V, Meddens, Sf, Oskarsson, S, Pickrell, Jk, Thom, K, Timshel, P, de Vlaming, R, Abdellaoui, A, Ahluwalia, T, Bacelis, J, Baumbach, C, Bjornsdottir, G, Brandsma, Jh, Concas, MARIA PINA, Derringer, J, Furlotte, Na, Galesloot, Te, Girotto, Giorgia, Gupta, R, Hall, Lm, Harris, Se, Hofer, E, Horikoshi, M, Huffman, Je, Kaasik, K, Kalafati, Ip, Karlsson, R, Kong, A, Lahti, J, van der Lee, Sj, de Leeuw, C, Lind, Pa, Lindgren, Ko, Liu, T, Mangino, M, Marten, J, Mihailov, E, Miller, Mb, van der Most, Pj, Oldmeadow, C, Payton, A, Pervjakova, N, Peyrot, Wj, Qian, Y, Raitakari, O, Rueedi, R, Salvi, E, Schmidt, B, Schraut, Ke, Shi, J, Smith, Av, Poot, Ra, St Pourcain, B, Teumer, A, Thorleifsson, G, Verweij, N, Vuckovic, Dragana, Wellmann, J, Westra, Hj, Yang, J, Zhao, W, Zhu, Z, Alizadeh, Bz, Amin, N, Bakshi, A, Baumeister, Se, Biino, G, Bønnelykke, K, Boyle, Pa, Campbell, H, Cappuccio, Fp, De Neve, Je, Deloukas, P, Demuth, I, Ding, J, Eibich, P, Eisele, L, Eklund, N, Evans, Dm, Faul, Jd, Feitosa, Mf, Forstner, Aj, Gandin, Ilaria, Gunnarsson, B, Halldórsson, Bv, Harris, Tb, Heath, Ac, Hocking, Lj, Holliday, Eg, Homuth, G, Horan, Ma, Hottenga, Jj, de Jager, Pl, Jugessur, A, Kaakinen, Ma, Kähönen, M, Kanoni, S, Keltigangas Järvinen, L, Kiemeney, La, Kolcic, I, Koskinen, S, Kraja, At, Kroh, M, Kutalik, Z, Latvala, A, Launer, Lj, Lebreton, Mp, Levinson, Df, Lichtenstein, P, Lichtner, P, Loukola, A, Madden, Pa, Mägi, R, Mäki Opas, T, Marques Vidal, P, Meddens, Ga, Mcmahon, G, Meisinger, C, Meitinger, T, Milaneschi, Y, Milani, L, Montgomery, Gw, Myhre, R, Nelson, Cp, Nyholt, Dr, Ollier, We, Palotie, A, Paternoster, L, Pedersen, Nl, Petrovic, Ke, Räikkönen, K, Ring, Sm, Robino, Antonietta, Rostapshova, O, Rudan, I, Rustichini, A, Salomaa, V, Sanders, Ar, Sarin, Ap, Schmidt, H, Scott, Rj, Smith, Bh, Smith, Ja, Staessen, Ja, Steinhagen Thiessen, E, Strauch, K, Terracciano, A, Tobin, Md, Ulivi, Sheila, Vaccargiu, S, Quaye, L, van Rooij, Fj, Venturini, C, Vinkhuyzen, Aa, Völker, U, Völzke, H, Vonk, Jm, Vozzi, Diego, Waage, J, Ware, Eb, Willemsen, G, Attia, Jr, Bennett, Da, Berger, K, Bertram, L, Bisgaard, H, Boomsma, Di, Borecki, Ib, Bultmann, U, Chabris, Cf, Cucca, F, Cusi, D, Dedoussis, Gv, van Duijn, Cm, Eriksson, Jg, Franke, B, Franke, L, Gasparini, Paolo, Gejman, Pv, Gieger, C, Grabe, Hj, Gratten, J, Groenen, Pj, Gudnason, V, van der Harst, P, Hinds, Da, Hoffmann, W, Iacono, Wg, Jacobsson, B, Järvelin, Mr, Jöckel, Kh, Kaprio, J, Kardia, Sl, Lehtimäki, T, Lehrer, Sf, Magnusson, Pk, Martin, Ng, Mcgue, M, Pendleton, N, Penninx, Bw, Perola, M, Pirastu, Nicola, Pirastu, M, Polasek, O, Posthuma, D, Power, C, Province, Ma, Samani, Nj, Schlessinger, D, Schmidt, R, Sørensen, Ti, Spector, Td, Stefansson, K, Thorsteinsdottir, U, Thurik, Ar, Timpson, Nj, Tiemeier, H, Tung, Jy, Uitterlinden, Ag, Vitart, V, Vollenweider, P, Weir, Dr, Wright, Af, Conley, Dc, Krueger, Rf, Smith, Gd, Hofman, A, Laibson, Di, Medland, Se, Meyer, Mn, Johannesson, M, Visscher, Pm, Koellinger, Pd, Cesarini, D, and Benjamin, Dj
Subjects: Netherlands Twin Register (NTR), 0301 basic medicine, Male, Parents, education: longevity: prediction: polygenic score [genetics], Multifactorial Inheritance, polygenic, Lebenserwartung, Cohort Studies, 0302 clinical medicine, Databases, Genetic, Medicine, genetics, polygenic score, longevity, education, gene, Soziales und Gesundheit, media_common, Aged, 80 and over, education, Multidisciplinary, Longevity, Middle Aged, Biobank, humanities, 3. Good health, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Cohort, Educational Status, Female, Cohort study, Estonia, education, longevity, polygenic, Offspring, media_common.quotation_subject, Kultursektor, Prognose, Lernen, Lower risk, Education, 03 medical and health sciences, longevity, SDG 3 - Good Health and Well-being, Commentaries, Polygenic score, Journal Article, Genetics, Humans, Non-Profit-Sektor, Genetic Association Studies, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, ta1184, Genetic Variation, prediction, Educational attainment, United Kingdom, Gesundheitsstatistik, 030104 developmental biology, Genetic epidemiology, Scotland, Gesundheitszustand, Genetische Forschung, business, Prediction, Bildung, 030217 neurology & neurosurgery, Demography
Abstract: Educational attainment is associated with many health outcomes, including longevity. It is also known to be substantially heritable. Here, we used data from three large genetic epidemiology cohort studies (Generation Scotland, n = ∼17,000; UK Biobank, n = ∼115,000; and the Estonian Biobank, n = ∼6,000) to test whether education-linked genetic variants can predict lifespan length. We did so by using cohort members' polygenic profile score for education to predict their parents' longevity. Across the three cohorts, meta-analysis showed that a 1 SD higher polygenic education score was associated with ∼2.7% lower mortality risk for both mothers (total n deaths = 79,702) and ∼2.4% lower risk for fathers (total n deaths = 97,630). On average, the parents of offspring in the upper third of the polygenic score distribution lived 0.55 y longer compared with those of offspring in the lower third. Overall, these results indicate that the genetic contributions to educational attainment are useful in the prediction of human longevity. Marioni RE, Ritchie SJ, Joshi PK, Hagenaars SP, Okbay A, Fischer K, Adams MJ, Hill WD, Davies G, Social Science Genetic Association Consortium, Nagy R, Amador C, Läll K, Metspalu A, Liewald DC, Campbell A, Wilson JF, Hayward C, Esko T, Porteous DJ, Proceedings of the National Academy of Sciences of the United States of America, 2016, vol. 113, no. 47, pp. 13366-13371, 2016 Refereed/Peer-reviewed
Published: 2016
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212. Shared genetic variants suggest common pathways in allergy and autoimmune diseases

Author: Adnan Custovic, David P. Strachan, Joel N. Hirschhorn, Marjo-Riitta Järvelin, Nicholas J. Timpson, Nicole M. Warrington, Hans Bisgaard, Marie Standl, Elaine Fuertes, Lude Franke, John Henderson, Angela Simpson, Manuel A. R. Ferreira, David A. Hinds, Alan James, Tune H. Pers, Carla M. T. Tiesler, Johannes Waage, Joyce Y. Tung, Susanne Brix, Eskil Kreiner, Craig E. Pennell, Gerard H. Koppelman, Alexessander Couto Alves, Dirkje S. Postma, Klaus Bønnelykke, Medical Research Council (MRC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: 0301 basic medicine, HAY-FEVER, Allergy, Genetic association studies, genetic association studies, NF-KAPPA-B, Autoimmunity, Genome-wide association study, medicine.disease_cause, Autoimmune Disease, Genetic Association Studies, Single Nucleotide Polymorphism, 0302 clinical medicine, single nucleotide polymorphism, Autoimmune disease, Immunology and Allergy, Genetics, IMMUNE-RESPONSES, autoimmunity, CD4 T-CELLS, MULTIPLE-SCLEROSIS, 3. Good health, 1107 Immunology, Life Sciences & Biomedicine, SUSCEPTIBILITY LOCI, Immunology, Single-nucleotide polymorphism, autoimmune disease, Biology, Polymorphism, Single Nucleotide, Autoimmune Diseases, 03 medical and health sciences, Immune system, medicine, Hypersensitivity, SNP, Humans, GENOME-WIDE ASSOCIATION, 1,25-DIHYDROXYVITAMIN D-3, Genetic association, Science & Technology, medicine.disease, RISK LOCI, Single nucleotide polymorphism, RHEUMATOID-ARTHRITIS, 030104 developmental biology, 25-DIHYDROXYVITAMIN D-3, 030215 immunology, Genome-Wide Association Study
Abstract: Background: The relationship between allergy and autoimmune disorders is complex and poorly understood.Objective: We sought to investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms.Methods: We meta-analyzed 2 genome-wide association studies on self-reported allergy and sensitization comprising a total of 62,330 subjects. These results were used to calculate enrichment for single nucleotide polymorphisms (SNPs) previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites and characterized commonalities in variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DNase-hypersensitive site data. Finally, we compared the allergy data with those of all known diseases.Results: Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy (P = 1.4e-17) encompassing 29 loci at a false discovery rate of less than 0.05. Such enrichment seemed to be a general characteristic for autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in patients with autoimmune diseases but not those with other diseases.Conclusion: We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared disease mechanisms. Further studies of these shared genetic mechanisms might help in understanding the complex relationship between these diseases, including the parallel increase in disease prevalence.
Published: 2016
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213. Evidence for mitochondrial genetic control of autosomal gene expression

Author: Nicholas G. Martin, Luke R. Lloyd-Jones, Peter M. Visscher, Allan F. McRae, Alexander Holloway, Irfahan Kassam, Grant W. Montgomery, Joseph E. Powell, Lude Franke, Marc Jan Bonder, Anjali K. Henders, Tuan Qi, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: 0301 basic medicine, Male, Mitochondrial DNA, Nuclear gene, Pair-rule gene, GENOMES, NUCLEAR, Biology, Genome, DNA, Mitochondrial, Polymorphism, Single Nucleotide, DISEASE, Chromosomes, 03 medical and health sciences, 0302 clinical medicine, MTDNA, Gene cluster, Genetics, Animals, Humans, Allele, Molecular Biology, Gene, Genetics (clinical), Alleles, Regulation of gene expression, Cell Nucleus, Sex Characteristics, ASSOCIATION, General Medicine, Articles, ORGANELLAR, Mitochondria, 030104 developmental biology, Drosophila melanogaster, Gene Expression Regulation, Protein Biosynthesis, Female, 030217 neurology & neurosurgery
Abstract: The mitochondrial and nuclear genomes coordinate and co-evolve in eukaryotes in order to adapt to environmental changes. Variation in the mitochondrial genome is capable of affecting expression of genes on the nuclear genome. Sex-specific mitochondrial genetic control of gene expression has been demonstrated in Drosophila melanogaster, where males were found to drive most of the total variation in gene expression. This has potential implications for male-related health and disease resulting from variation in mtDNA solely inherited from the mother. We used a family-based study comprised of 47,323 gene expression probes and 78 mitochondrial SNPs (mtSNPs) from n = 846 individuals to examine the extent of mitochondrial genetic control of gene expression in humans. This identified 15 significant probe-mtSNP associations (P
Published: 2016

214. The effect of host genetics on the gut microbiome

Author: Daisy Jonkers, Soesma A Jankipersadsing, Ad A.M. Masclee, Jingyuan Fu, Lude Franke, Marc Jan Bonder, Ramnik J. Xavier, Daria V. Zhernakova, Cisca Wijmenga, Marten H. Hofker, Floris Imhann, Tommi Vatanen, Leo A. B. Joosten, Yang Li, Alexander Kurilshikov, María Carmen Cenit, Arnau Vich Vila, Melanie Schirmer, Zlatan Mujagic, Morris A. Swertz, Rinse K. Weersma, Hermie J. M. Harmsen, Martin Jaeger, Vinod Kumar, Sanne P. Smeekens, Patrick Deelen, Ettje F. Tigchelaar, Marije Oosting, Mihai G. Netea, Alexandra Zhernakova, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Microbes in Health and Disease (MHD), Center for Liver, Digestive and Metabolic Diseases (CLDM), Vascular Ageing Programme (VAP), Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL), MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), Promovendi NTM, Interne Geneeskunde, MUMC+: MA Maag Darm Lever (9), and RS: NUTRIM - R2 - Gut-liver homeostasis
Subjects: Adult, Male, 0301 basic medicine, EXPRESSION, Adolescent, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], DIVERSITY, Genome-wide association study, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], VARIANTS, Polymorphism, Single Nucleotide, Genome, LACTASE PERSISTENCE, Article, COLORECTAL-CANCER, Cohort Studies, Mice, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Genetics, Animals, Humans, SNP, GENOME-WIDE ASSOCIATION, Aged, Bifidobacterium, ta113, biology, RECEPTOR, Genome, Human, Gastrointestinal Microbiome, Immunity, Middle Aged, biology.organism_classification, CROHNS-DISEASE, 030104 developmental biology, Metagenomics, OBESITY, Microbial genetics, Female, Human genome, 030217 neurology & neurosurgery, Genome-Wide Association Study, INFLAMMATORY-BOWEL-DISEASE
Abstract: Contains fulltext : 171719.pdf (Publisher’s version ) (Closed access) The gut microbiome is affected by multiple factors, including genetics. In this study, we assessed the influence of host genetics on microbial species, pathways and gene ontology categories, on the basis of metagenomic sequencing in 1,514 subjects. In a genome-wide analysis, we identified associations of 9 loci with microbial taxonomies and 33 loci with microbial pathways and gene ontology terms at P < 5 x 10-8. Additionally, in a targeted analysis of regions involved in complex diseases, innate and adaptive immunity, or food preferences, 32 loci were identified at the suggestive level of P < 5 x 10-6. Most of our reported associations are new, including genome-wide significance for the C-type lectin molecules CLEC4F-CD207 at 2p13.3 and CLEC4A-FAM90A1 at 12p13. We also identified association of a functional LCT SNP with the Bifidobacterium genus (P = 3.45 x 10-8) and provide evidence of a gene-diet interaction in the regulation of Bifidobacterium abundance. Our results demonstrate the importance of understanding host-microbe interactions to gain better insight into human health.
Published: 2016

215. Genetic variants in RBFOX3 are associated with sleep latency

Author: Igor Rudan, Tõnu Esko, Wilfred F. J. van IJcken, Alan F. Wright, Caroline Hayward, Nathaniel F. Watson, Ben A. Oostra, Karla V. Allebrandt, Scott A. Melville, Steven R. Cummings, Aaron Isaacs, Gonneke Willemsen, Yurii S. Aulchenko, Albert Hofman, Fran Borovečki, Maris Teder-Laving, Sina A. Gharib, Brenda W.J.H. Penninx, Cornelia M. van Duijn, Josine G. van Mill, Dorret I. Boomsma, Harry Campbell, James F. Wilson, Katie L. Stone, Rutger W W Brouwer, Philip R. Gehrman, Annemarie I. Luik, Ozren Polasek, Naresh M. Punjabi, Jouke-Jan Hottenga, Jennifer E. Huffman, Daniel S. Evans, Martina Müller-Nurasyid, Ashley van der Spek, Andrew A. Hicks, Susan Redline, Peter P. Pramstaller, Fabiola M. Del Greco, Rudolf S N Fehrmann, Bertram Müller-Myhsok, Nicole Vogelzangs, Man Li, Lude Franke, Edwin Oole, Ayse Demirkan, Lina Zgaga, Karin Hek, Mirjam C G N van den Hout, Wen Hong Linda Kao, Gregory J. Tranah, Enda M. Byrne, Bruce M. Psaty, Hamdi Mbarek, Martha Merrow, Kristin D. Marciante, Josef Coresh, Henning Tiemeier, Grant W. Montgomery, Till Roenneberg, Susan Campbell, Ivana Kolcic, Juha Karjalainen, Zoran Dogas, Andres Metspalu, Ting Hsu Chen, Najaf Amin, André G. Uitterlinden, Nicholas G. Martin, Daniel J. Gottlieb, Andrew C. Heath, Thomas Meitinger, Heinz Erich Wichmann, Jacqueline M. Vink, Evelin Mihailov, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Biochemie, RS: FHML MaCSBio, RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Psychiatry, EMGO - Mental health, Epidemiology, Cell biology, Internal Medicine, Clinical Genetics, Child and Adolescent Psychiatry / Psychology, and Biological Psychology
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), EXPRESSION, Candidate gene, medicine.medical_specialty, Single-nucleotide polymorphism, Genome-wide association study, Delayed sleep phase, Nerve Tissue Proteins, DETERMINANTS, Biology, RECORDED SLEEP, Polymorphism, Single Nucleotide, Synaptic Transmission, Article, ONSET INSOMNIA, SELF-REPORT, sleep latency, gene, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Genetic linkage, Molecular genetics, Genetics, medicine, Insomnia, IMPUTATION, Humans, GENOME-WIDE ASSOCIATION, Genetics (clinical), Genetic association, LINKAGE ANALYSIS, Brain, Antigens, Nuclear, medicine.disease, FAMILY, 030104 developmental biology, CANDIDATE-GENE, medicine.symptom, Sleep, Developmental Psychopathology, 030217 neurology & neurosurgery
Abstract: Time to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 × 10(-08), 6.59 × 10(-)(08) and 9.17 × 10(-)(08)). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 × 10(-)(02), 7.0 × 10(-)(03) and 2.5 × 10(-)(03); combined meta-analysis P-values=5.5 × 10(-07), 5.4 × 10(-07) and 1.0 × 10(-07)). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 × 10(-316)) and the central nervous system (P-value=7.5 × 10(-)(321)). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitters including gamma-aminobutyric acid and various monoamines (P-values
Published: 2016
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216. Genomic analyses for age at menarche identify 389 independent signals and indicate BMI-independent effects of puberty timing on cancer susceptibility

Author: Nora Franceschini, Rico Rueedi, Gerardo Heiss, Behrooz Z. Alizadeh, Marike Gabrielson, Henry Völzke, Daniela Ruggiero, Judith S. Brand, Stig E. Bojesen, Iffat Rahman, Fergus J. Couch, Patrick Sulem, Harold Snieder, Jenny Chang-Claude, Caterina Barbieri, Ute Hamann, Hinds D, Pascal Guénel, Amanda B. Spurdle, Paul M. Ridker, Ulla Sovio, Roger L. Milne, Hamdi Mbarek, H Brenner, Hilary K. Finucane, Maristella Steri, Lude Franke, Emmi Tikkanen, Ivana Kolcic, Vitart, Ken K. Ong, Alison M. Dunning, Aarno Palotie, Caroline Hayward, Jouke J. Hottenga, Abhishek Sarkar, Stefania Lenarduzzi, Nicholas G. Martin, Katharina E. Schraut, Eva Albrecht, Hiltrud Brauch, Lisette Stolk, Joop S.E. Laven, Penelope A. Lind, Ilaria Gandin, Patrik K. E. Magnusson, Ellen A. Nohr, Tanguy Corre, Jing Hua Zhao, N J Timpson, Jenny A. Visser, Harald Grallert, P. A. Fasching, Susan M. Ring, Stöckl D, Grant W. Montgomery, Marzyeh Amini, Velez Edwards Dr, Thomas Meitinger, Qinghua Wang, David Karasik, Daniel I. Chasman, Nicholas J. Wareham, Alexander Teumer, Mellissa C. Southey, Kathryn L. Lunetta, S. E. Medland, Dieter Flesch-Janys, Maartje J. Hooning, Lili Milani, D Lambrechts, Ozren Polasek, Po-Ru Loh, James F. Wilson, Campbell A, Julian Peto, Ellen W. Demerath, Christian Gieger, de Geus Ej, Cox A, Javier Benítez, Mitul Shah, Eric Boerwinkle, Matthias W. Beckmann, Thorsteindottir U, Julie E. Buring, De Vivo I, Hannes Helgason, Paolo Radice, Tracy A. O'Mara, L. J. Launer, D. F. Gudbjartsson, Frits R. Rosendaal, C.A. Hartman, Stefania Bandinelli, Felix R. Day, Lynda M. Rose, van Dijk Kw, Natalia Perjakova, Anneli Pouta, Igor Rudan, Sven Bergmann, Kamila Czene, Georgia Chenevix-Trench, Pau Navarro, Sean Whalen, Heli Nevanlinna, Teresa Nutile, Diana L. Cousminer, Albert V. Smith, Massimo Mangino, Uwe Völker, Michela Traglia, Lindsay Fernández-Rhodes, Ayush Giri, Linda Broer, Albertine J. Oldehinkel, Isabel dos-Santos-Silva, Peter Vollenweider, Jian'an Luan, Nancy L. Pedersen, Irene L. Andrulis, Reedik Mägi, Robert Winqvist, Gonneke Willemsen, John L. Hopper, Gudnason, Marjanka K. Schmidt, David G. Hunter, Robert A. Scott, T.B. Harris, Joanne M. Murabito, David J. Porteous, Harry Campbell, Eleonora Porcu, D.I. Boomsma, Thibaud Boutin, M. A. Ikram, Doug Easton, Magdalena Zoledziewska, Meir J. Stampfer, Katherine S. Pollard, Eulalia Catamo, Tõnu Esko, M-R Jarvelin, Laura Crisponi, Claudia Langenberg, Marek Zygmunt, Antonietta Robino, Emily Hallberg, Manjeet K. Bolla, Ruth Ks, Bruce H W Wolffenbuttel, Lavinia Paternoster, Tyrer Jp, P. Kraft, George Davey-Smith, Robert Karlsson, Graham G. Giles, Jingmei Li, Pharoah Pd, Segrè Av, Marina Ciullo, Perry, Brumat Marco, Peter K. Joshi, Chunyan He, Sara Lindström, Joe Dennis, Thérèse Truong, Yongmei Liu, Anna Marie Mulligan, Mike A. Nalls, Cinzia Sala, K. Stefansson, Murray A, Debbie A Lawlor, Tung Jy, Deborah J. Thompson, Dennis O. Mook-Kanamori, Daniela Toniolo, Luigi Ferrucci, Peter Devilee, S. Chanock, Cristina Menni, George McMahon, Murielle Bochud, A. Metspalu, Tomohiro Tanaka, E. Widen, Hae Kyung Im, Dale R. Nyholt, Ilja M. Nolte, Thomas Brüning, Christina Meisinger, Annette Peters, Kyriaki Michailidou, Per Hall, Rossella Sorice, Genevieve Lachance, Johan G. Eriksson, Francesco Cucca, A.G. Uitterlinden, Z. Kutalik, Mark I. McCarthy, Frank B. Hu, Konstantin Strauch, Tim D. Spector, Elisabeth Altmaier, S. Ulivi, Alkes L. Price, Arto Mannermaa, Raymond Noordam, and de Mutsert R
Subjects: Genetics, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Genotype, Menarche, Trait, Cancer susceptibility, Genomics, Biology, 030304 developmental biology
Abstract: The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Here, we analyse 1000-Genome reference panel imputed genotype data on up to ~370,000 women and identify 389 independent signals (all P−8) for age at menarche, a notable milestone in female pubertal development. In Icelandic data from deCODE, these signals explain ~7.4% of the population variance in age at menarche, corresponding to one quarter of the estimated heritability. We implicate over 250 genes via coding variation or associated gene expression, and demonstrate enrichment across genes active in neural tissues. We identify multiple rare variants near the imprinted genes MKRN3 and DLK1 that exhibit large effects on menarche only when paternally inherited. Disproportionate effects of variants on early or late puberty timing are observed: single variant and heritability estimates are larger for early than late puberty timing in females. The opposite pattern is seen in males, with larger estimates for late than early puberty timing. Mendelian randomization analyses indicate causal inverse associations, independent of BMI, between puberty timing and risks for breast and endometrial cancers in women, and prostate cancer in men. In aggregate, our findings reveal new complexity in the genetic regulation of puberty timing and support new causal links with adult cancer risks.
Published: 2016
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217. Gene co-expression analysis for functional classification and gene-disease predictions

Author: Sipko, van Dam, Urmo, Võsa, Adriaan, van der Graaf, Lude, Franke, and João Pedro, de Magalhães
Subjects: Paper, Gene Expression Profiling, Computational Biology, transcriptomics, Phenotype, disease gene prediction, Gene Expression Regulation, Genes, Humans, Disease, Gene Regulatory Networks, next-generation sequencing, functional genomics, network analysis
Abstract: Gene co-expression networks can be used to associate genes of unknown function with biological processes, to prioritize candidate disease genes or to discern transcriptional regulatory programmes. With recent advances in transcriptomics and next-generation sequencing, co-expression networks constructed from RNA sequencing data also enable the inference of functions and disease associations for non-coding genes and splice variants. Although gene co-expression networks typically do not provide information about causality, emerging methods for differential co-expression analysis are enabling the identification of regulatory genes underlying various phenotypes. Here, we introduce and guide researchers through a (differential) co-expression analysis. We provide an overview of methods and tools used to create and analyse co-expression networks constructed from gene expression data, and we explain how these can be used to identify genes with a regulatory role in disease. Furthermore, we discuss the integration of other data types with co-expression networks and offer future perspectives of co-expression analysis.
Published: 2016

218. Corrigendum: Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Author: Aysu, Okbay, Bart M L, Baselmans, Jan-Emmanuel De, Neve, Patrick, Turley, Michel G, Nivard, Mark Alan, Fontana, S Fleur W, Meddens, Richard Karlsson, Linnér, Cornelius A, Rietveld, Jaime, Derringer, Jacob, Gratten, James J, Lee, Jimmy Z, Liu, Ronald, de Vlaming, Tarunveer S, Ahluwalia, Jadwiga, Buchwald, Alana, Cavadino, Alexis C, Frazier-Wood, Nicholas A, Furlotte, Victoria, Garfield, Marie Henrike, Geisel, Juan R, Gonzalez, Saskia, Haitjema, Robert, Karlsson, Sander W, van der Laan, Karl-Heinz, Ladwig, Jari, Lahti, Sven J, van der Lee, Penelope A, Lind, Tian, Liu, Lindsay, Matteson, Evelin, Mihailov, Michael B, Miller, Camelia C, Minica, Ilja M, Nolte, Dennis, Mook-Kanamori, Peter J, van der Most, Christopher, Oldmeadow, Yong, Qian, Olli, Raitakari, Rajesh, Rawal, Anu, Realo, Rico, Rueedi, Börge, Schmidt, Albert V, Smith, Evie, Stergiakouli, Toshiko, Tanaka, Kent, Taylor, Gudmar, Thorleifsson, Juho, Wedenoja, Juergen, Wellmann, Harm-Jan, Westra, Sara M, Willems, Wei, Zhao, Najaf, Amin, Andrew, Bakshi, Sven, Bergmann, Gyda, Bjornsdottir, Patricia A, Boyle, Samantha, Cherney, Simon R, Cox, Gail, Davies, Oliver S P, Davis, Jun, Ding, Nese, Direk, Peter, Eibich, Rebecca T, Emeny, Ghazaleh, Fatemifar, Jessica D, Faul, Luigi, Ferrucci, Andreas J, Forstner, Christian, Gieger, Richa, Gupta, Tamara B, Harris, Juliette M, Harris, Elizabeth G, Holliday, Jouke-Jan, Hottenga, Philip L De, Jager, Marika A, Kaakinen, Eero, Kajantie, Ville, Karhunen, Ivana, Kolcic, Meena, Kumari, Lenore J, Launer, Lude, Franke, Ruifang, Li-Gao, David C, Liewald, Marisa, Koini, Anu, Loukola, Pedro, Marques-Vidal, Grant W, Montgomery, Miriam A, Mosing, Lavinia, Paternoster, Alison, Pattie, Katja E, Petrovic, Laura, Pulkki-Råback, Lydia, Quaye, Katri, Räikkönen, Igor, Rudan, Rodney J, Scott, Jennifer A, Smith, Angelina R, Sutin, Maciej, Trzaskowski, Anna E, Vinkhuyzen, Lei, Yu, Delilah, Zabaneh, John R, Attia, David A, Bennett, Klaus, Berger, Lars, Bertram, Dorret I, Boomsma, Harold, Snieder, Shun-Chiao, Chang, Francesco, Cucca, Ian J, Deary, Cornelia M, van Duijn, Johan G, Eriksson, Ute, Bültmann, Eco J C, de Geus, Patrick J F, Groenen, Vilmundur, Gudnason, Torben, Hansen, Catharine A, Hartman, Claire M A, Haworth, Caroline, Hayward, Andrew C, Heath, David A, Hinds, Elina, Hyppönen, William G, Iacono, Marjo-Riitta, Järvelin, Karl-Heinz, Jöckel, Jaakko, Kaprio, Sharon L R, Kardia, Liisa, Keltikangas-Järvinen, Peter, Kraft, Laura D, Kubzansky, Terho, Lehtimäki, Patrik K E, Magnusson, Nicholas G, Martin, Matt, McGue, Andres, Metspalu, Melinda, Mills, Renée, de Mutsert, Albertine J, Oldehinkel, Gerard, Pasterkamp, Nancy L, Pedersen, Robert, Plomin, Ozren, Polasek, Christine, Power, Stephen S, Rich, Frits R, Rosendaal, Hester M, den Ruijter, David, Schlessinger, Helena, Schmidt, Rauli, Svento, Reinhold, Schmidt, Behrooz Z, Alizadeh, Thorkild I A, Sørensen, Tim D, Spector, John M, Starr, Kari, Stefansson, Andrew, Steptoe, Antonio, Terracciano, Unnur, Thorsteinsdottir, A Roy, Thurik, Nicholas J, Timpson, Henning, Tiemeier, André G, Uitterlinden, Peter, Vollenweider, Gert G, Wagner, David R, Weir, Jian, Yang, Dalton C, Conley, George Davey, Smith, Albert, Hofman, Magnus, Johannesson, David I, Laibson, Sarah E, Medland, Michelle N, Meyer, Joseph K, Pickrell, Tõnu, Esko, Robert F, Krueger, Jonathan P, Beauchamp, Philipp D, Koellinger, Daniel J, Benjamin, Meike, Bartels, and David, Cesarini
Subjects: Journal Article, Medizin, Genetics, Article
Abstract: We conducted genome-wide association studies of three phenotypes: subjective well-being (N = 298,420), depressive symptoms (N = 161,460), and neuroticism (N = 170,910). We identified three variants associated with subjective well-being, two with depressive symptoms, and eleven with neuroticism, including two inversion polymorphisms. The two depressive symptoms loci replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ̂| ≈ 0.8) strengthen the overall credibility of the findings, and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal/pancreas tissues are strongly enriched for association.
Published: 2016

219. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

Author: Aleksey Shatunov, An Goris, John Hardy, Thomas F. Meyer, Sandra D'Alfonso, Christian A. Hübner, Karol Estrada, Susana Pinto, Cristina Moglia, Perry T.C. van Doormaal, Simona Arcuti, Thomas Meitinger, Siddharthan Chandran, Kim A. Staats, Cinzia Bertolin, Peter M. Andersen, Ricardo Rojas-García, William Sproviero, Katie Sidle, François Salachas, Robert Swingler, Anna M. Blokhuis, Thomas M. Ringer, Emily P. McCann, Garth A. Nicholson, Lude Franke, Sven Cichon, Julian Grosskreutz, Markus M. Nöthen, Bernhard Landwehrmeyer, Lukas Tittmann, Jennifer A. Fifita, Christian R. Andres, Alice Vajda, Viviana Pensato, Lauren Elman, Gijs H.P. Tazelaar, Christian Lunetta, Patrick Vourc'h, Christopher Shaw, Gilbert Bensimon, Orla Hardiman, Kuang Lin, Pamela J. Shaw, Alessandro Padovani, Massimiliano Filosto, Jan H. Veldink, Boris Rogelj, Giacomo P. Comi, Matthew C. Kiernan, Philippe Corcia, Giancarlo Logroscino, Ammar Al-Chalabi, Blaž Koritnik, Safaa Saker-Delye, Ian P. Blair, Alexis Brice, Jochen H. Weishaupt, Gianni Sorarù, Maura Brunetti, Alan M. Pittman, Vincenzo Silani, Cindy Maurel, Alexandra Durr, Catherine Lomen-Hoerth, Matthew R. Robinson, Russell L. McLaughlin, Martina Wiedau-Pazos, Chiara Zecca, Nilo Riva, Ashley R. Jones, Andre Franke, Tune H. Pers, Roberto Del Bo, Dominic B. Rowe, Susanne Petri, Sara L. Pulit, John Q. Trojanowski, Wim Robberecht, Christine Payan, Otto W. Witte, Katharine Y. Zhang, Jesus S. Mora, Rick A.A. van der Spek, Urmo Võsa, Kevin P. Kenna, Marcella Rietschel, Milena Radivojkov-Blagojevic, Tino Prell, Philip Van Damme, Leja Dolenc Grošelj, Androniki Menelaou, Beatrice Stubendorff, Cristina Cereda, Kristel R. van Eijk, Leo McCluskey, Jean-François Dartigues, Rosa Capozzo, Markus Weber, Cinzia Tiloca, Michael A. van Es, Wouter van Rheenen, Paul I.W. de Bakker, Carsten Drepper, Bradley N. Smith, Ettore Beghi, Jian Yang, Peter M. Visscher, Hamid Hamzeiy, John Landers, A. Nazli Basak, Hylke M. Blauw, Annelot M. Dekker, Richard W. Orrell, Silvana Penco, Fernando Rivadeneira, Marianne de Visser, Ceren Tunca, Cathryn M. Lewis, Vincent Meininger, Andrea Malaspina, Raymond D. Schellevis, Leonard H. van den Berg, Rosanna Tortelli, Shuna Colville, Anneke J. van der Kooi, Ingo Kurth, Roger Pamphlett, Stéphanie Millecamps, Janez Zidar, Michael Sendtner, Simone de Jong, Roel A. Ophoff, Mamede de Carvalho, Karen E. Morrison, Robbert Jan Stuit, Letizia Mazzini, Jonathan D. Glass, Yesim Parman, Albert Hofman, Lea Leonardis, Naomi R. Wray, Meraida Polak, William J. Brands, Susanne Abdulla, Bernard Muller, Cinzia Gellera, Max Koppers, Pietro Fratta, John Powell, Charles Curtis, Peter Lichtner, Frank P. Diekstra, Adriano Chiò, Isabella Fogh, Federico Casale, Nicholas W. Wood, Katarina Vrabec, André G. Uitterlinden, Vivianna M. Van Deerlin, Gerome Breen, Wolfgang Lieb, Oliver Harschnitz, Nicola Ticozzi, P. Nigel Leigh, R. Jeroen Pasterkamp, Simon Topp, Metka Ravnik-Glavač, Christophe Tzourio, Robert H. Brown, Andrea Calvo, Orietta Pansarasa, Jelena Medic, Albert C. Ludolph, Elisabetta Pupillo, Antonia Ratti, Philippe Amouyel, Repositório da Universidade de Lisboa, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Erasmus MC other, Pediatric Surgery, Internal Medicine, Epidemiology, Neurology, and ANS - Neurodegeneration
Subjects: 0301 basic medicine, Population, EFFICIENT, Genome-wide association study, Locus (genetics), Biology, SUSCEPTIBILITY, SEQUENCE, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Munc18 Proteins, medicine, Journal Article, Genetics, Humans, Genetic Predisposition to Disease, Comparative Study, Amyotrophic lateral sclerosis, education, POPULATION, Genetic association, Netherlands, PITFALLS, education.field_of_study, HEXANUCLEOTIDE REPEAT, COMPLEX, Project MinE, Amyotrophic Lateral Sclerosis, Proteins, PATHWAYS, FRONTOTEMPORAL DEMENTIA, medicine.disease, Genetic architecture, Cytoskeletal Proteins, 030104 developmental biology, Case-Control Studies, Mutation, ALS, 030217 neurology & neurosurgery, Imputation (genetics), Myelin Proteins, Genome-Wide Association Study
Abstract: Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved., To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
Published: 2016
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220. Tobacco smoking is associated with DNA methylation of diabetes susceptibility genes

Author: Joyce Van Meurs, Marc Jan Bonder, Oscar Franco, Eric Sijbrands, Morris Swertz, René Pool, H. Eka D. Suchiman, Cornelia Van Duijn, Jenny Van Dongen, Pieternella Slagboom, Marian Beekman, Szymon Kiełbasa, Lude Franke, Abbas Dehghan, Patrick Deelen, Epidemiology, Internal Medicine, Biological Psychology, and Pediatric surgery
Subjects: 0301 basic medicine, Male, Endocrinology, Diabetes and Metabolism, LOCI, BIOS consortium, Genome-wide association study, Disease, Type 2 diabetes, DISEASE, 0302 clinical medicine, 1114 Paediatrics And Reproductive Medicine, Genetics, DNA methylation, Smoking, Middle Aged, Tobacco smoking, GENOME, ADIPOSE-TISSUE, 1117 Public Health And Health Services, CpG site, 030220 oncology & carcinogenesis, CPG SITES, Female, Life Sciences & Biomedicine, VALIDATION, Article, Endocrinology & Metabolism, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Diabetes mellitus, Internal Medicine, medicine, Humans, Risk factor, Gene, METAANALYSIS, Aged, Science & Technology, business.industry, 1103 Clinical Sciences, medicine.disease, 030104 developmental biology, Diabetes Mellitus, Type 2, REPLICATION, CIGARETTE-SMOKING, Gene expression, WIDE ANALYSIS, business, Genome-Wide Association Study
Abstract: Aims/hypothesis Tobacco smoking, a risk factor for diabetes, is an established modifier of DNA methylation. We hypothesised that tobacco smoking modifies DNA methylation of genes previously identified for diabetes. Methods We annotated CpG sites available on the Illumina Human Methylation 450K array to diabetes genes previously identified by genome-wide association studies (GWAS), and investigated them for an association with smoking by comparing current to never smokers. The discovery study consisted of 630 individuals (Bonferroni-corrected p = 1.4 × 10−5), and we sought replication in an independent sample of 674 individuals. The replicated sites were tested for association with nearby genetic variants and gene expression and fasting glucose and insulin levels. Results We annotated 3,620 CpG sites to the genes identified in the GWAS on type 2 diabetes. Comparing current smokers to never smokers, we found 12 differentially methylated CpG sites, of which five replicated: cg23161492 within ANPEP (p = 1.3 × 10−12); cg26963277 (p = 1.2 × 10−9), cg01744331 (p = 8.0 × 10−6) and cg16556677 (p = 1.2 × 10−5) within KCNQ1 and cg03450842 (p = 3.1 × 10−8) within ZMIZ1. The effect of smoking on DNA methylation at the replicated CpG sites attenuated after smoking cessation. Increased DNA methylation at cg23161492 was associated with decreased gene expression levels of ANPEP (p = 8.9 × 10−5). rs231356-T, which was associated with hypomethylation of cg26963277 (KCNQ1), was associated with a higher odds of diabetes (OR 1.06, p = 1.3 × 10−5). Additionally, hypomethylation of cg26963277 was associated with lower fasting insulin levels (p = 0.04). Conclusions/interpretation Tobacco smoking is associated with differential DNA methylation of the diabetes risk genes ANPEP, KCNQ1 and ZMIZ1. Our study highlights potential biological mechanisms connecting tobacco smoking to excess risk of type 2 diabetes. Electronic supplementary material The online version of this article (doi:10.1007/s00125-016-3872-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Published: 2016
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221. Proton pump inhibitors affect the gut microbiome

Author: Daisy Jonkers, Soesma A Jankipersadsing, Gerard Dijkstra, Zlatan Mujagic, Floris Imhann, María Carmen Cenit, Jingyuan Fu, Ramnik J. Xavier, Hermie J. M. Harmsen, Rinse K. Weersma, Lisa Vork, Ettje F. Tigchelaar, Lude Franke, Marc Jan Bonder, Alexandra Zhernakova, Cisca Wijmenga, Arnau Vich Vila, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Microbes in Health and Disease (MHD), Translational Immunology Groningen (TRIGR), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Organ Transplantation (GIOT), MUMC+: MA Med Staf Artsass Interne Geneeskunde (9), Promovendi NTM, RS: NUTRIM - R2 - Gut-liver homeostasis, and Interne Geneeskunde
Subjects: 0301 basic medicine, medicine.drug_class, Antibiotics, medicine.disease_cause, CLOSTRIDIUM-DIFFICILE INFECTION, THERAPY, Microbiology, COLONIZATION, 03 medical and health sciences, 0302 clinical medicine, DYSBIOSIS, INTESTINAL MICROBIOTA, medicine, ENTERIC INFECTIONS, Gut Microbiota, Escherichia coli, PATHOGENS, biology, Streptococcus, INTESTINAL BACTERIA, Gastrointestinal Microbiome, Gastroenterology, Clostridium difficile, biology.organism_classification, medicine.disease, PROTON PUMP INHIBITION, DIARRHEA, 3. Good health, Diarrhea, 030104 developmental biology, Enterococcus, OBESITY, BACTERIA, 030211 gastroenterology & hepatology, medicine.symptom, Dysbiosis, RESISTANCE
Abstract: BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or promoting colonisation by pathogens. In this study, we investigated the influence of PPI use on the gut microbiome.METHODS: The gut microbiome composition of 1815 individuals, spanning three cohorts, was assessed by tag sequencing of the 16S rRNA gene. The difference in microbiota composition in PPI users versus non-users was analysed separately in each cohort, followed by a meta-analysis.RESULTS: 211 of the participants were using PPIs at the moment of stool sampling. PPI use is associated with a significant decrease in Shannon's diversity and with changes in 20% of the bacterial taxa (false discovery rate CONCLUSIONS: The differences between PPI users and non-users observed in this study are consistently associated with changes towards a less healthy gut microbiome. These differences are in line with known changes that predispose to C. difficile infections and can potentially explain the increased risk of enteric infections in PPI users. On a population level, the effects of PPI are more prominent than the effects of antibiotics or other commonly used drugs.
Published: 2016

222. Genome-wide analysis shows no genomic predictors of ovarian response to stimulation by exogenous FSH for IVF

Author: Bart C.J.M. Fauser, Jeroen van Disseldorp, Cisca Wijmenga, Rene Eijkemans, Nick S. Macklon, Lude Franke, Frank J.M. Broekmans, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: Oncology, Infertility, Adult, SINGLE NUCLEOTIDE POLYMORPHISM, medicine.medical_specialty, Genotype, Granulosa cell, Single-nucleotide polymorphism, Genome-wide association study, Fertilization in Vitro, Biology, HORMONE RECEPTOR POLYMORPHISMS, Polymorphism, Single Nucleotide, INFERTILITY, Pregnancy, Internal medicine, medicine, SNP, Humans, CYCLE, genes, ovarian response, Likelihood Functions, genome-wide association study, PHARMACOGENETICS, IDENTIFICATION, Ovary, Obstetrics and Gynecology, WOMEN, medicine.disease, GENE, ovarian stimulation, REPRODUCTION, Endocrinology, Reproductive Medicine, HYPERSTIMULATION, IVF, Oocytes, Female, Follicle Stimulating Hormone, Body mass index, Embryo quality, Pharmacogenetics, Developmental Biology
Abstract: The current proof of principle study explores the possibility that a genetic single-nucleotide polymorphism (SNP) profile is associated with ovarian response to standardized stimulation for IVF using exogenous FSH. Such a pharmacogenomic approach could aid in rendering ovarian stimulation for IVF more tailored to the patient, potentially improving the delicate balance between efficacy, side effects and chances for complications. Genome-wide association (GWA) analysis using Illumina Human 610-Quad BeadChips was used in a homogeneous group of 102 healthy, Caucasian, regularly cycling, non-smoking women aged 38 years or less with a body mass index
Published: 2011
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223. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

Author: Dermot P.B. McGovern, Cathryn Edwards, Jeffrey C. Barrett, Katherine I. Morley, Michel Georges, Jonas Halfvarson, Lude Franke, Martine De Vos, Caroline Lagacé, Mauro D'Amato, Marc Lémann, Jerome I. Rotter, Richard H. Duerr, Vibeke Andersen, Marcin Imielinski, Deborah D. Proctor, Orazio Palmieri, David C. Wilson, Theodore M. Bayless, Nicholas K. Hayward, Talin Haritunians, Frank Seibold, Nicholas P. Anagnou, Marla Dubinsky, Leila Amininejad, Steven R. Brant, Christopher G. Mathew, Ramnik J. Xavier, John C. Mansfield, Julián Panés, Vito Annese, Mark J. Daly, Rebecca L. Roberts, James A B Floyd, Lisa A. Simms, Stephen L. Guthery, Murray L. Barclay, Laurent Peyrin-Biroulet, Debby Laukens, Richard K Russell, Stephan R. Targan, Mark Seielstad, Hakon Hakonarson, Miquel Sans, Thomas D. Walters, Gabrielle Boucher, Craig Mowat, Mathias Chamaillard, Carsten Büning, Stefan Schreiber, Arie Levine, Yashoda Sharma, Natalie J. Prescott, Gilles Jobin, Charlie W. Lees, A. Hillary Steinhart, Roel A. Ophoff, Suzannah Bumpstead, Edouard Louis, Nicole L. Glazer, David Ellinghaus, Richard B. Gearry, Kent D. Taylor, Cécile Libioulle, Rinse K. Weersma, Philippe Goyette, Leonard H. van den Berg, John D. Rioux, Cisca Wijmenga, Cyriel Y. Ponsioen, Jack Satsangi, Grant W. Montgomery, Timothy H. Florin, Rudolf S N Fehrmann, Limas Kupčinskas, Leonard Baidoo, Stephan Brand, Jürgen Glas, Carl A. Anderson, Anne M. Phillips, Ian C. Lawrance, Tariq Ahmad, Jeremy D. Sanderson, Judy H. Cho, Miles Parkes, Maria Gazouli, Laura Papi, Harm-Jan Westra, Robert N. Baldassano, James Lee, Zhen Zhen Zhao, Andre Franke, Paul Rutgeerts, Anne M. Griffiths, Aylwin Ng, Regan Scott, Jean-Frederic Colombel, Denis Franchimont, Hein W. Verspaget, Graham L. Radford-Smith, William G. Newman, Lee A. Denson, Leif Törkvist, Monica Milla, Subra Kugathasan, Philip Schumm, Severine Vermeire, Morten H. Vatn, Mark S. Silverberg, Jurgita Sventoraityte, Anna Latiano, Tom H. Karlsen, Jean-Pierre Hugot, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: Risk, Candidate gene, SUSCEPTIBILITY LOCI, PROTEIN, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Biology, Inflammatory bowel disease, Article, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, MULTIPLE, Genetics, medicine, Humans, GENOME-WIDE ASSOCIATION, 030304 developmental biology, Genetic association, GENE-EXPRESSION, 0303 health sciences, COMMON VARIANTS, medicine.disease, Ulcerative colitis, CROHNS-DISEASE, 3. Good health, Immunology, Expression quantitative trait loci, CELLS, 030211 gastroenterology & hepatology, Colitis, Ulcerative, ENRICHMENT, inflammatory-bowel-disease genome-wide association susceptibility loci crohns-disease common variants gene-expression cells multiple protein enrichment, INFLAMMATORY-BOWEL-DISEASE, Genome-Wide Association Study
Abstract: Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 x 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.
Published: 2011
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224. Author Correction: Individual variations in cardiovascular-disease-related protein levels are driven by genetics and gut microbiome

Author: Annique Claringbould, Cisca Wijmenga, Daria V. Zhernakova, Jingyuan Fu, Alexander Kurilshikov, Patrick Deelen, Marten H. Hofker, Folkert Kuipers, Biljana Atanasovska, Rudolf A. de Boer, Urmo Võsa, Serena Sanna, Trang H. Le, Lude Franke, Marc Jan Bonder, Alexandra Zhernakova, and Mihai G. Netea
Subjects: Genetics, Intestinal permeability, medicine, Disease, Biology, Line (text file), medicine.disease, Typographical error, Article, Sentence, Gut microbiome
Abstract: Despite a growing body of evidence, the role of the gut microbiome in cardiovascular diseases (CVDs) is still unclear. Here we present a systems-genome-wide and metagenome-wide association study on plasma concentrations of 92 CVD-related proteins in the population cohort Lifelines-DEEP. We identified genetic components for 73 proteins and microbial associations for 41 proteins, of which 31 were associated to both. The genetic and microbial factors identified mostly exert additive effects and collectively explain up to 76.6% of inter-individual variation (17.5% on average). Genetics contributes most to concentrations of immune-related proteins, while the gut microbiome contributes most to proteins involved in metabolism and intestinal health. We found several host-microbe interactions that impact proteins involved in epithelial function, lipid metabolism and central nervous system function. This study reveals important evidence for a joint genetic and microbial effect in cardiovascular disease and provides directions for future applications in personalized medicine.
Published: 2018
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225. Analysis of SNPs with an effect on gene expression identifies UBE2L3 and BCL3 as potential new risk genes for Crohn's disease

Author: Karin Fransen, Jinyuan Y. Fu, Adriaan A. van Bodegraven, Pieter Zanen, Daniel W. Hommes, J. Bart A. Crusius, Cleo C. van Diemen, Eleonora A. M. Festen, Rinse K. Weersma, Marijn C. Visschedijk, Cisca Wijmenga, Suzanne van Sommeren, Pieter C. F. Stokkers, Dirk J. de Jong, Lude Franke, Gastroenterology and hepatology, CCA - Disease profiling, Pathology, Gastroenterology and Hepatology, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: Male, medicine.medical_specialty, SUSCEPTIBILITY LOCI, PATHOGENESIS, Gene Expression, Genome-wide association study, Single-nucleotide polymorphism, Disease, Biology, Quantitative trait locus, VARIANTS, Polymorphism, Single Nucleotide, White People, Cohort Studies, Crohn Disease, B-Cell Lymphoma 3 Protein, Proto-Oncogene Proteins, Molecular genetics, Genetics, medicine, Humans, SNP, Genetic Predisposition to Disease, Molecular gastro-enterology and hepatology [IGMD 2], GENOME-WIDE ASSOCIATION, Molecular Biology, Gene, Genetics (clinical), genome-wide association inflammatory-bowel-disease susceptibility loci variants pathogenesis, Genetic association, General Medicine, Case-Control Studies, Ubiquitin-Conjugating Enzymes, Female, Genome-Wide Association Study, Transcription Factors, INFLAMMATORY-BOWEL-DISEASE
Abstract: Item does not contain fulltext Genome-wide association studies (GWAS) for Crohn's disease (CD) have identified loci explaining approximately 20% of the total genetic risk of CD. Part of the other genetic risk loci is probably partly hidden among signals discarded by the multiple testing correction needed in the analysis of GWAS data. Strategies for finding these hidden loci require large replication cohorts and are costly to perform. We adopted a strategy of selecting SNPs for follow-up that showed a correlation to gene expression [cis-expression quantitative trait loci (eQTLs)] since these have been shown more likely to be trait-associated. First we show that there is an overrepresentation of cis-eQTLs in the known CD-associated loci. Then SNPs were selected for follow-up by screening the top 500 SNP hits from a CD GWAS data set. We identified 10 cis-eQTL SNPs. These 10 SNPs were tested for association with CD in two independent cohorts of Dutch CD patients (1539) and healthy controls (2648). In a combined analysis, we identified two cis-eQTL SNPs that were associated with CD rs2298428 in UBE2L3 (P=5.22x10(-5)) and rs2927488 in BCL3 (P=2.94x10(-4)). After adding additional publicly available data from a previously reported meta-analysis, the association with rs2298428 almost reached genome-wide significance (P=2.40x10(-7)) and the association with rs2927488 was corroborated (P=6.46x10(-4)). We have identified UBE2L3 and BCL3 as likely novel risk genes for CD. UBE2L3 is also associated with other immune-mediated diseases. These results show that eQTL-based pre-selection for follow-up is a useful approach for identifying risk loci from a moderately sized GWAS.
Published: 2010
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226. Unintended Side Effects of the Digital Transition: European Scientists’ Messages from a Proposition-Based Expert Round Table

Author: Gerald Steiner, Dirk Helbing, Lorenz M. Hilty, André Reichel, Gabriela Viale Pereira, Arnim Grunwald, Roland W. Scholz, Sarah Diefenbach, Günther Schuh, Lude Franke, Stefan Klauser, Peter Parycek, Christian Montag, Ortwin Renn, Richard Hill, Jan Philipp Prote, Eric J. Bartelsman, Mattias Höjer, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), University of Zurich, Scholz, Roland W, Economics, and Tinbergen Institute
Subjects: Value (ethics), Technology, Knowledge management, Sociotechnical system, INFORMATION, Geography, Planning and Development, 2105 Renewable Energy, Sustainability and the Environment, 010501 environmental sciences, 01 natural sciences, Renewable energy sources, Digital transformation, 2308 Management, Monitoring, Policy and Law, GE1-350, Unintended side effects (unseens), Geography, Policy and Law, Environmental effects of industries and plants, MULTILEVEL, 05 social sciences, 333.7, Stakeholder, Digital curtain, Justice and Strong Institutions, Management, digital curtain, ddc:333.7, digital transformation, SDG 16 - Peace, Monitoring, Human systems engineering, 10009 Department of Informatics, Supply chain, TJ807-830, 000 Computer science, knowledge & systems, Management, Monitoring, Policy and Law, TD194-195, unintended side effects (unseens), proposition-based expert round tables, digital vaulting, SUSTAINABILITY, 3305 Geography, Planning and Development, FUTURE, SYSTEMS, 0502 economics and business, TECHNOLOGY, Renewable Energy, PRODUCTIVITY PARADOX, INTERNET, Value chain, 0105 earth and related environmental sciences, Planning and Development, ECONOMIC-GROWTH, Sustainability and the Environment, Renewable Energy, Sustainability and the Environment, business.industry, unintended side effects (unseens), proposition-based expert round tables, SDG 16 - Peace, Justice and Strong Institutions, Proposition-based expert round tables, Environmental sciences, Content analysis, ICT, Digital vaulting, SDG 12 - Responsible Consumption and Production, business, ddc:600, 050203 business & management
Abstract: We present the main messages of a European Expert Round Table (ERT) on the unintended side effects (unseens) of the digital transition. Seventeen experts provided 42 propositions from ten different perspectives as input for the ERT. A full-day ERT deliberated communalities and relationships among these unseens and provided suggestions on (i) what the major unseens are, (ii) how rebound effects of digital transitioning may become the subject of overarching research, and (iii) what unseens should become subjects of transdisciplinary theory and practice processes for developing socially robust orientations. With respect to the latter, the experts suggested that the &ldquo, ownership, economic value, use and access of data&rdquo, and, related to this, algorithmic decision-making call for transdisciplinary processes that may provide guidelines for key stakeholder groups on how the responsible use of digital data can be developed. A cluster-based content analysis of the propositions, the discussion and inputs of the ERT, and a theoretical analysis of major changes to levels of human systems and the human&ndash, environment relationship resulted in the following greater picture: The digital transition calls for redefining economy, labor, democracy, and humanity. Artificial Intelligence (AI)-based machines may take over major domains of human labor, reorganize supply chains, induce platform economics, and reshape the participation of economic actors in the value chain. (Digital) Knowledge and data supplement capital, labor, and natural resources as major economic variables. Digital data and technologies lead to a post-fuel industry (post-) capitalism. Traditional democratic processes can be (intentionally or unintentionally) altered by digital technologies. The unseens in this field call for special attention, research and management. Related to the conditions of ontogenetic and phylogenetic development (humanity), the ubiquitous, global, increasingly AI-shaped interlinkage of almost every human personal, social, and economic activity and the exposure to indirect, digital, artificial, fragmented, electronically mediated data affect behavioral, cognitive, psycho-neuro-endocrinological processes on the level of the individual and thus social relations (of groups and families) and culture, and thereby, the essential quality and character of the human being (i.e., humanity). The findings suggest a need for a new field of research, i.e., focusing on sustainable digital societies and environments, in which the identification, analysis, and management of vulnerabilities and unseens emerging in the sociotechnical digital transition play an important role.
Published: 2018
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227. Systematic genotype-phenotype analysis of autism susceptibility loci implicates additional symptoms to co-occur with autism

Author: Chantal Kemner, Lude Franke, Jacobine E. Buizer-Voskamp, Cisca Wijmenga, Herman van Engeland, Emma van Daalen, Roel A. Ophoff, J.A.S. Vorstman, Wouter G. Staal, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: databases, GENETICS, phenotype, genotype, Epigenetics of autism, CHILDREN, SPECTRUM DISORDERS, Biology, Contiguous gene syndrome, Article, Genetic linkage, medicine, OMIM : Online Mendelian Inheritance in Man, Cluster Analysis, Data Mining, Humans, Genetic Predisposition to Disease, Heritability of autism, medical subject headings, Genetic Association Studies, Genetics (clinical), EPILEPSY, Genetic association, Genetics, GENOMEWIDE SCREEN, PSYCHIATRIC-DISORDERS, HUMAN PHENOME, medicine.disease, Developmental disorder, ASSOCIATION ANALYSIS, Genetic Loci, Autism, autistic disorder, genetic, HUMAN HEIGHT, MENTAL-RETARDATION
Abstract: Many genetic studies in autism have been performed, resulting in the identification of multiple linkage regions and cytogenetic aberrations, but little unequivocal evidence for the involvement of specific genes exists. By identifying novel symptoms in these patients, enhanced phenotyping of autistic individuals not only improves understanding and diagnosis but also helps to define biologically more homogeneous groups of patients, improving the potential to detect causative genes. Supported by recent copy number variation findings in autism, we hypothesized that for some susceptibility loci, autism resembles a contiguous gene syndrome, caused by aberrations within multiple (contiguous) genes, which jointly increases autism susceptibility. This would result in various different clinical manifestations that might be rather atypical, but that also co-occur with autism. To test this hypothesis, 13 susceptibility loci, identified through genetic linkage and cytogenetic analyses, were systematically analyzed. The Online Mendelian Inheritance in Man database was used to identify syndromes caused by mutations in the genes residing in each of these loci. Subsequent analysis of the symptoms expressed within these disorders allowed us to identify 33 symptoms (significantly more than expected, P = 0.037) that were over-represented in previous reports mapping to these loci. Some of these symptoms, including seizures and craniofacial abnormalities, support our hypothesis as they are already known to co-occur with autism. These symptoms, together with ones that have not previously been described to co-occur with autism, might be considered for use as inclusion or exclusion criteria toward defining etiologically more homogeneous groups for molecular genetic studies of autism European Journal of Human Genetics (2010) 18, 588-595; doi:10.1038/ejhg.2009.206; published online 25 November 2009
Published: 2010
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228. Multiple common variants for celiac disease influencing immune gene expression

Author: Anna Rybak, Luigi Greco, Joseph A. Murray, Graham A. Heap, Katherine I. Morley, Maria Teresa Bardella, Päivi Saavalainen, Graham Turner, Jeffrey C. Barrett, Alexandra Zhernakova, Veikko Salomaa, Bárbara Dema, Róza Ádány, Lude Franke, Charles A. Mein, Owen T. McCann, Sarah E. Hunt, Roel A. Ophoff, Susan L. Neuhausen, Rudolf S N Fehrmann, Karen A. Hunt, Patrick Dubois, Kalle Kurppa, Roderick H. J. Houwen, Bożena Cukrowska, Nicholas A. Bockett, M. Luisa Mearin, Leena Peltonen, Elena Urcelay, Emilio G. de la Concha, Maria Cristina Mazzilli, Vanisha Mistry, Rinse K. Weersma, Concepción Núñez, Ross McManus, Harry J.M. Groen, Joachim J. Schweizer, Cisca Wijmenga, Gosia Trynka, Greetje J. Tack, Markku Mäki, Alessandra Curtotti, Rhian Gwilliam, Padraic MacMathuna, Maria Pia Sperandeo, Peter M. Green, David A. van Heel, Jihane Romanos, Dermot Kelleher, Ilma Rita Korponay-Szabó, Victorien M. Wolters, Isabel Polanco, Katri Kaukinen, Szilvia Fiatal, Elvira Grandone, Wieke H. M. Verbeek, Arpo Aromaa, Panos Deloukas, Leonard H. van den Berg, Elvira Oosterom, Barbara Mora, Donatella Barisani, Muddassar M. Mirza, Jan H. Veldink, Mathieu Platteel, Chris J. J. Mulder, Miguel Fernández-Arquero, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), Gastroenterology and hepatology, CCA - Immuno-pathogenesis, Dubois, P, Trynka, G, Franke, L, Hunt, K, Romanos, J, Curtotti, A, Zhernakova, A, Heap, G, Adány, R, Aromaa, A, Bardella, M, van den Berg, L, Bockett, N, de la Concha, E, Dema, B, Fehrmann, R, Fernández Arquero, M, Fiatal, S, Grandone, E, Green, P, Groen, H, Gwilliam, R, Houwen, R, Hunt, S, Kaukinen, K, Kelleher, D, Korponay Szabo, I, Kurppa, K, Macmathuna, P, Mäki, M, Mazzilli, M, Mccann, O, Mearin, M, Mein, C, Mirza, M, Mistry, V, Mora, B, Morley, K, Mulder, C, Murray, J, Núñez, C, Oosterom, E, Ophoff, R, Polanco, I, Peltonen, L, Platteel, M, Rybak, A, Salomaa, V, Schweizer, J, Sperandeo, M, Tack, G, Turner, G, Veldink, J, Verbeek, W, Weersma, R, Wolters, V, Urcelay, E, Cukrowska, B, Greco, L, Neuhausen, S, Mcmanus, R, Barisani, D, Deloukas, P, Barrett, J, Saavalainen, P, Wijmenga, C, and van Heel, D
Subjects: POSITIVE SELECTION, HETERODIMER, Genes, MHC Class I, Gene Expression, Genome-wide association study, Medical and Health Sciences, MHC Class I, 0302 clinical medicine, Immunopathology, RISK VARIANTS, 2.1 Biological and endogenous factors, Aetiology, POPULATION, Genetics, 0303 health sciences, education.field_of_study, THYMUS, Orvostudományok, Single Nucleotide, THYMOCYTES, Biological Sciences, 3. Good health, 030220 oncology & carcinogenesis, Egészségtudományok, Human, Biotechnology, Risk, SUSCEPTIBILITY LOCI, Population, Single-nucleotide polymorphism, CLEC16A, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Meta-Analysis as Topic, Humans, Allele, GENOME-WIDE ASSOCIATION, Polymorphism, education, 030304 developmental biology, Gene Expression Profiling, Human Genome, BIO/13 - BIOLOGIA APPLICATA, ALLELES, RHEUMATOID-ARTHRITIS, Gene expression profiling, Celiac Disease, Genes, Case-Control Studies, genome-wide association rheumatoid-arthritis susceptibility loci positive selection risk variants population alleles thymus heterodimer thymocytes, Digestive Diseases, Genome-Wide Association Study, Developmental Biology
Abstract: We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS)
Published: 2010
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229. Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction

Author: Bruno H. Stricker, Igor Rudan, Kenneth Rice, Karol Estrada, John M. C. Connell, Thomas Meitinger, Ying A. Wang, Mark Eijgelsheim, Stephan B. Felix, Gerjan Navis, Ozren Polasek, Jingyuan Fu, Fernando Rivadeneira, Joshua C. Bis, Elsayed Z. Soliman, James F. Wilson, Albert V. Smith, Alan F. Wright, Heyo K. Kroemer, Albert Hofman, David S. Siscovick, Steven Giovannone, Caroline Hayward, Fangyu Liu, Alvaro Alonso, Rinse K. Weersma, Aaron R. Folsom, Mark J. Caulfield, Alexander Teumer, Glenn I. Fishman, Christopher J. O'Donnell, Kristin D. Marciante, Martina Müller, Tamara B. Harris, Harold Snieder, Arne Pfeufer, Man Li, Andrew A. Hicks, Moritz F. Sinner, Wiek H. van Gilst, Sarah H. Wild, Nona Sotoodehnia, Jared W. Magnani, Leonard H. van den Berg, Patricia B. Munroe, L. Adrienne Cupples, Paul I.W. de Bakker, Jiaxiang Qu, Roel A. Ophoff, Daniel Levy, Mark P.S. Sie, Toby Johnson, Cornelia M. van Duijn, Lude Franke, Jacqueline C.M. Witteman, Tim D. Spector, Claudia B. Volpato, Folkert W. Asselbergs, Aravinda Chakravarti, Rudolf S N Fehrmann, Xiaowen Lu, Astrid Petersmann, Anna F. Dominiczak, Yalda Jamshidi, W. H. Linda Kao, Anna Köttgen, Susan R. Heckbert, Vilmundur Gudnason, H-Erich Wichmann, Nilesh J. Samani, Marcus Dörr, Christopher Newton-Cheh, Jan A. Kors, Thor Aspelund, Harry J.M. Groen, Irene Mateo Leach, Eric Boerwinkle, Gé van Herpen, Ben A. Oostra, Peter P. Pramstaller, Sandosh Padmanabhan, André G. Uitterlinden, Cisca Wijmenga, Dan E. Arking, Dirk J. van Veldhuisen, Rudolf A. de Boer, Bruce M. Psaty, Christine Schwienbacher, Ilja M. Nolte, Thomas J. Wang, Stefan Kääb, Christian Fuchsberger, Norman Klopp, Lenore J. Launer, Henry Völzke, Siegfried Perz, Aaron Isaacs, Sina A. Gharib, Uwe Völker, Harry Campbell, Jerome I. Rotter, Gerard J. te Meerman, Pim van der Harst, Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), Epidemiology, Public Health, Intensive Care, Internal Medicine, Medical Informatics, and Clinical Genetics
Subjects: Candidate gene, 030204 cardiovascular system & hematology, ELECTROCARDIOGRAM, DISEASE, Sodium Channels, genome-wide, QRS, Electrocardiography, Mice, 0302 clinical medicine, PR INTERVAL, Chromosomes, Human, Myocytes, Cardiac, TRANSCRIPTION FACTOR, GENE-EXPRESSION, Genetics, 0303 health sciences, RICH REPEAT PROTEIN, medicine.diagnostic_test, Models, Animal, Cardiology, cardiovascular system, Electrical conduction system of the heart, medicine.medical_specialty, QT INTERVAL DURATION, HEART-RATE, Mice, Transgenic, Biology, Sudden death, QT interval, Polymorphism, Single Nucleotide, NAV1.8 Voltage-Gated Sodium Channel, 03 medical and health sciences, QRS complex, Heart Conduction System, Internal medicine, medicine, Animals, Humans, cardiovascular diseases, PR interval, GENOME-WIDE ASSOCIATION, 030304 developmental biology, Computational Biology, medicine.disease, Animals, Newborn, Genetic Loci, Heart failure, SYSTEM, Genome-Wide Association Study
Abstract: The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genomewide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration ( P < 5 x 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.
Published: 2010
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230. Genome-wide analysis of allelic expression imbalance in human primary cells by high-throughput transcriptome resequencing

Author: Kate Downes, Matthew Rodesch, Patrick Dubois, Lude Franke, Thomas J. Albert, Nicholas A. Bockett, Barry C. Healy, Karen A. Hunt, John A. Todd, Richard Dobson, David Clayton, Charles A. Mein, Vincent Plagnol, David A. van Heel, Jennie H M Yang, and Graham A. Heap
Subjects: Heterozygote, Sequence analysis, Genome-wide association study, Biology, Allelic Imbalance, Polymorphism, Single Nucleotide, Epigenesis, Genetic, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Bias, Genetics, Humans, Disease, False Positive Reactions, Copy-number variation, RNA, Messenger, International HapMap Project, Molecular Biology, Gene, Base Pairing, Genetics (clinical), Alleles, Cells, Cultured, 030304 developmental biology, Sanger sequencing, 0303 health sciences, Gene Expression Profiling, Computational Biology, Reproducibility of Results, General Medicine, Articles, Sequence Analysis, DNA, High-Throughput Screening Assays, Genetic Loci, Expression quantitative trait loci, symbols, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Many disease-associated variants identified by genome-wide association (GWA) studies are expected to regulate gene expression. Allele-specific expression (ASE) quantifies transcription from both haplotypes using individuals heterozygous at tested SNPs. We performed deep human transcriptome-wide resequencing (RNA-seq) for ASE analysis and expression quantitative trait locus discovery. We resequenced double poly(A)-selected RNA from primary CD4(+) T cells (n = 4 individuals, both activated and untreated conditions) and developed tools for paired-end RNA-seq alignment and ASE analysis. We generated an average of 20 million uniquely mapping 45 base reads per sample. We obtained sufficient read depth to test 1371 unique transcripts for ASE. Multiple biases inflate the false discovery rate which we estimate to be approximately 50% for random SNPs. However, after controlling for these biases and considering the subset of SNPs that pass HapMap QC, 4.6% of heterozygous SNP-sample pairs show evidence of imbalance (P < 0.001). We validated four findings by both bacterial cloning and Sanger sequencing assays. We also found convincing evidence for allelic imbalance at multiple reporter exonic SNPs in CD6 for two samples heterozygous at the multiple sclerosis-associated variant rs17824933, linking GWA findings with variation in gene expression. Finally, we show in CD4(+) T cells from a further individual that high-throughput sequencing of genomic DNA and RNA-seq following enrichment for targeted gene sequences by sequence capture methods offers an unbiased means to increase the read depth for transcripts of interest, and therefore a method to investigate the regulatory role of many disease-associated genetic variants.
Published: 2009

231. Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappa B signalling

Author: Donatella Barisani, Chris J. J. Mulder, Graham A. Heap, M.L. Mearin, Jihane Romanos, Cisca Wijmenga, Fiona M. Stevens, Gosia Trynka, Marcel Bruinenberg, David S Sanders, Graham Turner, Peter D. Howdle, Valerie Trimble, D A van Heel, Lude Franke, Wieke H. M. Verbeek, Dermot Kelleher, Alexandra Zhernakova, C. G. F. de Kovel, Karen A. Hunt, Geoffrey Holmes, Ross McManus, Julian R.F. Walters, Anthony W. Ryan, Maria Teresa Bardella, Mathieu Platteel, University of Groningen, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL), Gastroenterology and hepatology, Other Research, Trynka, G, Zhernakova, A, Romanos, J, Franke, L, Hunt, K, Turner, G, Bruinenberg, M, Heap, G, Platteel, M, Ryan, A, de Kovel, C, Holmes, G, Howdle, P, Walters, J, Sanders, D, Mulder, C, Mearin, M, Verbeek, W, Trimble, V, Stevens, F, Kelleher, D, Barisani, D, Bardella, M, Mcmanus, R, van Heel, D, and Wijmenga, C
Subjects: Male, Linkage disequilibrium, Genotype, Genome-wide association study, Single-nucleotide polymorphism, Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, TNFAIP3, Linkage Disequilibrium, Coeliac disease, 6Q23, REGION, INFLAMMATION, medicine, Humans, IMMUNE-RESPONSE, Genetic Predisposition to Disease, Risk factor, GENOME-WIDE ASSOCIATION, SYSTEMIC-LUPUS-ERYTHEMATOSUS, Tumor Necrosis Factor alpha-Induced Protein 3, GENE-EXPRESSION, BIO/13 - BIOLOGIA APPLICATA, Intracellular Signaling Peptides and Proteins, NF-kappa B, Gastroenterology, Case-control study, Nuclear Proteins, celiac disease, NFkB, medicine.disease, RHEUMATOID-ARTHRITIS, DNA-Binding Proteins, Celiac Disease, A20, Case-Control Studies, Immunology, Female, Genes, rel, Signal Transduction
Abstract: Objective: Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the human leucocyte antigen (HLA) region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 single nucleotide polymorphisms (SNPs) that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts. Design: 458 SNPs were assayed in 1682 cases and 3258 controls from three populations (UK, Irish and Dutch). We combined the results with the original GWAS cohort (767 UK cases and 1422 controls); six SNPs showed association with p
Published: 2009
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232. Using genome-wide pathway analysis to unravel the etiology of complex diseases

Author: Yvonne T. van der Schouw, Clara C. Elbers, Cisca Wijmenga, Kristel R. van Eijk, Lude Franke, Flip Mulder, N. Charlotte Onland-Moret, University of Groningen, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: Risk, HAPLOTYPE MAP, Epidemiology, Concordance, Gene regulatory network, Single-nucleotide polymorphism, Genome-wide association study, pathway classification, VARIANTS, Biology, Polymorphism, Single Nucleotide, Genome, Humans, Genetic Predisposition to Disease, DGI, NETWORK, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Genetic association, Inflammation, Genetics, Models, Statistical, WTCCC, Models, Genetic, Haplotype, Genetic Diseases, Inborn, Case-control study, Chromosome Mapping, ASSOCIATION, RISK LOCI, GENE, INSIGHTS, Diabetes Mellitus, Type 2, Haplotypes, Case-Control Studies, genome-wide association studies, REPLICATION, type 2 diabetes, Genome-Wide Association Study
Abstract: Several genome-wide association studies (GWAS) have been published on various complex diseases. Although, new loci are found to be associated with these diseases, still only very little of the genetic risk for these diseases can be explained. As GWAS are still underpowered to find small main effects, and gene-gene interactions are likely to play a role, the data might currently not be analyzed to its full potential. In this study, we evaluated alternative methods to study GWAS data. Instead of focusing on the single nucleotide polymorphisms (SNPs) with the highest statistical significance, we took advantage of prior biological information and tried to detect overrepresented pathways in the GWAS data. We evaluated whether pathway classification analysis can help prioritize the biological pathways most likely to be involved in the disease etiology. In this study, we present the various benefits and limitations of pathway-classification tools in analyzing GWAS data. We show multiple differences in outcome between pathway tools analyzing the same dataset. Furthermore, analyzing randomly selected SNPs always results in significantly overrepresented pathways, large pathways have a higher chance of becoming statistically significant and the bioinformatics tools used in this study are biased toward detecting well-defined pathways. As an example, we analyzed data from two GWAS on type 2 diabetes (T2D): the Diabetes Genetics Initiative (DGI) and the Wellcome Trust Case Control Consortium (WTCCC). Occasionally the results from the DGI and the WTCCC GWAS showed concordance in overrepresented pathways, but discordance in the corresponding genes. Thus, incorporating gene networks and pathway classification tools into the analysis can point toward significantly overrepresented molecular pathways, which cannot be picked up using traditional single-locus analyses. However, the limitations discussed in this study, need to be addressed before these methods can be widely used. Geriet. Epidemiol. 33:419-431, 2009. (C) 2009 Wiley-Liss, Inc.
Published: 2009
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233. Genome-wide association study in premature ovarian failure patients suggests ADAMTS19 as a possible candidate gene

Author: Erik A H, Knauff, Lude, Franke, Michael A, van Es, Leonard H, van den Berg, Yvonne T, van der Schouw, Joop S E, Laven, Cornelius B, Lambalk, Annemieke, Hoek, Angelique J, Goverde, Sophie, Christin-Maitre, Aaron J, Hsueh, Cisca, Wijmenga, Bart C J M, Fauser, B J, Cohlen, Reproductive Origins of Adult Health and Disease (ROAHD), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Obstetrics & Gynecology, Immunology, ARD - Amsterdam Reproduction and Development, Center for Reproductive Medicine, Obstetrics and gynaecology, NCA - Hormones and the Brain, and ICaR - Ischemia and repair
Subjects: Adult, DISRUPTION, Candidate gene, endocrine system diseases, Single-nucleotide polymorphism, Genome-wide association study, Primary Ovarian Insufficiency, Biology, premature ovarian failure, Polymorphism, Single Nucleotide, DISEASE, 03 medical and health sciences, ADAMTS Proteins, 0302 clinical medicine, HORMONE, single nucleotide polymorphism, medicine, Humans, SNP, Allele, Allele frequency, 030304 developmental biology, Genetics, 0303 health sciences, 030219 obstetrics & reproductive medicine, genome-wide association study, Genome, Human, MOTHERS, Rehabilitation, DAUGHTERS, PREMUTATION, Obstetrics and Gynecology, candidate gene, WOMEN, MENOPAUSAL AGE, ADAMTS19, medicine.disease, female genital diseases and pregnancy complications, Premature ovarian failure, Human Reproduction [NCEBP 12], ADAM Proteins, Reproductive Medicine, GROWTH, Female, Candidate Disease Gene
Abstract: Contains fulltext : 80633.pdf (Publisher’s version ) (Closed access) BACKGROUND: Spontaneous premature ovarian failure (POF) occurs in 1% of women and has major implications for their fertility and health. Besides X chromosomal aberrations and fragile X premutations, no common genetic risk factor has so far been discovered in POF. Using high-density single nucleotide polymorphism (SNP) arrays, we set out to identify new genetic variants involved in this condition. METHODS: A genome-wide association study involving 309 158 SNPs was performed in 99 unrelated idiopathic Caucasian POF patients and 235 unrelated Caucasian female controls. A replication study on the most significant finding was performed. We specifically focused on chromosomal areas and candidate genes previously implicated in POF. RESULTS: Suggestive genome-wide significant association was observed for rs246246 (allele frequency P = 6.0 x 10(-7)) which mapped to an intron of ADAMTS19, a gene known to be up-regulated in the female mouse gonads during sexual differentiation. However, replication in an independent Dutch cohort (60 POF patients and 90 controls) could not confirm a clear association (P = 4.1 x 10(-5) in a joint analysis). We did not observe strong evidence for any of 74 selected POF candidate genes or linkage regions being associated with idiopathic POF in Caucasian females, although suggestive association (P < 0.005) was observed for SNPs that mapped in BDNF, CXCL12, LHR, USP9X and TAF4B. CONCLUSION: We observed a possible association between POF and a SNP in a biologically plausible candidate gene. Although limited by sample size, this proof-of-principle study's findings reveal ADAMTS19 as a possible candidate gene for POF and thus a larger follow-up study is warranted.
Published: 2009
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234. Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP

Author: Alienke J. Monsuur, Cisca Wijmenga, Alexandra Zhernakova, Gosia Trynka, Rian M. Nijmeijer, Ruben van 't Slot, Adriaan A. van Bodegraven, Lude Franke, Marianna Bevova, E Festen, Pieter C. F. Stokkers, Roel Heijmans, J. Bart A. Crusius, H. Marike Boezen, Rinse K. Weersma, David A. van Heel, Cleo C. van Diemen, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, CCA -Cancer Center Amsterdam, Gastroenterology and Hepatology, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Groningen Research Institute for Asthma and COPD (GRIAC), Stem Cell Aging Leukemia and Lymphoma (SALL), Gastroenterology and hepatology, CCA - Disease profiling, and Pathology
Subjects: Male, EXPRESSION, Linkage disequilibrium, Population, PATHOGENESIS, Single-nucleotide polymorphism, Genome-wide association study, Biology, ADAPTER PROTEIN CARD9, Inflammatory bowel disease, Linkage Disequilibrium, Crohn Disease, Report, Genetics, medicine, RISK VARIANTS, Humans, SNP, Genetics(clinical), Genetic Predisposition to Disease, Interleukin-18 Receptor beta Subunit, GENOME-WIDE ASSOCIATION, education, Genetics (clinical), POPULATION, TOLL-LIKE RECEPTORS, Crohn's disease, education.field_of_study, medicine.disease, Ulcerative colitis, Immunity, Innate, digestive system diseases, CARD Signaling Adaptor Proteins, Immunology, CELLS, Colitis, Ulcerative, Female, IL-18, INFLAMMATORY-BOWEL-DISEASE
Abstract: The two main phenotypes of inflammatory bowel disease (IBD)--Crohn's disease (CD) and ulcerative colitis (UC)--are chronic intestinal inflammatory disorders with a complex genetic background. Using a three-stage design, we performed a functional candidate-gene analysis of innate immune pathway in IBD. In phase I, we typed 354 SNPs from 85 innate immunity genes in 520 Dutch IBD patients (284 CD, 236 UC) and 808 controls. In phase II, ten autosomal SNPs showing association at p < 0.006 in phase I were replicated in a second cohort of 545 IBD patients (326 CD, 219 UC) and 360 controls. In phase III, four SNPs with p < 0.01 in the combined phase I and phase II analysis were genotyped in an additional 786 IBD samples (452 CD, 334 UC) and 768 independent controls. Joint analysis of 1851 IBD patients (1062 CD, 789 UC) and 1936 controls demonstrated strong association to the IL18RAP rs917997 SNP for both CD and UC (p(IBD) 1.9 x 10(-8); OR 1.35). Association in CD is independently supported by the Crohn's disease dataset of the Wellcome Trust Case Control Consortium (imputed SNP rs917997, p = 9.19 x 10(-4)). In addition, an association of the CARD9 rs10870077 SNP to CD and UC was observed (p(IBD) = 3.25 x 10(-5); OR 1.21). Both genes are located in extended haplotype blocks on 2q11-2q12 and 9q34.3, respectively. Our results indicate two IBD loci and further support the importance of the innate immune system in the predisposition to both CD and UC.
Published: 2008
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235. HHEX gene polymorphisms are associated with type 2 diabetes in the Dutch Breda cohort

Author: Yvonne T. van der Schouw, Ronit Shiri-Sverdlov, Cisca Wijmenga, Jana V. van Vliet-Ostaptchouk, Clara C. Elbers, Lude Franke, Timon W. van Haeften, Marten H. Hofker, N. Charlotte Onland-Moret, Moleculaire Genetica, RS: NUTRIM - R2 - Gut-liver homeostasis, RS: CARIM School for Cardiovascular Diseases, University of Groningen, Science in Healthy Ageing & healthcaRE (SHARE), Bioinformatics, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Center for Liver, Digestive and Metabolic Diseases (CLDM), Vascular Ageing Programme (VAP), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: Male, Hematopoietically expressed homeobox, VARIANT, SNP, Genome-wide association study, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, susceptibility, HHEX, Cohort Studies, WNT, Genetic model, Genetics, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Genetics (clinical), Aged, Genes, Dominant, Netherlands, Aged, 80 and over, Homeodomain Proteins, biology, Haplotype, Case-control study, association, Odds ratio, Middle Aged, RISK LOCI, INSULIN, Breda cohort, TCF7L2, Diabetes Mellitus, Type 2, Haplotypes, Case-Control Studies, REPLICATION, HEX, Female, type 2 diabetes, biology.gene, Transcription Factors
Abstract: Recently, the hematopoietically expressed homeobox ( HHEX) gene, encoding a transcription factor, was identified in a large genome-wide scan in French individuals as a type 2 diabetes ( T2D)-susceptibility locus. We aimed to check whether this finding could be replicated in a Dutch T2D cohort. Two common variants ( rs7923837 and rs1111875) located near the HHEX gene were genotyped in 501 unrelated T2D patients and in 920 healthy controls. The major alleles of both variants were overrepresented in T2D cases compared with controls ( 66.7 vs 64.1%, P = 0.16 for rs7923837 and 64.6 vs 60.4%, P = 0.027 for rs1111875). For both polymorphisms, the risk for T2D was significantly increased in carriers of the major alleles ( rs7923837: odds ratio ( OR): 1.57, 95% confidence interval ( CI): 1.08 - 2.27, P = 0.017 and rs1111875: OR: 1.68, 95% CI: 1.19 - 2.35, P = 0.003). The haplotype analysis did not reveal a risk haplotype that provided stronger evidence for association with T2D than each variant individually. Assuming a dominant genetic model, the population-attributable risks for diabetes due to the at- risk alleles of rs7923837 and rs1111875 were estimated to be 33 and 36%, respectively. These data provide evidence that variants near the HHEX gene contribute to the risk of T2D in a Dutch population.
Published: 2008

236. Newly identified genetic risk variants for celiac disease related to the immune response

Author: Ross McManus, Julian R.F. Walters, M. Luisa Mearin, Daniel J. Pennington, Fiona M. Stevens, Martin C. Wapenaar, Davinder Panesar, Graham A. Heap, Chris J. J. Mulder, Peter D. Howdle, Dermot Kelleher, Alexandra Zhernakova, Geoffrey Holmes, Raymond J. Playford, Gosia Trynka, Rhian Gwilliam, David A. van Heel, Wieke H. M. Verbeek, William M. McLaren, Karen A. Hunt, Wendy L. McArdle, Panos Deloukas, Lotte C. Dinesen, Ralph McGinnis, Graham Turner, Cisca Wijmenga, Lude Franke, Colm O'Morain, Fumihiko Takeuchi, Marcel Bruinenberg, David S Sanders, David P. Strachan, Nicholas P. Kennedy, Anthony W. Ryan, Charles A. Mein, Jihane Romanos, Valerie Trimble, Gastroenterology and hepatology, Pediatric surgery, CCA - Disease profiling, University of Groningen, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: Male, Linkage disequilibrium, PROTEIN, Genome-wide association study, Disease, MOUSE, Polymerase Chain Reaction, Linkage Disequilibrium, Cohort Studies, ACTIVATION, Mice, Risk Factors, Immunopathology, IL12A, Genotype, Immunology, Inflammation & Infection, Tissue Distribution, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), POPULATION, Genetics, education.field_of_study, Chromosome Mapping, Female, Genes & Society, International Development, Genetic Markers, EXPRESSION, Receptors, CCR3, Population, Biology, B-LYMPHOCYTES, Polymorphism, Single Nucleotide, Interleukin-12 Subunit p35, Article, REGION, HLA-DQ Antigens, Animals, Humans, Genetic Predisposition to Disease, RNA, Messenger, Interleukin-18 Receptor beta Subunit, GENOME-WIDE ASSOCIATION, education, Genome, Human, Case-control study, RHEUMATOID-ARTHRITIS, Celiac Disease, Diabetes Mellitus, Type 1, Case-Control Studies, Immunology, REPLICATION, Biomarkers, RGS Proteins
Abstract: PUBLISHED, * Joint Senior Authors, We acknowledge funding from Coeliac UK (to DAvH); the Coeliac Disease Consortium (an innovative cluster approved by the Netherlands Genomics Initiative and partly funded by the Dutch Government, grant BSIK03009 to CW); the European Union (STREP 036383); the Netherlands Organization for Scientific Research (VICI grant 918.66.620 to CW); the Science Foundation Ireland; the Irish Health Research Board; Hitachi Europe Ltd.; and the Wellcome Trust (GR068094MA Clinician Scientist Fellowship to DAvH; New Blood Fellowship to RMcM; support for the work of RMcG and PD). We thank the Barts and The London Genome Centre for genotyping support; J Swift, P. Kumar, D.P. Jewell, S.P.L. Travis, K. Moriarty for collection of UKGWAS and additional samples. We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by the UK Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02.. We thank A. Monsuur for patient recruitment, G. Meijer and J. Meijer for histology review, K. Duran for DNA extraction, H. van Someren and F. Mulder for clinical database management, M. Plateel and the Genotyping facilities at UMCG and UMC Utrecht for technical assistance (the Netherlands). We thank M. Abuzakouk, R. McLoughlin, K. Brophy, C. Feighery, J. McPartlin for sample collection. Irish Control DNA was supplied by Irish Blood Transfusion Service/Trinity College Dublin Biobank. We thank the Wellcome Trust Centre for Human Genetics, University of Oxford for provision of computing facilities and G. McVean for recombination rate data. We thank all celiac and control individuals for participating in this study.
Published: 2008
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237. Copy-number variation in sporadic amyotrophic lateral sclerosis: a genome-wide screen

Author: John H. J. Wokke, Jan H. Veldink, Christiaan G J Saris, J. Peter H. Burbach, Paul W.J. van Vught, Bert van der Zwaag, Leonard H. van den Berg, Lude Franke, Michael A. van Es, Hylke M. Blauw, and Roel A. Ophoff
Subjects: Adult, Male, Gene Dosage, Locus (genetics), Single-nucleotide polymorphism, Biology, Gene Frequency, medicine, Humans, SNP, Genetic Predisposition to Disease, Genetic Testing, Copy-number variation, Amyotrophic lateral sclerosis, Gene, Aged, Oligonucleotide Array Sequence Analysis, Aged, 80 and over, Genetics, Genome, Amyotrophic Lateral Sclerosis, Chromosome Mapping, Genetic Variation, Middle Aged, medicine.disease, Actin cytoskeleton, Female, Neurology (clinical), SNP array
Abstract: Summary Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the selective death of motor neurons in the brain and spinal cord. Genetic risk factors have been implicated in susceptibility to ALS. Like single nucleotide polymorphisms (SNPs), copy-number variants (CNVs) are a source of genetic variation that have important effects on gene expression and disease phenotypes, and our aim was to identify CNVs that predispose to sporadic ALS. Methods We did a genome-wide screen for CNVs by analysis of Illumina 317K SNP arrays for 406 patients with sporadic ALS and 404 controls. We examined CNVs for association with ALS, and used the Kyoto Encyclopedia of Genes and Genomes database and the Gene Ontology database to investigate the functionality of genes that were deleted exclusively in patients with ALS. Findings We detected 2328 CNVs in 810 individuals. No CNV locus was significantly associated with sporadic ALS. 406 genes were duplicated or deleted exclusively in patients with ALS and have not been reported in previous studies of CNVs. Of the 390 genes heterozygously deleted in patients with sporadic ALS, 155 (40%) deletions were recorded exclusively in patients. By contrast, of the 323 genes heterozygously deleted in control participants, only 51 (16%) were exclusive to the controls (p=2·15×10 −12 for difference between groups). Products of the genes deleted specifically in patients with sporadic ALS include proteins involved in oxidative phosphorylation, regulation of the actin cytoskeleton, and interactions between cytokines and their receptors. Interpretation Common CNVs in the regions of the genome represented on the SNP array are unlikely to be associated with sporadic ALS. However, the high number of genes deleted specifically in patients with ALS strongly suggests that multiple rare deletions might have an important role in ALS pathogenesis.
Published: 2008
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238. Genetic and environmental influences interact with age and sex in shaping the human methylome

Author: Joyce Van Meurs, Marc Jan Bonder, Marleen Van Greevenbroek, Michel Nivard, Morris Swertz, René Pool, H. Eka D. Suchiman, Coen Stehouwer, Marijn Verkerk, Cornelia Van Duijn, Jenny Van Dongen, Pieternella Slagboom, Marian Beekman, Casper G Schalkwijk, Szymon Kiełbasa, Lude Franke, Rick Jansen, Gonneke Willemsen, Carla Van der Kallen, Patrick Deelen, Interne Geneeskunde, RS: CARIM - R3.01 - Vascular complications of diabetes and the metabolic syndrome, MUMC+: HVC Pieken Maastricht Studie (9), MUMC+: MA Interne Geneeskunde (3), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Biological Psychology, and Internal Medicine
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Adult, Male, Aging, Adolescent, Science, Inheritance Patterns, General Physics and Astronomy, Single-nucleotide polymorphism, Biology, Genome, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Sex Factors, SDG 3 - Good Health and Well-being, Genetic variation, Twins, Dizygotic, Humans, Gene–environment interaction, Genetics, Multidisciplinary, Genome, Human, Smoking, Age Factors, General Chemistry, Twins, Monozygotic, Heritability, DNA Methylation, Explained variation, 030104 developmental biology, Phenotype, Child, Preschool, DNA methylation, CpG Islands, Female, Gene-Environment Interaction
Abstract: The methylome is subject to genetic and environmental effects. Their impact may depend on sex and age, resulting in sex- and age-related physiological variation and disease susceptibility. Here we estimate the total heritability of DNA methylation levels in whole blood and estimate the variance explained by common single nucleotide polymorphisms at 411,169 sites in 2,603 individuals from twin families, to establish a catalogue of between-individual variation in DNA methylation. Heritability estimates vary across the genome (mean=19%) and interaction analyses reveal thousands of sites with sex-specific heritability as well as sites where the environmental variance increases with age. Integration with previously published data illustrates the impact of genome and environment across the lifespan at methylation sites associated with metabolic traits, smoking and ageing. These findings demonstrate that our catalogue holds valuable information on locations in the genome where methylation variation between people may reflect disease-relevant environmental exposures or genetic variation., Differential impact of genetic and environmental influences on DNA methylation may result in sex- and age-related physiological variation and disease susceptibility. By analysing DNA methylome of 2,603 individuals from twin families, here, the authors establish a catalogue of between-individual variation in DNA methylation.
Published: 2016
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239. A contribution of novel CNVs to schizophrenia from a genome-wide study of 41,321 subjects

Author: Aiden Corvin, Kenneth S. Kendler, Jouko Lönnqvist, Patricia T. Michie, Stephanie H. Witt, Annelie Nordin, Robin M. Murray, Benjamin M. Neale, Dermot Walsh, Peter Holmans, Richard A. Belliveau, Jacques Mallet, Matthew C. Keller, Hugh Gurling, Joseph I. Friedman, Giulio Genovese, Andrew Pocklington, Lieuwe de Haan, Marcelo Bertalan, Noa Carrera, Brian Kelly, Lude Franke, Carlos N. Pato, Inez Myin-Germeys, Brandon Wormley, Nicholas John Craddock, Sven Cichon, Manuel Mattheisen, Annette M. Hartmann, Ole A. Andreassen, Masashi Ikeda, Madhusudan Gujral, Edward M. Scolnick, Jeffrey A. Lieberman, Elodie Drapeau, Deborah A. Nertney, Richard Bruggeman, Bertram Müller-Myhsok, Raquelle I. Mesholam-Gately, Ingrid Melle, Jacob Gratten, Ingrid Agartz, Frans Henskens, Stephanie Godard, Andres Metspalu, Mark Weiser, Johan G. Eriksson, Christian R. Marshall, Preben Bo Mortensen, Tõnu Esko, Sarah E. Bergen, Ina Giegling, Carmel M. Loughland, Stephen W. Scherer, Panos Roussos, Colm McDonald, Douglas F. Levinson, David Cohen, Martilias S. Farrell, James J. Crowley, Sibylle G. Schwab, Stephanie Williams, Henrik B. Rasmussen, Wei Cheng, Ann Olincy, Anders D. Børglum, Andreas J. Forstner, Wenting Wu, Benedicto Crespo-Facorro, David J. Kavanagh, Aniket Shetty, Thomas Werge, Daniel P. Howrigan, Gary Donohoe, Stephan Ripke, Jo Knight, Michael Conlon O'Donovan, Erik Söderman, Luba Kalaydjieva, Silviu Alin Bacanu, Dragan M. Svrakic, Brion S. Maher, Alexander Richards, Digby Quested, Eadbhard O' Callaghan, René S. Kahn, Lili Milani, Karin V. Fuentes Fajarado, Mark Hansen, Douglas S. Greer, Sandra Meier, S. Hong Lee, Markus M. Nöthen, Brendan Bulik-Sullivan, Guiqing Cai, Lynn E. DeLisi, Thomas Hansen, Bernard Lerer, Jubao Duan, James T.R. Walters, Ulrich Schall, Ole Mors, Kai-How Farh, Randy L. Buckner, Andrew M. McIntosh, Kung-Yee Liang, Olli Pietiläinen, Colm O. Dushlaine, Paola Giusti-Rodríguez, Srdjan Djurovic, Jaana Suvisaari, Carin J. Meijer, Christos Pantelis, Peter Eichhammer, Nancy G. Buccola, Kristin K. Nicodemus, Phil Lee, Zhouzhi Wang, Dominique Campion, Rita M. Cantor, Ariel Darvasi, Christina M. Hultman, Dan Rujescu, Joshua R. Atkins, Naomi R. Wray, Michael Davidson, Michele T. Pato, Brien P. Riley, Tim B. Bigdeli, Patrik K. E. Magnusson, Aaron R. Wolen, Srinivas Thirumalai, Vahram Haroutunian, Joshua L. Roffman, Tiina Paunio, K Kähler Anna, Thomas G. Schulze, Assen Jablensky, Andrew McQuillin, Kimberley D. Chambert, John Powell, Douglas Blackwood, Ditte Demontis, Daniele Merico, Stefan Herms, Tune H. Pers, Bryan J. Mowry, Eric Strengman, Larry J. Seidman, Pablo V. Gejman, Laura Nisenbaum, Bettina Konte, Jennifer L. Moran, Donald W. Black, Michael Gill, Line Olsen, Aarno Palotie, Robert Freedman, Dalila Pinto, Abraham Reichenberg, Qingqin S. Li, Ann E. Pulver, Mark Reimers, Jurgen Del Favero, Murray J. Cairns, Patrick F. Sullivan, Deborah L. Levy, John L. Waddington, Menachem Fromer, Marcella Rietschel, Jonathan Sebat, Rolf Adolfsson, George Kirov, Veikko Salomaa, David Curtis, Rodney J. Scott, Jin P. Szatkiewicz, Jacqueline I. Goldstein, Tracey L. Petryshen, Nelson B. Freimer, Mads V. Hollegaard, Franziska Degenhardt, David M. Hougaard, Dimitris Dikeos, Pamela Sklar, Diana O. Perkins, Shaun Purcell, Yunjung Kim, Laurent Essioux, Dheeraj Malhotra, Wolfgang Maier, Eli A. Stahl, Per Hoffmann, David A. Collier, Farooq Amin, Juha Karjalainen, William M. Brandler, Clement C. Zai, A. Hofman, Nigel Williams, Hailiang Huang, Joseph D. Buxbaum, Danielle Posthuma, Kieran C. Murphy, Jonathan Pimm, Bradley T. Webb, Joel N. Hirschhorn, Elvira Bramon, Timothy G. Dinan, Jana Strohmaier, Wiepke Cahn, Erik G. Jönsson, F. Anthony O’ Neill, Dieter B. Wildenauer, Michael John Owen, Igor Nenadic, Vaughan J. Carr, Esben Agerbo, Younes Mokrab, Morten Mattingsdal, Elliot S. Gershon, Danny Antaki, Jim van Os, Bhooma Thiruvahindrapuram, Alan R. Sanders, Sang-Yun Oh, Alkes L. Price, Vihra Milanova, Juha Veijola, Chris C. A. Spencer, Nakao Iwata, Jeremy M. Silverman, Mark J. Daly, Elena Parkhomenko, Kenneth L. Davis, Jing Qin Wu, Robert W. McCarley, Steven A. McCarroll, Derek W. Morris, Douglas M. Ruderfer, Josef Frank, C. Robert Cloninger, George N. Papadimitriou, Paul Cormican, Lyudmila Georgieva, Enrico Domenici, Claudine Laurent, James L. Kennedy, Frank Dudbridge, Peter M. Visscher, Valentina Escott-Price, Inge Joa, Marian L. Hamshere, Jianxin Shi, Margot Albus, Jordan W. Smoller, Adam Savitz, T. Scott Stroup, Elizabeth Bevilacqua, James A. Knowles, William Byerley, Madeline Alexander, Stanley V. Catts, David St Clair, Sophie E. Legge, Roel A. Ophoff, Gerald Nestadt, Paul A. Tooney, and Ayman H. Fanous
Subjects: Genetics, 0303 health sciences, Genomics, Biology, medicine.disease, Genome, Phenotype, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Schizophrenia, Cohort, Etiology, medicine, Copy-number variation, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Genomic copy number variants (CNVs) have been strongly implicated in the etiology of schizophrenia (SCZ). However, apart from a small number of risk variants, elucidation of the CNV contribution to risk has been difficult due to the rarity of risk alleles, all occurring in less than 1% of cases. We sought to address this obstacle through a collaborative effort in which we applied a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. We observed a global enrichment of CNV burden in cases (OR=1.11, P=5.7e −15 ), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7e −6 ). CNV burden is also enriched for genes associated with synaptic function (OR = 1.68, P = 2.8e −11 ) and neurobehavioral phenotypes in mouse (OR = 1.18, P=7.3e −5 ). We identified genome-wide significant support for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. We find support at a suggestive level for nine additional candidate susceptibility and protective loci, which consist predominantly of CNVs mediated by non-allelic homologous recombination (NAHR).
Published: 2016
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240. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci

Author: Tom H. Karlsen, Mauro D'Amato, Valerie Collij, Michael Weichenthal, Adrian Cortes, Konstantinos N. Lazaridis, Trine Folseraas, Stephan Weidinger, Jonathan Barker, Tune H. Pers, Richard C. Trembath, Andre Franke, Andres Metspalu, David Ellinghaus, Tõnu Esko, Ulrich Mrowietz, Søren Brunak, Matthias Hübenthal, James T. Elder, Dermot P.B. McGovern, Matthew A. Brown, Jonas Halfvarson, Jeffrey C. Barrett, Lude Franke, Ole A. Andreassen, Yunpeng Wang, Harm-Jan Westra, Anders Boeck Jensen, Anders M. Dale, Yu Rang Park, Brian D. Juran, Andreas J. Forstner, Jörn Bethune, Jennie G. Pouget, Stephan Schreiber, Wolfgang Lieb, Luke Jostins, Miles Parkes, Eva Ellinghaus, Sarah L. Spain, Franziska Degenhardt, Buhm Han, Rinse K. Weersma, Andrea Hofmann, Soumya Raychaudhuri, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: 0301 basic medicine, Genotype, Cholangitis, Sclerosing, Quantitative Trait Loci, Genome-wide association study, Comorbidity, Disease, Biology, VARIANTS, Inflammatory bowel disease, Article, Primary sclerosing cholangitis, KINASE C-THETA, Genetic Heterogeneity, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, Pleiotropy, Genetics, medicine, Genetic Pleiotropy, Psoriasis, Humans, Spondylitis, Ankylosing, Genetic Predisposition to Disease, BOWEL-DISEASE, GENOME-WIDE ASSOCIATION, METAANALYSIS, GENE-EXPRESSION, Inflammation, 030203 arthritis & rheumatology, Genetic heterogeneity, Genetic Variation, Bayes Theorem, PRIMARY SCLEROSING CHOLANGITIS, medicine.disease, RISK LOCI, 3. Good health, 030104 developmental biology, ULCERATIVE-COLITIS, Chronic Disease, PSORIASIS SUSCEPTIBILITY LOCI, Colitis, Ulcerative, Genome-Wide Association Study
Abstract: © 2016 Nature America, Inc. We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.
Published: 2016
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241. Genome-wide association study identifies 74 loci associated with educational attainment

Author: K. Petrovic, Massimo Mangino, Daniele Cusi, Ozren Polasek, Rodney J. Scott, Yong Qian, Aysu Okbay, Jari Lahti, Bjarni Gunnarsson, George McMahon, Elizabeth G. Holliday, Thomas Meitinger, Frank J. A. van Rooij, Mika Kähönen, Martin Kroh, Ian J. Deary, Neil Pendleton, Pamela A. F. Madden, David J. Porteous, Lambertus A. Kiemeney, Sven Oskarsson, Edith Hofer, Robert F. Krueger, Olga Rostapshova, Georg Homuth, Paolo Gasparini, Aldo Rustichini, Sarah E. Medland, Christian Gieger, Veronique Vitart, Nicholas J. Timpson, George Dedoussis, Joseph K. Pickrell, Christopher Oldmeadow, Aldi T. Kraja, Johan G. Eriksson, Lydia Quaye, William G. Iacono, Danielle Posthuma, George Davey Smith, Karl-Oskar Lindgren, David C. Liewald, Pim van der Harst, Börge Schmidt, Christine Power, Francesco P. Cappuccio, Francesco Cucca, Simona Vaccargiu, Joyce Y. Tung, Aarno Palotie, Natalia Pervjakova, Jonas Bacelis, Jouke-Jan Hottenga, Helena Schmidt, Kari Stefansson, Tamara B. Harris, Momoko Horikoshi, Lude Franke, Wolfgang Hoffmann, Ingrid B. Borecki, William E R Ollier, Johannes Waage, Andreas J. Forstner, Caroline Hayward, Penelope A. Lind, Patricia A. Boyle, Kadri Kaasik, Jian Yang, Gerardus A. Meddens, Antti Latvala, John Attia, Pascal Timshel, Vilmundur Gudnason, Maël Lebreton, Valur Emilsson, James F. Wilson, Jonathan Marten, Ute Bültmann, Erika Salvi, Olli T. Raitakari, Peter M. Visscher, Niek Verweij, Elisabeth Steinhagen-Thiessen, Cristina Venturini, Lili Milani, Tessel E. Galesloot, Kevin Thom, Klaus Berger, Paul Lichtenstein, Tian Liu, Philipp Koellinger, Riccardo E. Marioni, Marjo-Riitta Järvelin, Clemens Baumbach, Unnur Thorsteinsdottir, Magnus Johannesson, Susan M. Ring, David A. Bennett, Anu Loukola, Hans-Jörgen Grabe, Jan A. Staessen, Igor Rudan, Ginevra Biino, Nicholas G. Martin, Jingyun Yang, Anna A. E. Vinkhuyzen, Katri Räikkönen, Zhihong Zhu, Gudmar Thorleifsson, Mary F. Feitosa, Ivana Kolcic, Alexander Teumer, Jaakko Kaprio, David Schlessinger, Katharina E. Schraut, Konstantin Strauch, Ilja Demuth, Albert V. Smith, Juergen Wellmann, Jennifer E. Huffman, Panos Deloukas, Mario Pirastu, Reedik Mägi, Maria Pina Concas, Jaime Derringer, Patrick J. F. Groenen, Henry Völzke, Wei Zhao, Abdel Abdellaoui, Andres Metspalu, Nicholas A. Furlotte, Christopher P. Nelson, Barbara Franke, Steven F. Lehrer, Patrick Turley, Tõnu Esko, Jun Ding, Pedro Marques-Vidal, S. Fleur W. Meddens, Zoltán Kutalik, Gonneke Willemsen, Andrew C. Heath, Michelle N. Meyer, James J. Lee, Roy Thurik, Antonietta Robino, Henning Tiemeier, Grant W. Montgomery, C. deLeeuw, Astanand Jugessur, Antti-Pekka Sarin, Veikko Salomaa, Dalton Conley, Tim D. Spector, Sebastian E. Baumeister, Gyda Bjornsdottir, Lavinia Paternoster, Tune H. Pers, Jacob Gratten, Martin D. Tobin, Daniel J. Benjamin, Douglas F. Levinson, Stavroula Kanoni, Elina Hyppönen, David R. Weir, Peter J. van der Most, Terho Lehtimäki, David A. Hinds, Pablo V. Gejman, Uwe Völker, Cornelia M. van Duijn, Karl-Heinz Jöckel, Bjarni V. Halldorsson, Markus Perola, Nicola Pirastu, Klaus Bønnelykke, Robert Karlsson, David Cesarini, Michael A. Province, Jianxin Shi, Najaf Amin, Dale R. Nyholt, Lenore J. Launer, Nilesh J. Samani, Sven J. van der Lee, Dorret I. Boomsma, Harry Campbell, Peter Vollenweider, Liisa Keltigangas-Jarvinen, David Laibson, Ronald de Vlaming, Lynne J. Hocking, Christopher F. Chabris, Blair H. Smith, Gail Davies, Niina Eklund, Ioanna P. Kalafati, Bo Jacobsson, Sheila Ulivi, Alan F. Wright, Sarah E. Harris, Mark Alan Fontana, Diego Vozzi, Tomi Mäki-Opas, Albert Hofman, Hans Bisgaard, Andrew Bakshi, Marika Kaakinen, Johannes H. Brandsma, Christa Meisinger, Ilaria Gandin, Tarunveer S. Ahluwalia, Jennifer A. Smith, Beate St Pourcain, Rico Rueedi, Lewin Eisele, Michael B. Miller, Brenda W.J.H. Penninx, Alan R. Sanders, Thorkild I. A. Sørensen, André G. Uitterlinden, Cornelius A. Rietveld, Peter Lichtner, Dragana Vuckovic, Giorgia Girotto, Behrooz Z. Alizadeh, Reinhold Schmidt, Raymond A. Poot, Judith M. Vonk, Antony Payton, Wouter J. Peyrot, Augustine Kong, Y. Milaneschi, Jessica D. Faul, Patrik K. E. Magnusson, Antonio Terracciano, David M. Evans, Sharon L.R. Kardia, Peter K. Joshi, Michael A. Horan, Matt McGue, Richa Gupta, Jonathan P. Beauchamp, Peter Eibich, Erin B. Ware, Lars Bertram, Philip L. De Jager, Nancy L. Pedersen, Ronny Myhre, Guo-Bo Chen, Harm-Jan Westra, Jan-Emmanuel De Neve, Evelin Mihailov, Leanne M. Hall, Seppo Koskinen, Rush University Medical Center [Chicago], Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Helmholtz-Zentrum München (HZM), University of Queensland [Brisbane], Erasmus University Rotterdam, Universidad de Navarra [Pamplona] (UNAV), National Institute for Health and Welfare [Helsinki], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Consiglio Nazionale delle Ricerche (CNR), Montpellier Research in Management (MRM), Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Perpignan Via Domitia (UPVD)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université de Montpellier (UM), University of Bristol [Bristol], Queensland Institute of Medical Research, Massachusetts General Hospital [Boston], Medical University Graz, Institut des Sciences Moléculaires (ISM), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), King‘s College London, Tampere University Hospital, University of Turku, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Edinburgh, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Imperial College London, Reykjavík University, Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Karolinska Institutet [Stockholm], Department of Health Sciences [Leicester], University of Leicester, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Department of Medical Epidemiology and Biostatistics (MEB), Dpt of Pharmacology and Personalised Medicine [Maastricht], Maastricht University [Maastricht], Florida State University [Tallahassee] (FSU), IT University of Copenhagen, University of Helsinki-University of Helsinki, Université Montpellier 1 (UM1)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Perpignan Via Domitia (UPVD), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Université Sciences et Technologies - Bordeaux 1-Université Montesquieu - Bordeaux 4-Institut de Chimie du CNRS (INC), Faculteit Economie en Bedrijfskunde, Microeconomics (ASE, FEB), LifeLines Cohort Study, Alizadeh, BZ., de Boer, RA., Boezen, HM., Bruinenberg, M., Franke, L., van der Harst, P., Hillege, HL., van der Klauw, MM., Navis, G., Ormel, J., Postma, DS., Rosmalen, JG., Slaets, JP., Snieder, H., Stolk, RP., Wolffenbuttel, BH., Wijmenga, C., Applied Economics, Cell biology, Epidemiology, Erasmus MC other, Econometrics, Child and Adolescent Psychiatry / Psychology, Psychiatry, Internal Medicine, EMGO+ - Mental Health, Complex Trait Genetics, Biological Psychology, Functional Genomics, Economics, Amsterdam Neuroscience - Complex Trait Genetics, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), Public Health Research (PHR), Cardiovascular Centre (CVC), Life Course Epidemiology (LCE), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Okbay, Aysu, Beauchamp, Jonathan P., Fontana, Mark Alan, Lee, James J., Pers, Tune H., Rietveld, Cornelius A., Turley, Patrick, Chen, Guo Bo, Emilsson, Valur, Meddens, S. Fleur W., Oskarsson, Sven, Pickrell, Joseph K., Thom, Kevin, Timshel, Pascal, De Vlaming, Ronald, Abdellaoui, Abdel, Ahluwalia, Tarunveer S., Bacelis, Jona, Baumbach, Clemen, Bjornsdottir, Gyda, Brandsma, Johannes H., Concas, MARIA PINA, Derringer, Jaime, Furlotte, Nicholas A., Galesloot, Tessel E., Girotto, Giorgia, Gupta, Richa, Hall, Leanne M., Harris, Sarah E., Hofer, Edith, Horikoshi, Momoko, Huffman, Jennifer E., Kaasik, Kadri, Kalafati, Ioanna P., Karlsson, Robert, Kong, Augustine, Lahti, Jari, Van Der Lee, Sven J., Deleeuw, Christiaan, Lind, Penelope A., Lindgren, Karl Oskar, Liu, Tian, Mangino, Massimo, Marten, Jonathan, Mihailov, Evelin, Miller, Michael B., Van Der Most, Peter J., Oldmeadow, Christopher, Payton, Antony, Pervjakova, Natalia, Peyrot, Wouter J., Qian, Yong, Raitakari, Olli, Rueedi, Rico, Salvi, Erika, Schmidt, Börge, Schraut, Katharina E., Shi, Jianxin, Smith, Albert V., Poot, Raymond A., St Pourcain, Beate, Teumer, Alexander, Thorleifsson, Gudmar, Verweij, Niek, Vuckovic, Dragana, Wellmann, Juergen, Westra, Harm Jan, Yang, Jingyun, Zhao, Wei, Zhu, Zhihong, Alizadeh, Behrooz Z., Amin, Najaf, Bakshi, Andrew, Baumeister, Sebastian E., Biino, Ginevra, Bønnelykke, Klau, Boyle, Patricia A., Campbell, Harry, Cappuccio, Francesco P., Davies, Gail, De Neve, Jan Emmanuel, Deloukas, Pano, Demuth, Ilja, Ding, Jun, Eibich, Peter, Eisele, Lewin, Eklund, Niina, Evans, David M., Faul, Jessica D., Feitosa, Mary F., Forstner, Andreas J., Gandin, Ilaria, Gunnarsson, Bjarni, Halldórsson, Bjarni V., Harris, Tamara B., Holliday, Elizabeth G., Heath, Andrew C., Hocking, Lynne J., Homuth, Georg, Horan, Michael A., Hottenga, Jouke Jan, De Jager, Philip L., Joshi, Peter K., Jugessur, Astanand, Kaakinen, Marika A., Kähönen, Mika, Kanoni, Stavroula, Keltigangas Järvinen, Liisa, Kiemeney, Lambertus A. L. M., Kolcic, Ivana, Koskinen, Seppo, Kraja, Aldi T., Kroh, Martin, Kutalik, Zoltan, Latvala, Antti, Launer, Lenore J., Lebreton, Maël P., Levinson, Douglas F., Lichtenstein, Paul, Lichtner, Peter, Liewald, David C. M., Loukola, Anu, Madden, Pamela A., Mägi, Reedik, Mäki Opas, Tomi, Marioni, Riccardo E., Marques Vidal, Pedro, Meddens, Gerardus A., Mcmahon, George, Meisinger, Christa, Meitinger, Thoma, Milaneschi, Yusplitri, Milani, Lili, Montgomery, Grant W., Myhre, Ronny, Nelson, Christopher P., Nyholt, Dale R., Ollier, William E. R., Palotie, Aarno, Paternoster, Lavinia, Pedersen, Nancy L., Petrovic, Katja E., Porteous, David J., Raïkkönen, Katri, Ring, Susan M., Robino, Antonietta, Rostapshova, Olga, Rudan, Igor, Rustichini, Aldo, Salomaa, Veikko, Sanders, Alan R., Sarin, Antti Pekka, Schmidt, Helena, Scott, Rodney J., Smith, Blair H., Smith, Jennifer A., Staessen, Jan A., Steinhagen Thiessen, Elisabeth, Strauch, Konstantin, Terracciano, Antonio, Tobin, Martin D., Ulivi, Sheila, Vaccargiu, Simona, Quaye, Lydia, Van Rooij, Frank J. A., Venturini, Cristina, Vinkhuyzen, Anna A. E., Völker, Uwe, Völzke, Henry, Vonk, Judith M., Vozzi, Diego, Waage, Johanne, Ware, Erin B., Willemsen, Gonneke, Attia, John R., Bennett, David A., Berger, Klau, Bertram, Lar, Bisgaard, Han, Boomsma, Dorret I., Borecki, Ingrid B., Bültmann, Ute, Chabris, Christopher F., Cucca, Francesco, Cusi, Daniele, Deary, Ian J., Dedoussis, George V., Van Duijn, Cornelia M., Eriksson, Johan G., Franke, Barbara, Franke, Lude, Gasparini, Paolo, Gejman, Pablo V., Gieger, Christian, Grabe, Hans Jörgen, Gratten, Jacob, Groenen, Patrick J. F., Gudnason, Vilmundur, Van Der Harst, Pim, Hayward, Caroline, Hinds, David A., Hoffmann, Wolfgang, Hyppönen, Elina, Iacono, William G., Jacobsson, Bo, Järvelin, Marjo Riitta, Jöckel, Karl Heinz, Kaprio, Jaakko, Kardia, Sharon L. R., Lehtimäki, Terho, Lehrer, Steven F., Magnusson, Patrik K. E., Martin, Nicholas G., Mcgue, Matt, Metspalu, Andre, Pendleton, Neil, Penninx, Brenda W. J. H., Perola, Marku, Pirastu, Nicola, Pirastu, Mario, Polasek, Ozren, Posthuma, Danielle, Power, Christine, Province, Michael A., Samani, Nilesh J., Schlessinger, David, Schmidt, Reinhold, Sørensen, Thorkild I. A., Spector, Tim D., Stefansson, Kari, Thorsteinsdottir, Unnur, Thurik, A. Roy, Timpson, Nicholas J., Tiemeier, Henning, Tung, Joyce Y., Uitterlinden, André G., Vitart, Veronique, Vollenweider, Peter, Weir, David R., Wilson, James F., Wright, Alan F., Conley, Dalton C., Krueger, Robert F., Davey Smith, George, Hofman, Albert, Laibson, David I., Medland, Sarah E., Meyer, Michelle N., Yang, Jian, Johannesson, Magnu, Visscher, Peter M., Esko, Toñu, Koellinger, Philipp D., Cesarini, David, Benjamin, Daniel J., EMGO - Mental health, IOO, Human genetics, Beauchamp, Jonathan P, Lee, James JJ, Hypponen, Elina, and Benjamin, Daniel J
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Candidate gene, Bipolar Disorder, Medizin, Genome-wide association study, Genome-wide association studies, 0302 clinical medicine, Cognition, Alzheimer Disease, Brain, Computational Biology, Fetus, Gene Expression Regulation, Gene-Environment Interaction, Great Britain, Humans, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Schizophrenia, Educational Status, Genome-Wide Association Study, Medicine (all), Multidisciplinary, Fetu, tau, Gene–environment interaction, Soziales und Gesundheit, Genetics, [QFIN]Quantitative Finance [q-fin], HERITABILITY, General Commentary, Alzheimer's disease, Biobank, Phenotype, Multidisciplinary Sciences, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], educational attainment, Behavioural genetics, Science & Technology - Other Topics, Bildungsniveau, TRAITS, Human, General Science & Technology, Kultursektor, SNP, ta3111, Polymorphism, Single Nucleotide, Learning and memory, Alzheimer Disease/genetics, Bipolar Disorder/genetics, Brain/metabolism, Fetus/metabolism, Gene Expression Regulation/genetics, Polymorphism, Single Nucleotide/genetics, Schizophrenia/genetics, 03 medical and health sciences, ACHIEVEMENT, MD Multidisciplinary, Non-Profit-Sektor, QH426, Science & Technology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], tauopathies, Data Science, gene, education, school, Heritability, Educational Statu, Educational attainment, United Kingdom, 030104 developmental biology, IQ, Genetische Forschung, Psychiatric disorders, Bildung, 030217 neurology & neurosurgery, LifeLines Cohort Study, Neuroscience
Abstract: Contains fulltext : 167137.pdf (Publisher’s version ) (Closed access) Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
Published: 2016
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242. Association analysis of copy numbers of FC-gamma receptor genes for rheumatoid arthritis and other immune-mediated phenotypes

Author: Alexandros Kanterakis, Lude Franke, Tom W J Huizinga, Viktor Guryev, Javier Gutierrez-Achury, Alexandra Zhernakova, Cisca Wijmenga, Rinse K. Weersma, Dorothée Diogo, René E. M. Toes, Joel M. Kremer, Robert M. Plenge, Peter K. Gregersen, Morris A. Swertz, Klaas Kok, Rachel Knevel, Jeff Greenberg, Diahann T. S. L. Jansen, Lisbeth Ärlestig, Andreea Ioan-Facsinay, Gosia Trynka, Hanane El Bannoudi, Annette H M van der Helm-van Mil, Karin Fransen, Solbritt Rantapää-Dahlqvist, Dimitrios A. Pappas, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Translational Immunology Groningen (TRIGR), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: 0301 basic medicine, Male, DNA Copy Number Variations, Genotype, Locus (genetics), FCGR2B, Biology, FCGR2A, GPI-Linked Proteins, Polymorphism, Single Nucleotide, Article, Arthritis, Rheumatoid, 03 medical and health sciences, Genetics, Humans, Genetic Predisposition to Disease, Genotyping, Genetics (clinical), Genetic Association Studies, Genetic association, Segmental duplication, Receptors, IgG, FCGR3A, FCGR3B, Inflammatory Bowel Diseases, 030104 developmental biology, Phenotype, Female
Abstract: Segmental duplications (SDs) comprise about 5% of the human genome and are enriched for immune genes. SD loci often show copy numbers variations (CNV), which are difficult to tag with genotyping methods. CNV in the Fcγ receptor region (FCGR) has been suggested to be associated with rheumatic diseases. The objective of this study was to delineate association of FCGR-CNV with rheumatoid arthritis (RA), coeliac disease and Inflammatory bowel disease incidence. We developed a method to accurately quantify CNV in SD loci based on the intensity values from the Immunochip platform and applied it to the FCGR locus. We determined the method's validity using three independent assays: segregation analysis in families, arrayCGH, and whole genome sequencing. Our data showed the presence of two separate CNVs in the FCGR locus. The first region encodes FCGR2A, FCGR3A and part of FCGR2C gene, the second encodes another part of FCGR2C, FCGR3B and FCGR2B. Analysis of CNV status in 4578 individuals with RA and 5457 controls indicated association of duplications in the FCGR3B gene in antibody-negative RA (P=0.002, OR=1.43). Deletion in FCGR3B was associated with increased risk of antibody-positive RA, consistently with previous reports (P=0.023, OR=1.23). A clear genotype-phenotype relationship was observed: CNV polymorphisms of the FCGR3A gene correlated to CD16A expression (encoded by FCGR3A) on CD8 T-cells. In conclusion, our method allows determining the CNV status of the FCGR locus, we identified association of CNV in FCGR3B to RA and showed a functional relationship between CNV in the FCGR3A gene and CD16A expression.European Journal of Human Genetics advance online publication, 13 May 2015; doi:10.1038/ejhg.2015.95.
Published: 2016

243. Schizophrenia risk from complex variation of complement component 4

Author: Andrew Pocklington, Ole Mors, Tune Pers, Rolf Adolfsson, Andrew McQuillin, Vanessa Van Doren, James Walters, Hon-Cheong So, Joseph Buxbaum, Douglas Ruderfer, Lili Milani, Markus Nöthen, Joanne Knight, Silviu-Alin Bacanu, Avery Davis Bell, Samuel Rose, Danielle Posthuma, Inez Myin-Germeys, Francis Anthony O'Neill, Robert Handsaker, Antonio Julià Cano, Peter Visscher, Morten Mattingsdal, Thomas Folkmann Hansen, Esben Agerbo, Nolan Kamitaki, Benedicto Crespo-Facorro, Petr Slominsky, Sara Marsal, Joshua Roffman, Jingqin Wu, Ditte Demontis, David Collier, Jaana Suvisaari, Enrico Domenici, Fritz Zimprich, Hannelore Ehrenreich, Richard Bruggeman, Elvira Bramon, Sarah Bergen, Erik Jönsson, Bryan Mowry, Patrik Magnusson, Lude Franke, Srdjan Djurovic, Katherine Tooley, Matthew Baum, Peter Holmans, Murray Cairns, Kang Sim, Anders Børglum, Brian Kelly, Jennifer Moran, Sophie Legge, Sergi Papiol, Bradley Webb, Elisabeth Stögmann, Universidad de Cantabria, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Other departments, ANS - Complex Trait Genetics, Adult Psychiatry, Psychiatrie & Neuropsychologie, and RS: MHeNs School for Mental Health and Neuroscience
Subjects: 0301 basic medicine, Synaptic pruning, Messenger, Gene Dosage, Poison control, Major Histocompatibility Complex, Synapse, Mice, 0302 clinical medicine, Models, Risk Factors, Alleles, Amino Acid Sequence, Animals, Axons, Base Sequence, Brain, Complement C4, Complement Pathway, Classical, Dendrites, Gene Expression Regulation, Genetic Predisposition to Disease, Genetic Variation, Haplotypes, Humans, Models, Animal, Neuronal Plasticity, Polymorphism, Single Nucleotide, RNA, Messenger, Schizophrenia, Synapses, Genetics, Complement component 4, Multidisciplinary, biology, Single Nucleotide, medicine.anatomical_structure, Major histocompatibility complex, Article, 03 medical and health sciences, mental disorders, medicine, Polymorphism, Allele, Genetic association, Animal, C4A, Classical, 030104 developmental biology, Complement Pathway, biology.protein, RNA, 030217 neurology & neurosurgery
Abstract: Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia. This work was supported by R01 HG 006855 (to S.A.M), by the Stanley Center for Psychiatric Research (to S.A.M and B.S.), by R01 MH077139 (to the PGC), and by T32 GM007753 (to A.S. and M.B.).
Published: 2016
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244. Differential Effects of Environmental and Genetic Factors on T and B Cell Immune Traits

Author: Sebo Withoff, Renate G. van der Molen, Esther van Rijssen, Cisca Wijmenga, Maria M. Zorro, Leo A. B. Joosten, Yang Li, Bram van Cranenbroek, Romana T. Netea, Lude Franke, Morris A. Swertz, Ramnik J. Xavier, Paulo C. M. Urbano, Raul Aguirre-Gamboa, Antonius E. van Herwaarden, Irma Joosten, Martin Jaeger, Vinod Kumar, Sanne P. Smeekens, Fred C.G.J. Sweep, Mihai G. Netea, Hans J. P. M. Koenen, Marije Oosting, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Molecular Neuroscience and Ageing Research (MOLAR), Stem Cell Aging Leukemia and Lymphoma (SALL), Institute for Medical Engineering and Science, and Xavier, Ramnik Joseph
Subjects: Male, 0301 basic medicine, T-Lymphocytes, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Genome-wide association study, DISEASE, Cohort Studies, Chromosomes, Human, Netherlands, Genetics, B-Lymphocytes, Immunity, Cellular, HERITABILITY, Age Factors, Middle Aged, IMMUNOGLOBULIN PRODUCTION, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, medicine.anatomical_structure, Female, Seasons, Antibody, Functional genomics, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5], Resource, Adult, Adolescent, Quantitative Trait Loci, Immunoglobulins, Single-nucleotide polymorphism, Environment, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Biology, Quantitative trait locus, General Biochemistry, Genetics and Molecular Biology, Myosin Type I, Young Adult, 03 medical and health sciences, AGE, Immune system, medicine, Humans, Lymphocyte Count, GENOME-WIDE ASSOCIATION, B cell, Aged, CYTOKINE PRODUCTION, Heritability, Lymphocyte Subsets, Cyclic Nucleotide Phosphodiesterases, Type 4, Immunity, Humoral, 030104 developmental biology, INNATE IMMUNITY, biology.protein, EXPRESSION ANALYSIS, SYSTEM
Abstract: Summary Effective immunity requires a complex network of cellular and humoral components that interact with each other and are influenced by different environmental and host factors. We used a systems biology approach to comprehensively assess the impact of environmental and genetic factors on immune cell populations in peripheral blood, including associations with immunoglobulin concentrations, from ∼500 healthy volunteers from the Human Functional Genomics Project. Genetic heritability estimation showed that variations in T cell numbers are more strongly driven by genetic factors, while B cell counts are more environmentally influenced. Quantitative trait loci (QTL) mapping identified eight independent genomic loci associated with leukocyte count variation, including four associations with T and B cell subtypes. The QTLs identified were enriched among genome-wide association study (GWAS) SNPs reported to increase susceptibility to immune-mediated diseases. Our systems approach provides insights into cellular and humoral immune trait variability in humans., Graphical Abstract, Highlights • Understanding inter-individual variation of immune cells and immunoglobulin levels • Season and gender influence B cell subpopulation abundance • Identification of genetic loci that might regulate B cell levels in blood • Cell count QTLs overlap with risk SNPs for (auto)immune/inflammatory disease, As part of the Human Functional Genomics Project, this study by Aguirre-Gamboa et al. maps the contribution of genetics and non-heritable factors onto immune-cell counts and immunoglobulin levels. They find that season and gender influence the abundance of most of B cell subpopulations.
Published: 2016
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245. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

Author: Timo A. Lakka, Kathleen Stirrups, Jean Ferrières, Ying Wu, Gulum Kosova, Toby Johnson, Heather M. Stringham, Bruce M. Psaty, Bruna Gigante, Göran Hallmans, Cornelia M. van Duijn, Kae Woei Liang, Niclas Eriksson, N. William Rayner, Lynda M. Rose, Stavroula Kanoni, Xueling Sim, Evangelos Evangelou, Philippe Froguel, Michel Burnier, Andrew P. Morris, Olle Melander, Martin Farrall, Albert V. Smith, Brendan J. Keating, Thomas Illig, Johan Sundström, Dorret I. Boomsma, Kate Witkowska, Ellen M. Schmidt, Aki S. Havulinna, Ann-Kristin Petersen, Paul F. O'Reilly, Young Jin Kim, Kari Kuulasmaa, Tom Wilsgaard, John D. Eicher, Marcus E. Kleber, Francis S. Collins, Rona J. Strawbridge, Ronald M. Krauss, Fotios Drenos, Stuart K. Kim, Ken K. Ong, Pascal Bovet, Danish Saleheen, Jaspal S. Kooner, Karl-Heinz Herzig, Tien Yin Wong, Benjamin F. Voight, Stefania Bandinelli, Stéphane Lobbens, Colin A. McKenzie, Jing Hua Zhao, Terrence Forrester, Louise A. Donnelly, Alice Stanton, Jean Dallongeville, Kirill V. Tarasov, Narisu Narisu, Jürgen Gräßler, Luigi Ferrucci, Peter S. Sever, Paul Elliott, Tune H. Pers, Andrew J. Smith, Tomas Axelsson, Young Ah Shin, Nora Franceschini, James F. Wilson, Vilmundur Gudnason, Kati Kristiansson, Andrew A. Hicks, Kent D. Taylor, Genovefa Kolovou, Andrew D. Morris, André G. Uitterlinden, Serena Sanna, Xiuqing Guo, Honghuang Lin, Aravinda Chakravarti, Wayne Huey-Herng Sheu, Panos Deloukas, Linda S. Adair, Diana Kuh, Murielle Bochud, Eric Boerwinkle, Inger Njølstad, Meena Kumari, Norman Klopp, Leo-Pekka Lyytikäinen, Steven C. Hunt, Weihua Zhang, Tõnu Esko, Pierre Meneton, Markus Perola, Erik P A Van Iperen, Georg Ehret, Veikko Salomaa, Lars Lind, Zoltán Kutalik, Cristiano Fava, Caroline Hayward, Hugh S. Markus, Teresa Ferreira, Stefan R. Bornstein, Vasyl Pihur, Patricia B. Munroe, Anne U. Jackson, Eirini Marouli, Gabriele Müller, Damiano Baldassarre, Jacques E. Rossouw, Dan E. Arking, Maija Hassinen, Nicholas J. Wareham, Robert Roberts, Daniel I. Chasman, I. Shou Chang, Sylvain Sebert, Tove Fall, Roby Joehanes, Patrik K. E. Magnusson, John C. Chambers, Peter Vollenweider, Wen Jane Lee, Dmitry Shungin, Mathias Gorski, Christopher Newton-Cheh, Anders Franco-Cereceda, Ching-Yu Cheng, Yun Kyoung Kim, Ruth J. F. Loos, Lude Franke, Karen L. Mohlke, Yii-Der Ida Chen, Carlos Iribarren, Martina Müller-Nurasyid, Alexander Teumer, Andrew D. Johnson, Antonella Mulas, Ulf Gyllensten, Martin D. Tobin, George Dedoussis, Rainford J. Wilks, Joshua C. Bis, Beverley Balkau, Jie Yao, Frida Renström, Themistocles L. Assimes, Morris Brown, Inês Barroso, Hyun Min Kang, Loic Yengo, Mika Kähönen, Christopher J. Groves, Kirsti Kvaløy, Rainer Rauramaa, Heribert Schunkert, Satu Männistö, Marjo-Riitta Järvelin, Nancy L. Pedersen, Karl Gertow, Rick Jansen, Thomas Quertermous, Jarmo Virtamo, Lazaros Lataniotis, Serge Hercberg, Paul M. Ridker, Osorio Meirelles, Jostein Holmen, Phil Howard, G. Kees Hovingh, Jeanette Erdmann, Jong-Young Lee, Peter Schwarz, Ramaiah Nagaraja, Elizabeth Theusch, Wei Zhao, Sonia Shah, Chao A. Hsiung, Santhi K. Ganesh, Richard S. Cooper, John M. C. Connell, Jian'an Luan, Graciela E. Delgado, Eric Kim, Daniel Levy, Li Lin, Jerome I. Rotter, Andres Metspalu, Nabila Bouatia-Naji, Christopher J. O'Donnell, Roberto Elosua, Andrew Wong, Alanna C. Morrison, Juha Saltevo, Michael R. Barnes, Alan B. Weder, Kay-Tee Khaw, Leena Moilanen, Peter S. Chines, Claudia Langenberg, Marika Kaakinen, Asif Rasheed, Annette Peters, Angela Döring, Alena Stančáková, Richard A. Jensen, Jaana Lindström, Alison H. Goodall, Toshiko Tanaka, Loukianos S. Rallidis, Dabeeru C. Rao, Ann-Christine Syvänen, Alun Evans, Brenda W.J.H. Penninx, Sarah Edkins, Xiaohui Li, Neil Poulter, Jouko Saramies, Ulf de Faire, Walter Palmas, Jaakko Tuomilehto, Louise V. Wain, Cristina Menni, Stephen Bevan, Maria X. Sosa, Nanette R. Lee, Anuj Goel, Germaine C. Verwoert, Kjell Nikus, Helen R. Warren, May E. Montasser, Ren-Hua Chung, Francesco Gianfagna, Kristian Hveem, Rainer Rettig, Unnur Thorsteinsdottir, Lori L. Bonnycastle, Tim D. Spector, Paul W. Franks, Bamidele O. Tayo, Ilja M. Nolte, John Danesh, E. Shyong Tai, Mika Kivimäki, Devin Absher, Oddgeir L. Holmen, Per Eriksson, Pirjo Komulainen, Peter P. Pramstaller, Cameron D. Palmer, He Gao, Elena Tremoli, H.-Erich Wichmann, Myriam Fornage, Gyda Bjornsdottir, Afshin Parsa, Anders Hamsten, Terho Lehtimäki, Lasse Folkersen, Janine F. Felix, Anna F. Dominiczak, Hinco J. Gierman, Edward G. Lakatta, Alex S. F. Doney, Erik Ingelsson, Colin N. A. Palmer, Najaf Amin, Hugh Watkins, Johanna Kuusisto, Vladan Mijatovic, Mark I. McCarthy, Joel N. Hirschhorn, Winfried März, Nilesh J. Samani, Stefan Enroth, Mark J. Caulfield, Gudmar Thorleifsson, Tsun-Po Yang, François Mach, Cristen J. Willer, Claudia P. Cabrera, Aline Wagner, Michael Boehnke, Elias Salfati, Sekar Kathiresan, Ramachandran S. Vasan, Franco Giulianini, Harm-Jan Westra, Harold Snieder, Mark O. Goodarzi, M. Arfan Ikram, Fred Paccaud, Johannes H. Smit, Anna-Liisa Hartikainen, Xiaofeng Zhu, Markku Laakso, Ahmad Vaez, Albert Hofman, Amy J. Swift, Maria Hughes, I. Te Lee, Aroon D. Hingorani, Matti Uusitupa, Oscar H. Franco, Kenneth Rice, Veronique Vitart, Ross M. Fraser, Jouke-Jan Hottenga, Kari Stefansson, Dhananjay Vaidya, Johns Hopkins University, School of Medicine, Hôpitaux Universitaires de Genève (HUG), Saw Swee Hock School of Public Health, National University of Singapore (NUS), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), Department of Biostatistics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Michigan System, Department of Computational Medicine and Bioinformatics (DCM&B), Queen Mary University of London (QMUL), GlaxoSmithKline, Glaxo Smith Kline, deCODE genetics [Reykjavik], University of Cambridge [UK] (CAM), University of Dundee, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Karolinska University Hospital [Stockholm], Umea University Hospital, Lund University [Lund], Queen's University [Belfast] (QUB), National Institutes of Health, Department of Genomics of Common Disease, Imperial College London, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), National Institute of Health and Welfare, Institute for Molecular Medicine Finland (FIMM), University College London Hospitals (UCLH), University Hospital of Heidelberg, Harbor UCLA Medical Center [Torrance, Ca.], University of Tampere, University of Verona (UNIVR), Uppsala University Hospital, Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Stanford University School of Medicine [CA, USA], Medical School University of Athens, Partenaires INRAE, Children's Hospital Oakland Research Institute, Boston Children's Hospital, Broad Institute of Harvard and MIT, University of Copenhagen = Københavns Universitet (KU), Statens Serum Institut [Copenhagen], Framingham Heart Dis Epidemiol Study, Department of Psychiatry, VU University Medical Center [Amsterdam], National Heart, Lung and Blood Institute, Osong Health Technology Administration Complex, University of Pennsylvania, Department of Genetics, University of North Carolina at Chapel Hill (UNC), Loyola University [Chicago], Centre Hospitalier Universitaire Vaudois (CHUV), Hudson Alpha Institute for Biotechnology, Erasmus University Rotterdam, Department of Medical Sciences, Uppsala University, Università degli Studi di Milano [Milano] (UNIMI), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Université Paris-Sud - Paris 11 (UP11), Azienda Sanitaria Firenze, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], University of Lincoln, University of Washington [Seattle], Amgen Inc., The University of Texas Health Science Center at Houston (UTHealth), VU University Amsterdam, University of Dresden Medical School, Université de Lausanne (UNIL), Healthcare NHS Trust, National Health Research Institutes, National University Health System [Singapore] (NUHS), Duke-NUS Medical School [Singapore], Singapore Eye Research Institute [Singapore] (SERI), National Human Genome Research Institute (NHGRI), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Radiology and nuclear medicine, EMGO - Mental health, Lin, Li, Mach, François, ProdInra, Migration, University of Oxford, Università degli studi di Verona = University of Verona (UNIVR), University of Copenhagen = Københavns Universitet (UCPH), Università degli Studi di Milano = University of Milan (UNIMI), Vrije Universiteit Amsterdam [Amsterdam] (VU), Université de Lausanne = University of Lausanne (UNIL), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), EMGO+ - Lifestyle, Overweight and Diabetes, Biological Psychology, APH - Amsterdam Public Health, Epidemiology and Data Science, Graduate School, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Luan, Jian'an [0000-0003-3137-6337], Barroso, Ines [0000-0001-5800-4520], Danesh, John [0000-0003-1158-6791], Khaw, Kay-Tee [0000-0002-8802-2903], Markus, Hugh [0000-0002-9794-5996], Ong, Kenneth [0000-0003-4689-7530], Johnson, Kathleen [0000-0002-6823-3252], Wareham, Nicholas [0000-0003-1422-2993], Zhao, Jing Hua [0000-0003-4930-3582], Langenberg, Claudia [0000-0002-5017-7344], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), CHARGE-EchoGen Consortium, CHARGE-HF Consortium, Wellcome Trust Case Control Consortium, Medical Microbiology & Infectious Diseases, Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Clinical Genetics, Biochemistry, National Institute for Health Research, and Medical Research Council (MRC)
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), CHROMATIN, [SDV]Life Sciences [q-bio], LOCI, Genome-wide association study, Blood Pressure, SUSCEPTIBILITY, Bioinformatics, Cardiovascular, Genome-wide association studies, Medical and Health Sciences, single nucleotide polymorphism, CHARGE-EchoGen consortium, GWAS, 2.1 Biological and endogenous factors, Aetiology, Cells, Cultured, African Continental Ancestry Group, Genetics & Heredity, Genetics, ddc:616, Kidney, Framingham Risk Score, Cultured, COMMON VARIANTS, 11 Medical And Health Sciences, Single Nucleotide, Biological Sciences, African Continental Ancestry Group/genetics, Asian Continental Ancestry Group/genetics, Blood Pressure/genetics, Genome-Wide Association Study, Humans, Hypertension/genetics, Hypertension/pathology, Microarray Analysis, Polymorphism, Single Nucleotide, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Hypertension/genetics/pathology, Hypertension, Medical genetics, Wellcome Trust Case Control Consortium, Life Sciences & Biomedicine, TRAITS, Biotechnology, Asian Continental Ancestry Group, medicine.medical_specialty, CHARGE-EchoGen Consortium, Cells, Black People, BIOLOGY, Single-nucleotide polymorphism, Biology, Blood pressure, hypertension, genetics, single nucleotide polymorphism, GWAS, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Asian People, medicine, Polymorphism, GENOME-WIDE ASSOCIATION, CELL-TYPES, METAANALYSIS, Genetic association, Science & Technology, CHARGE-HF consortium, 06 Biological Sciences, Genetic architecture, 030104 developmental biology, Blood pressure, CHARGE-HF Consortium, ARTERIAL-HYPERTENSION, Developmental Biology
Abstract: To dissect the genetic architecture of blood pressure (BP) and assess how its elevation promotes downstream cardiovascular diseases, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry. Genotypes from an additional 140,886 individuals of European ancestry were used as validation for loci reaching genome-wide significance but without prior support in the literature. We identified 66 BP loci, of which 17 were novel and 15 harbored multiple distinct association signals, and which together explain up to 3.5% of BP variation. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in BP control through modulating blood vessel tone and fluid filtration across multiple tissues, not solely the kidney. Importantly, the 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent (South-Asian, East-Asian and African), confirming that these are ancestral physiological effects that arose prior to human migration out of Africa. The 66-SNP BP risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our data expand current knowledge of BP pathways, and also, highlight that BP regulation and its effects may occur in multiple organs and tissues beyond the classic renal system.
Published: 2016
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246. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Author: Sharon L.R. Kardia, Melinda Mills, Ian J. Deary, Sven Bergmann, Magnus Johannesson, Igor Rudan, Nicholas J. Timpson, Richa Gupta, Hester M. den Ruijter, Rico Rueedi, Lars Bertram, Juliette Harris, Jennifer A. Smith, Eero Kajantie, Jian Yang, David C. Liewald, Ronald de Vlaming, Anu Realo, Jessica D. Faul, Patrik K. E. Magnusson, Jadwiga Buchwald, Philip L. De Jager, Rajesh Rawal, Marisa Koini, K. Petrovic, Unnur Thorsteinsdottir, Pedro Marques-Vidal, Roy Thurik, Evie Stergiakouli, Ivana Kolcic, William G. Iacono, Laura D. Kubzansky, Jaakko Kaprio, Behrooz Z. Alizadeh, Samantha Cherney, Reinhold Schmidt, Vilmundur Gudnason, Nicholas A. Furlotte, Nicholas G. Martin, Delilah Zabaneh, Rebecca T. Emeny, Eco J. C. de Geus, Klaus Berger, Lude Franke, Sven J. van der Lee, S. Fleur W. Meddens, Bart M. L. Baselmans, Dalton Conley, Jouke-Jan Hottenga, David A. Bennett, Saskia Haitjema, Jun Ding, Elina Hyppönen, Kari Stefansson, Henning Tiemeier, Grant W. Montgomery, Michelle N. Meyer, James J. Lee, Aysu Okbay, Lei Yu, Gyda Bjornsdottir, Marie Henrike Geisel, Albertine J. Oldehinkel, Liisa Keltikangas-Järvinen, George Davey Smith, Harold Snieder, Juho Wedenoja, Frits R. Rosendaal, Michel G. Nivard, Simon R. Cox, Christine Power, Dorret I. Boomsma, Börge Schmidt, David A. Hinds, Philipp Koellinger, Harm-Jan Westra, Terho Lehtimäki, Alison Pattie, Jan-Emmanuel De Neve, Torben Hansen, John M. Starr, Albert V. Smith, Antonio Terracciano, Juergen Wellmann, Albert Hofman, Katri Räikkönen, Patrick Turley, Andrew Steptoe, Jimmy Z. Liu, Evelin Mihailov, Jari Lahti, Marika Kaakinen, David R. Weir, Cornelia M. van Duijn, Maciej Trzaskowski, David Cesarini, Najaf Amin, Lydia Quaye, Sara M. Willems, Ghazaleh Fatemifar, Christopher Oldmeadow, Ville Karhunen, Alana Cavadino, Juan R. González, Caroline Hayward, Penelope A. Lind, Tamara B. Harris, Jaime Derringer, Camelia C. Minică, Jacob Gratten, Patrick J. F. Groenen, Ozren Polasek, Anu Loukola, Peter Vollenweider, Christian Gieger, Rodney J. Scott, Lindsay K. Matteson, Meike Bartels, Andrew Bakshi, David Laibson, Andrew C. Heath, Daniel J. Benjamin, Stephen S. Rich, Claire M. A. Haworth, C.A. Hartman, Angelina R. Sutin, Tian Liu, Johan G. Eriksson, Robert Plomin, Francesco Cucca, John Attia, Tarunveer S. Ahluwalia, Andreas J. Forstner, Gudmar Thorleifsson, Rauli Svento, Ute Bültmann, Olli T. Raitakari, Karl-Heinz Jöckel, Mark Alan Fontana, Oliver S. P. Davis, Yong Qian, Anna A. E. Vinkhuyzen, Wei Zhao, Elizabeth G. Holliday, Andres Metspalu, Alexis C. Frazier-Wood, Meena Kumari, Nese Direk, Miriam A. Mosing, Ilja M. Nolte, Sander W. van der Laan, Matt McGue, Tim D. Spector, Marjo-Riitta Järvelin, Peter Eibich, Nancy L. Pedersen, David Schlessinger, Toshiko Tanaka, Dennis O. Mook-Kanamori, Luigi Ferrucci, Gerard Pasterkamp, Jonathan P. Beauchamp, Robert Karlsson, Lenore J. Launer, Helena Schmidt, Renée de Mutsert, Gert G. Wagner, Peter Kraft, Joseph K. Pickrell, Thorkild I. A. Sørensen, André G. Uitterlinden, Patricia A. Boyle, Cornelius A. Rietveld, Robert F. Krueger, Karl-Heinz Ladwig, Michael B. Miller, Sarah E. Medland, Tõnu Esko, Kent D. Taylor, Lavinia Paternoster, Peter J. van der Most, Richard Karlsson Linnér, Laura Pulkki-Råback, Gail Davies, Victoria Garfield, Shun-Chiao Chang, Ruifang Li-Gao, Applied Economics, Pathology, Epidemiology, Public Health, Child and Adolescent Psychiatry / Psychology, Psychiatry, Internal Medicine, Ophthalmology, Social Science Genetic Association Consortium (SSGAC), CHARGE Consortium, Okbay, Aysu, Baselmans, Bart ML, De Neve, Jan-Emmanuel, Turley, Patrick, Hyppönen, Elina, Cesarini, David, EMGO+ - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Complex Trait Genetics, Biological Psychology, Functional Genomics, Economics, Amsterdam Neuroscience - Complex Trait Genetics, Queensland Institute of Medical Research, Massachusetts General Hospital [Boston], University of Queensland [Brisbane], Center for Research in Environmental Epidemiology (CREAL), Universitat Pompeu Fabra [Barcelona] (UPF)-Catalunya ministerio de salud, Universitat Pompeu Fabra [Barcelona] (UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Institut des Sciences Moléculaires (ISM), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Université Sciences et Technologies - Bordeaux 1-Université Montesquieu - Bordeaux 4-Institut de Chimie du CNRS (INC), Tampere University Hospital, University of Turku, King‘s College London, University of Helsinki, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Lausanne (UNIL), Birmingham City University (BCU), Helmholtz-Zentrum München (HZM), Department of Epidemiology and Public Health, University College of London [London] (UCL), Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], University of Edinburgh, Florida State University [Tallahassee] (FSU), Wuhan University [China], Rush University Medical Center [Chicago], Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Erasmus University Rotterdam, National Institute for Health and Welfare [Helsinki], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Dpt of Pharmacology and Personalised Medicine [Maastricht], Maastricht University [Maastricht], Montpellier Research in Management (MRM), Université Montpellier 1 (UM1)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Perpignan Via Domitia (UPVD), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Perpignan Via Domitia (UPVD)-Groupe Sup de Co Montpellier (GSCM) - Montpellier Business School-Université de Montpellier (UM), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Public Health Research (PHR), Sociology/ICS, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Stem Cell Aging Leukemia and Lymphoma (SALL), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and LifeLines Cohort Study
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), Medizin, Genome-wide association study, Disease, Genome-wide association studies, DISEASE, 0302 clinical medicine, well-being, neuroticism, Anxiety Disorders/genetics, Bayes Theorem, Depression/genetics, Genome-Wide Association Study, Humans, Phenotype, Polymorphism, Single Nucleotide, Genetics & Heredity, RISK, Genetics, PERSONALITY, [QFIN]Quantitative Finance [q-fin], Depression, HERITABILITY, COMMON VARIANTS, 11 Medical And Health Sciences, Anxiety Disorders, Neuroticism, depression, Behavioural genetics, Life Sciences & Biomedicine, Biology, personality, genetic, epidemiology, ta3111, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, RESOURCE, Journal Article, Human height, Subjective well-being, behavioural genetics, METAANALYSIS, Genetic association, HAPPINESS, Science & Technology, MAJOR DEPRESSION, 06 Biological Sciences, Heritability, 030104 developmental biology, genome-wide association studies, HUMAN HEIGHT, 030217 neurology & neurosurgery, LifeLines Cohort Study, Developmental Biology, genome-wide analysis
Abstract: Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
Published: 2016
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247. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

Author: Masato Isono, Jorma Viikari, Jianjun Liu, Xingwang Ye, Hao Peng, James Scott, Nanette R. Lee, Chris Hsu, Woon-Puay Koh, Torben Hansen, Vinicius Tragante, Christian Gieger, Tomohiro Katsuya, Aaron Isaacs, Norihiro Kato, Kjell Nikus, Dingliang Zhu, Tetsuro Miki, Zhirong Guo, Uzma Afzal, Hiroshi Kajio, Mika Kähönen, Terri L. Young, Jer-Yuarn Wu, Terho Lehtimäki, Oscar H. Franco, Niels Grarup, Stella Trompet, Rob M. van Dam, John Danesh, Weihua Zhang, Joanna D. Holbrook, Ryoichi Takayanagi, Miyako Kishimoto, Shuhei Yamaguchi, Jemma CHopewell, Thorkild I. A. Sørensen, André G. Uitterlinden, James Abbott, Cisca Wijmenga, Iris Postmus, Wilko Spiering, Gianluca Campanella, Michela Traglia, Ian J. Deary, Hirotsugu Ueshima, Tanja B. Grammer, Daniel OStram, Panos Deloukas, Huaixing Li, Tatsuaki Matsubara, Koichi Akiyama, Fumihiko Takeuchi, Young Jin Kim, Silke Szymczak, Dirk J. van Veldhuisen, Alexander W. Drong, Yu-Tang Gao, Imke Aits, Mark A. Pereira, Rajkumar Dorajoo, Marc Chadeau-Hyam, Benjamin Lehne, Bastiaan THeijman, Zuan Yu Mok, Timothy R. Braun, Mitsuhiro Yokota, Yechiel Friedlander, David C. Liewald, Pim van der Harst, Mahfuzar Rahman, Takayoshi Ohkubo, Aili Wang, Robert Clarke, Lisette Stolk, Pieter A. Doevendans, Wolfgang Lieb, Rebecca Mills, Sarah Parish, Katsuhiko Kohara, Martina Müller-Nurasyid, Nina Mononen, Steve Franks, Niek Verweij, Johanne Marie Justesen, Tin Aung, Rory Collins, J. Wouter Jukema, M.J. Pinidiyapathirage, Rory P. Wilson, Hong Kiat Ng, Joyce B. J. van Meurs, Yik Ying Teo, Wiek H. van Gilst, Wei Zheng, Robert WKoivula, John C. Chambers, Molly Scannell Bryan, Peng Chen, Gurpreet SWander, Lise Lotte N. Husemoen, David J. Stott, Li Ching Chang, Teresa Nutile, Lude Franke, Jaana Hartiala, Karen L. Mohlke, Folkert W. Asselbergs, Daniela Toniolo, Linda S. Adair, Tõnu Esko, Xueya Zhou, Marja Vääräsmäki, Ralhan Sarju, Hui Cai, Chiea Chuen Khor, Albert Hofman, Marc Jan Bonder, Shikta Das, Väinö Turjanmaa, Ying Wu, Masahiro Nakatochi, Habibul Ahsan, Michelle Ann Rozario, Andrew Bjonnes, Jaspal S. Kooner, Marcus E. Kleber, Rossella Sorice, Lavinia Paternoster, Yumi Matsushita, Tanika NKelly, Quang NNguyen, Stanley L. Hazen, Richa Saxena, Lin Tong, Kenneth Kwek, Keizo Ohnaka, Paolo Vineis, Sahoko Ichihara, Jos C. S. Kleinjans, Irene Mateo Leach, Yonghong Zhang, K. Sangher, Robin Young, Mika Kivimäki, Soterios A. Kyrtopoulos, Ching-Yu Cheng, William R. Scott, Andres Metspalu, Eranga N. Vithana, Ai Ling Teh, Tarunveer S. Ahluwalia, Alexandre F.R. Stewart, John M. Starr, Toru Nabika, Jeannette Lee, Andre Franke, Inês Barroso, Gail Davies, Olov Rolandsson, Wei Huang, Myron D. Gross, Yong-Bing Xiang, Cinzia Sala, Marjo-Riitta Järvelin, W. Frank Paul, Jian'an Luan, Jon White, Robert A. Scott, Torben Jørgensen, Jing He, Tien Yin Wong, Michiya Igase, Yi Zhang, Nur Sabrina Sapari, Simone Wahl, Ron T. Gansevoort, Rasheed Asif, Bruce H W Wolffenbuttel, Alauddin Ahmed, Annette Peters, Silva Kasela, Jiang He, Min Jin Go, Takao Sugiyama, Dongfeng Gu, Jagvir Grewal, Satoshi Umemura, Thomas Sparsø, Anna-Liisa Hartikainen, Hooman Allayee, Xu Wang, Meena Kumari, Eitaro Nakashima, Xu Lin, Harold Snieder, Ananda R. Wickremasinghe, Yun Kyoung Kim, Yuan-Tsong Chen, Chew-Kiat Heng, Alexessander Couto Alves, E. James Ames Hixso, Daniela Ruggiero, Kazuro Shimokawa, Muhammad GKibriya, Jong-Young Lee, Yasuharu Tabara, Oluf Pedersen, Bong Jo Kim, Marie Loh, Lili Milani, Loi D. Do, Dharambir Harambir, Joo Yeon Hwang, Thomas Meitinger, Todd L. Edwards, Danish Saleheen, Anuradhani Kasturiratne, Hiromi Rakugi, Sian Tsung Tan, Paul Elliott, Ken Yamamoto, Chien Hsiun Chen, Abbas Dehghan, Evelin Mihailov, Leo-Pekka Lyytikäinen, Xiao-Ou Shu, Richie Soong, Yiqin Wang, Marina Ciullo, Graciela E. Delgado, Olli TRaitakari, Jian-Min Yuan, Melanie Waldenberger, Jiemin Liao, E. Shyong Tai, Mark I. McCarthy, Winfried März, Nilesh J. Samani, Yap Seng Chong, Son TPham, Sarah E. Harris, Regina Courtney, Allan Linneberg, W.H. Wilson Tang, Epidemiology, Ophthalmology, Medical Microbiology & Infectious Diseases, Cardiology, Radiology & Nuclear Medicine, Internal Medicine, Erasmus MC other, Biochemie, Interne Geneeskunde, Toxicogenomics, RS: GROW - Oncology, RS: GROW - R1 - Prevention, Cardiovascular Centre (CVC), Groningen Kidney Center (GKC), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: Male, Vascular smooth muscle, Performance, Research Support, U.S. Gov't, P.H.S, Genome-wide association study, Blood Pressure, Expression, 030204 cardiovascular system & hematology, VARIANTS, P.H.S, genome-wide, 0302 clinical medicine, Risk Factors, Natriuretic Peptide, Brain, Disease, Non-U.S. Gov't, CENTRIC ARRAY, Genetics, Genetics & Heredity, Aged, 80 and over, 0303 health sciences, Research Support, Non-U.S. Gov't, 11 Medical And Health Sciences, Middle Aged, REGIONS, Phenotype, CpG site, Cardiovascular Diseases, CARDIOVASCULAR-DISEASE, DNA methylation, BIOS-consortium, Regression Analysis, Female, Life Sciences & Biomedicine, Adult, PULMONARY ARTERIAL-HYPERTENSION, Genotype, Population, Single-nucleotide polymorphism, Biology, Research Support, ta3111, Polymorphism, Single Nucleotide, White People, Article, N.I.H, 03 medical and health sciences, KIDNEY, Asian People, Research Support, N.I.H., Extramural, Journal Article, Humans, Genetic Predisposition to Disease, Gene, METAANALYSIS, 030304 developmental biology, Aged, Science & Technology, CARDIo GRAMplusCD, ta1184, Extramural, Genetic Variation, InterAct Consortium, 06 Biological Sciences, DNA Methylation, ta3121, Peptide Fragments, INDIVIDUALS, Blood pressure, Genetic Loci, TISSUE, RISK-FACTORS, U.S. Gov't, LifeLines Cohort Study, Developmental Biology, Genome-Wide Association Study
Abstract: We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 x 10(-11) to 5.0 x 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 x 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
Published: 2015
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248. Hypothesis-free identification of modulators of genetic risk factors

Author: Aaron Isaacs, Alexandra Zhernakova, André G. Uitterlinden, Joris Deelen, Martijn Vermaat, Leonard H. van den Berg, Ettje F. Tigchelaar, Cornelia M. van Duijn, René Pool, Matthijs Moed, Maarten van Iterson, Wibowo Arindrarto, Jenny van Dongen, Coen D.A. Stehouwer, Peter van ‘t Hof, P. Eline Slagboom, Patrick Deelen, Daria V. Zhernakova, Peter A C 't Hoen, Joyce B. J. van Meurs, Jan Bot, Diana van Heemst, Casper G. Schalkwijk, Albert Hofman, Hailiang Mei, Jouke J. Hottenga, Rick Jansen, Jan H. Veldink, Marleen M.J. van Greevenbroek, Cisca Wijmenga, Marijn Verkerk, Lude Franke, Marc Jan Bonder, Yang I. Li, Szymon M. Kielbasa, Bastiaan T. Heijmans, Michiel van Galen, Marian Beekman, Jeroen van Rooij, Carla J.H. van der Kallen, Harm-Jan Westra, P. Mila Jhamai, Irene Nooren, Morris A. Swertz, Freerk van Dijk, and Dorret I. Boomsma
Subjects: False discovery rate, Genetics, 0303 health sciences, Cell type, Single-nucleotide polymorphism, Disease, Biology, 03 medical and health sciences, 0302 clinical medicine, Type I interferon signaling pathway, Expression quantitative trait loci, Gene, Transcription factor, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Genetic risk factors often localize in non-coding regions of the genome with unknown effects on disease etiology. Expression quantitative trait loci (eQTLs) help to explain the regulatory mechanisms underlying the association of genetic risk factors with disease. More mechanistic insights can be derived from knowledge of the context, such as cell type or the activity of signaling pathways, influencing the nature and strength of eQTLs. Here, we generated peripheral blood RNA-seq data from 2,116 unrelated Dutch individuals and systematically identified these context-dependent eQTLs using a hypothesis-free strategy that does not require prior knowledge on the identity of the modifiers. Out of the 23,060 significant cis-regulated genes (false discovery rate ≤ 0.05), 2,743 genes (12%) show context-dependent eQTL effects. The majority of those were influenced by cell type composition, revealing eQTLs that are particularly strong in cell types such as CD4+ T-cells, erythrocytes, and even lowly abundant eosinophils. A set of 145 cis-eQTLs were influenced by the activity of the type I interferon signaling pathway and we identified several cis-eQTLs that are modulated by specific transcription factors that bind to the eQTL SNPs. This demonstrates that large-scale eQTL studies in unchallenged individuals can complement perturbation experiments to gain better insight in regulatory networks and their stimuli.
Published: 2015
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249. Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

Author: Dorret I. Boomsma, Arn M. J. M. van den Maagdenberg, Kai-How Farh, Linda M. Pedersen, Evelin Mihailov, Lydia Quaye, Bertram Müller-Myhsok, Zameel M. Cader, David A. Hinds, Albert Hofman, George McMahon, Lynn Cherkas, Andrea Byrnes, Christopher Sivert Nielsen, Priit Palta, Kauko Heikkilä, Lili Milani, Caleb Webber, Elizabeth Loehrer, Maija Wessman, Stacy Steinberg, Stefan Schreiber, John-Anker Zwart, Nicholas A. Furlotte, Nicholas G. Martin, Paul M. Ridker, Nicholas Eriksson, André G. Uitterlinden, M. Arfan Ikram, Anine H. Stam, Audun Stubhaug, Hieab H.H. Adams, Markus Färkkilä, Verneri Anttila, Antti-Pekka Sarin, Salli Vepsäläinen, Jouke-Jan Hottenga, Pamela A. F. Madden, Andrew C. Heath, Brenda W.J.H. Penninx, Tobias Kurth, Ester Cuenca-León, Kari Stefansson, Veikko Salomaa, Dale R. Nyholt, Jaakko Kaprio, Andrea Carmine Belin, Tune H. Pers, Cynthia Sandor, Eija Hamalainen, Hailiang Huang, Lude Franke, Jie Huang, George Davey Smith, Jes Olesen, Anne Francke Christensen, Juho Wedenoja, Tobias Freilinger, Scott G. Gordon, Mari A. Kaunisto, Hreinn Stefansson, Guntram Borck, Maria Gudlaug Hrafnsdottir, David P. Strachan, Ville Artto, Johan G. Eriksson, Minna Männikkö, Evie Stergiakouli, Thomas Meitinger, Markus Schürks, Olli T. Raitakari, Arpo Aromaa, Mark J. Daly, Marjo-Riitta Järvelin, Andres Ingason, Martin Dichgans, Tim D. Spector, Cornelia M. van Duijn, Mikko Muona, Daniel I. Chasman, Hartmut Göbel, Andres Metspalu, Aarno Palotie, Michel D. Ferrari, Grant W. Montgomery, Susan M. Ring, Caroline Ran, Thomas Werge, Lannie Ligthart, Terho Lehtimäki, Julie E. Buring, Christian Kubisch, Mikko Kallela, Phil Lee, Ann-Louise Esserlind, Bendik S. Winsvold, Markku Koiranen, Benjamin M. Neale, Tõnu Esko, Rainer Malik, Gisela M. Terwindt, Thomas Hansen, and Padhraig Gormley
Subjects: Subset Analysis, Genetics, 0303 health sciences, Aura, Single-nucleotide polymorphism, Locus (genetics), Disease, Biology, medicine.disease, Migraine with aura, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Migraine, Meta-analysis, medicine, medicine.symptom, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Migraine is a debilitating neurological disorder affecting around 1 in 7 people worldwide, but its molecular mechanisms remain poorly understood. Some debate exists over whether migraine is a disease of vascular dysfunction, or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we performed the largest genetic study of migraine to date, comprising 59,674 cases and 316,078 controls from 22 GWA studies. We identified 45 independent single nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 x 10-8) that map to 38 distinct genomic loci, including 28 loci not previously reported and the first locus identified on chromosome X. Furthermore, a subset analysis for migraine without aura (MO) identified seven of the same loci as from the full sample, whereas no loci reached genome-wide significance in the migraine with aura (MA) subset. In subsequent computational analyzes, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.
Published: 2015
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250. Cohort profile: LifeLines DEEP, a prospective, general population cohort study in the northern Netherlands: study design and baseline characteristics

Author: Lude Franke, Gerben D. A. Hermes, Cisca Wijmenga, Agnieszka Baranska, Patrick Deelen, Alexandra Zhernakova, Jackie A M Dekens, Ettje F. Tigchelaar, Ronald P. Stolk, Zlatan Mujagic, Salome Scholtens, Angélica M Muñoz, Edith J. M. Feskens, María Carmen Cenit, Morris A. Swertz, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Groningen Energy & Sustainability Programme, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: Research design, Male, Nutrition and Disease, IRRITABLE-BOWEL-SYNDROME, Gastrointestinal Diseases, Epidemiology, Disease, Bioinformatics, Microbiologie, QUALITY-OF-LIFE, Voeding en Ziekte, IMPUTATION, Prospective Studies, Prospective cohort study, Netherlands, Aged, 80 and over, education.field_of_study, Data Collection, CELIAC-DISEASE, Estudios Prospectivos, General Medicine, Middle Aged, CATALOG, COMMUNITY, Phenotype, Plant Production Systems, Research Design, Cohort, Epidemiological Monitoring, Population study, Female, Public Health, PUBLIC HEALTH, COUNTRIES, Adult, medicine.medical_specialty, Adolescent, GENETICS, Population, General Population Cohort, Salud Pública, Disease Prevention, Microbiology, Young Adult, Environmental health, Genetics, medicine, Epidemiología, Life Science, Humans, GENOME-WIDE ASSOCIATION, education, VLAG, Aged, ENVIRONMENT, Cohort Profile, business.industry, Genetic Variation, Genética, Biomarcadores, Plantaardige Productiesystemen, business, Prevención de Enfermedades, Biomarkers
Abstract: Purpose: There is a critical need for population-based prospective cohort studies because they follow individuals before the onset of disease, allowing for studies that can identify biomarkers and disease-modifying effects, and thereby contributing to systems epidemiology.Participants: This paper describes the design and baseline characteristics of an intensively examined subpopulation of the LifeLines cohort in the Netherlands. In this unique subcohort, LifeLines DEEP, we included 1539 participants aged 18 years and older.Findings to date: We collected additional blood (n= 1387), exhaled air (n= 1425) and faecal samples (n= 1248), and elicited responses to gastrointestinal health questionnaires (n= 1176) for analysis of the genome, epigenome, transcriptome, microbiome, metabolome and other biological levels. Here, we provide an overview of the different data layers in LifeLines DEEP and present baseline characteristics of the study population including food intake and quality of life. We also describe how the LifeLines DEEP cohort allows for the detailed investigation of genetic, genomic and metabolic variation for a wide range of phenotypic outcomes. Finally, we examine the determinants of gastrointestinal health, an area of particular interest to us that can be addressed by LifeLines DEEP.Future plans: We have established a cohort of which multiple data levels allow for the integrative analysis of populations for translation of this information into biomarkers for disease, and which will offer new insights into disease mechanisms and prevention.
Published: 2015

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