Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders
In: Am J Hum Genet Pool, R, de Geus, E, Hottenga, Jg. 103 Ligthart (2018-11-01), S. 691-706
Online
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Zugriff:
International audience; C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.Copyright © 2018 American Society of Human Genetics. All rights reserved.
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Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders
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| Autor/in / Beteiligte Person: | Ligthart, Symen ; Vaez, Ahmad ; Võsa, Urmo ; Stathopoulou, Maria G. ; Paul S. de Vries ; Prins, Bram P. ; Peter J. Van der Most ; Tanaka, Toshiko ; Naderi, Elnaz ; Rose, Lynda M. ; Wu, Ying ; Karlsson, Robert ; Barbalic, Maja ; Lin, Honghuang ; Pool, René ; Zhu, Gu ; Macé, Aurélien ; Sidore, Carlo ; Trompet, Stella ; Mangino, Massimo ; Sabater-Lleal, Maria ; Kemp, John P. ; Abbasi, Ali ; Kacprowski, Tim ; Verweij, Niek ; Smith, Albert V. ; Huang, Tao ; Marzi, Carola ; Feitosa, Mary F. ; Lohman, Kurt K. ; Kleber, Marcus E. ; Milaneschi, Yuri ; Mueller, Christian ; Huq, Mahmudul ; Vlachopoulou, Efthymia ; Lyytikäinen, Leo-Pekka ; Oldmeadow, Christopher ; Deelen, Joris ; Perola, Markus ; Jing Hua Zhao ; Feenstra, Bjarke ; Amini, Marzyeh ; Lahti, Jari ; Schraut, Katharina E. ; Fornage, Myriam ; Suktitipat, Bhoom ; Chen, Wei-Min ; Li, Xiaohui ; Nutile, Teresa ; Malerba, Giovanni ; Luan, Jian’an ; Bak, Tom ; Schork, Nicholas ; Fabiola Del Greco M. ; Thiering, Elisabeth ; Mahajan, Anubha ; Marioni, Riccardo E. ; Mihailov, Evelin ; Eriksson, Joel ; Ayse Bilge Ozel ; Zhang, Weihua ; Nethander, Maria ; Cheng, Yu-Ching ; Aslibekyan, Stella ; Ang, Wei ; Gandin, Ilaria ; Yengo, Loïc ; Portas, Laura ; Kooperberg, Charles ; Hofer, Edith ; Rajan, Kumar B. ; Schurmann, Claudia ; Wouter den Hollander ; Ahluwalia, Tarunveer S. ; Zhao, Jing ; Harmen H.M. Draisma ; Ford, Ian ; Timpson, Nicholas ; Teumer, Alexander ; Huang, Hongyan ; Wahl, Simone ; Liu, YongMei ; Huang, Jie ; Uh, Hae-Won ; Geller, Frank ; Joshi, Peter K. ; Yanek, Lisa R. ; Trabetti, Elisabetta ; Lehne, Benjamin ; Vozzi, Diego ; Verbanck, Marie ; Biino, Ginevra ; Saba, Yasaman ; Meulenbelt, Ingrid ; O’Connell, Jeff R. ; Laakso, Markku ; Giulianini, Franco ; Patrik K.E. Magnusson ; Ballantyne, Christie M. ; Jouke Jan Hottenga ; Montgomery, Grant W. ; Rivadineira, Fernando ; Rueedi, Rico ; Steri, Maristella ; Herzig, Karl-Heinz ; Stott, David J. ; Menni, Cristina ; Frånberg, Mattias ; Beate St. Pourcain ; Felix, Stephan B. ; Pers, Tune H. ; Stephan J.L. Bakker ; Kraft, Peter ; Peters, Annette ; Vaidya, Dhananjay ; Delgado, Graciela ; Smit, Johannes H. ; Großmann, Vera ; Sinisalo, Juha ; Seppälä, Ilkka ; Williams, Stephen R. ; Holliday, Elizabeth G. ; Moed, Matthijs ; Langenberg, Claudia ; Räikkönen, Katri ; Ding, Jingzhong ; Campbell, Harry ; Sale, Michele M. ; Chen, Yii-Der I. ; James, Alan L. ; Ruggiero, Daniela ; Soranzo, Nicole ; Hartman, Catharina A. ; Smith, Erin N. ; Berenson, Gerald S. ; Fuchsberger, Christian ; Hernandez, Dena ; Carla M.T. Tiesler ; Giedraitis, Vilmantas ; Liewald, David ; Fischer, Krista ; Mellström, Dan ; Larsson, Anders ; Wang, Yunmei ; Scott, William R. ; Lorentzon, Matthias ; Beilby, John ; Ryan, Kathleen A. ; Pennell, Craig E. ; Vuckovic, Dragana ; Balkau, Beverly ; Maria Pina Concas ; Schmidt, Reinhold ; Carlos F. Mendes de Leon ; Bottinger, Erwin P. ; Kloppenburg, Margreet ; Paternoster, Lavinia ; Boehnke, Michael ; Musk, A.W. ; Willemsen, Gonneke ; Evans, David M. ; Pamela A.F. Madden ; Kähönen, Mika ; Kutalik, Zoltán ; Zoledziewska, Magdalena ; Karhunen, Ville ; Kritchevsky, Stephen B. ; Sattar, Naveed ; Lachance, Genevieve ; Clarke, Robert ; Harris, Tamara B. ; Raitakari, Olli T. ; Attia, John R. ; Diana van Heemst ; Kajantie, Eero ; Sorice, Rossella ; Gambaro, Giovanni ; Scott, Robert A. ; Hicks, Andrew A. ; Ferrucci, Luigi ; Standl, Marie ; Lindgren, Cecilia M. ; Starr, John M. ; Karlsson, Magnus ; Lind, Lars ; Li, Jun Z. ; Chambers, John C. ; Mori, Trevor A. ; Eco J.C.N. de Geus ; Heath, Andrew C. ; Martin, Nicholas G. ; Auvinen, Juha ; Buckley, Brendan M. ; Anton J.M. de Craen ; Waldenberger, Melanie ; Strauch, Konstantin ; Meitinger, Thomas ; Scott, Rodney J. ; McEvoy, Mark ; Beekman, Marian ; Bombieri, Cristina ; Ridker, Paul M. ; Mohlke, Karen L. ; Pedersen, Nancy L. ; Morrison, Alanna C. ; Boomsma, Dorret I. ; Whitfield, John B. ; Strachan, David P. ; Hofman, Albert ; Vollenweider, Peter ; Cucca, Francesco ; Jarvelin, Marjo-Riitta ; J. Wouter Jukema ; Spector, Tim D. ; Hamsten, Anders ; Zeller, Tanja ; Uitterlinden, André G. ; Nauck, Matthias ; Gudnason, Vilmundur ; Qi, Lu ; Grallert, Harald ; Borecki, Ingrid B. ; Rotter, Jerome I. ; März, Winfried ; Wild, Philipp S. ; Lokki, Marja-Liisa ; Boyle, Michael ; Salomaa, Veikko ; Melbye, Mads ; Eriksson, Johan G. ; Wilson, James F. ; Brenda W.J.H. Penninx ; Becker, Diane M. ; Worrall, Bradford B. ; Gibson, Greg ; Krauss, Ronald M. ; Ciullo, Marina ; Zaza, Gianluigi ; Wareham, Nicholas J. ; Oldehinkel, Albertine J. ; Palmer, Lyle J. ; Murray, Sarah S. ; Pramstaller, Peter P. ; Bandinelli, Stefania ; Heinrich, Joachim ; Ingelsson, Erik ; Deary, Ian J. ; Mägi, Reedik ; Vandenput, Liesbeth ; Pim van der Harst ; Desch, Karl C. ; Kooner, Jaspal S. ; Ohlsson, Claes ; Hayward, Caroline ; Lehtimäki, Terho ; Shuldiner, Alan R. ; Arnett, Donna K. ; Beilin, Lawrence J. ; Robino, Antonietta ; Froguel, Philippe ; Pirastu, Mario ; Jess, Tine ; Koenig, Wolfgang ; Ruth J.F. Loos ; Evans, Denis A. ; Schmidt, Helena ; George Davey Smith ; P. Eline Slagboom ; Eiriksdottir, Gudny ; Morris, Andrew P. ; Psaty, Bruce M. ; Tracy, Russell P. ; Nolte, Ilja M. ; Boerwinkle, Eric ; Visvikis-Siest, Sophie ; Reiner, Alex P. ; Gross, Myron ; Bis, Joshua C. ; Franke, Lude ; Franco, Oscar H. ; Benjamin, Emelia J. ; Chasman, Daniel I. ; Dupuis, Josée ; Snieder, Harold ; Dehghan, Abbas ; Alizadeh, Behrooz Z. ; H. Marike Boezen ; Navis, Gerjan ; Rots, Marianne ; Swertz, Morris ; Bruce H.R. 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Hôpitaux Universitaires de Genève (HUG) ; Infectious diseases division, Department of internal medicine ; Washington University in Saint Louis (WUSTL) ; Luleå University of Technology (LUT) ; Recherche en épidémiologie et biostatistique ; Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM) ; Austrian Institute of Technology [Vienna] (AIT) ; Icahn School of Medicine at Mount Sinai [New York] (MSSM) ; Department of Rheumatology and Clinical Epidemiology, Leiden University Medical Center (LUMC) ; Department of Rheumatology and Clinical Epidemiology [Leiden University Medical Center] (LUMC) ; Leiden University Medical Center (LUMC) ; Universiteit Leiden-Universiteit Leiden-Leiden University Medical Center (LUMC) ; Universiteit Leiden-Universiteit Leiden ; Department of Biostatistics and Center for Statistical Genetics ; University of Michigan [Ann Arbor] ; University of Michigan System-University of Michigan System ; University of Virginia ; 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University of Oulu ; Medizinische Klinik und Poliklinik ; Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU) ; Institute of Clinical Chemistry and Laboratory Medicine ; Icelandic Heart Association ; Heart Preventive Clinic and Research Institute ; Departments of Epidemiology and Nutrition ; Institute of Epidemiology [Neuherberg] (EPI) ; Medical University Graz ; Transplantation Laboratory [Helsinki] ; Haartman Institute [Helsinki] ; Faculty of Medecine [Helsinki] ; Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki] ; Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki ; Department of Chronic Disease Prevention ; National Institute for Health and Welfare [Helsinki] ; Dept. of Epidemiology Research ; Statens Serum Institut [Copenhagen] ; Psychology, CLinical ; 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Human Genetics Branch ; National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH) ; Faculty of Medicine and Life Sciences [Tampere] ; University of Tampere [Finland] ; German Center for Cardiovascular Research (DZHK) ; Berlin Institute of Health (BIH) ; MRC Centre for Neuropsychiatric Genetics and Genomics ; Medical Research Council-Cardiff University ; Department of Social Medicine ; School of Medicine [Los Angeles] ; University of California [Los Angeles] (UCLA) ; University of California (UC)-University of California (UC) ; Department of Medicine [Aurora, CO, USA] ; University of Colorado [Denver] ; Institute for Molecular Medicine Finland [Helsinki] (FIMM) ; Helsinki Institute of Life Science (HiLIFE) ; Mathematical Institute [Oxford] (MI) ; Institute of Psychiatry, Psychology & Neuroscience, King's College London ; LifeLines Cohort Study ; CHARGE Inflammation Working Group ; Ligthart, S. ; Vaez, A. ; Vosa, U. ; Stathopoulou, M. G. ; de Vries, P. S. ; Prins, B. P. ; Van der Most, P. J. ; Tanaka, T. ; Naderi, E. ; Rose, L. M. ; Wu, Y. ; Karlsson, R. ; Barbalic, M. ; Lin, H. ; Pool, R. ; Zhu, G. ; Mace, A. ; Sidore, C. ; Trompet, S. ; Mangino, M. ; Sabater-Lleal, M. ; Kemp, J. P. ; Abbasi, A. ; Kacprowski, T. ; Verweij, N. ; Smith, A. V. ; Huang, T. ; Marzi, C. ; Feitosa, M. F. ; Lohman, K. K. ; Kleber, M. E. ; Milaneschi, Y. ; Mueller, C. ; Huq, M. ; Vlachopoulou, E. ; Lyytikainen, L. P. ; Oldmeadow, C. ; Deelen, J. ; Perola, M. ; Zhao, J. H. ; Feenstra, B. ; Alizadeh, B. Z. ; Boezen, H. M. ; Franke, L. ; van der Harst, P. ; Navis, G. ; Rots, M. ; Snieder, H. ; Swertz, M. ; Wolffenbuttel, B. H. R. ; Wijmenga, C. ; Amini, M. ; Benjamin, E. ; Chasman, D. I. ; Dehghan, A. ; Ahluwalia, T. S. ; Meigs, J. ; Tracy, R. ; Bis, J. ; Eiriksdottir, G. ; Pankratz, N. ; Gross, M. ; Rainer, A. ; Wilson, J. G. ; Psaty, B. M. ; Dupuis, J. ; Prins, B. ; Vaso, U. ; Stathopoulou, M. ; Lehtimaki, T. ; Koenig, W. ; Jamshidi, Y. ; Siest, S. ; Uitterlinden, A. G. ; Abdollahi, M. ; Schnabel, R. ; Schick, U. M. ; Nolte, I. M. ; Kraja, A. ; Hsu, Y. H. ; Tylee, D. S. ; Zwicker, A. ; Uher, R. ; Davey-Smith, G. ; Morrison, A. C. ; Hicks, A. ; van Duijn, C. M. ; Ward-Caviness, C. ; Boerwinkle, E. ; Rice, K. ; Lange, L. ; de Geus, E. ; Morris, A. P. ; Makela, K. M. ; Stacey, D. ; Eriksson, J. ; Frayling, T. M. ; Slagboom, E. P. ; Lahti, J. ; Schraut, K. E. ; Fornage, M. ; Suktitipat, B. ; Chen, W. M. ; Li, X. ; Nutile, T. ; Malerba, G. ; Luan, J. ; Bak, T. ; Schork, N. ; Del Greco, M. F. ; Thiering, E. ; Mahajan, A. ; Marioni, R. E. ; Mihailov, E. ; Ozel, A. B. ; Zhang, W. ; Nethander, M. ; Cheng, Y. C. ; Aslibekyan, S. ; Ang, W. ; Gandin, I. ; Yengo, L. ; Portas, L. ; Kooperberg, C. ; Hofer, E. ; Rajan, K. B. ; Schurmann, C. ; den Hollander, W. ; Zhao, J. ; Draisma, H. H. M. ; Ford, I. ; Timpson, N. ; Teumer, A. ; Huang, H. ; Wahl, S. ; Liu, Y. ; Huang, J. ; Uh, H. W. ; Geller, F. ; Joshi, P. K. ; Yanek, L. R. ; Trabetti, E. ; Lehne, B. ; Vozzi, D. ; Verbanck, M. ; Biino, G. ; Saba, Y. ; Meulenbelt, I. ; O'Connell, J. R. ; Laakso, M. ; Giulianini, F. ; Magnusson, P. K. E. ; Ballantyne, C. M. ; Hottenga, J. J. ; Montgomery, G. W. ; Rivadineira, F. ; Rueedi, R. ; Steri, M. ; Herzig, K. H. ; Stott, D. J. ; Menni, C. ; Franberg, M. ; S, t. Pourcain B. ; Felix, S. B. ; Pers, T. H. ; Bakker, S. J. L. ; Kraft, P. ; Peters, A. ; Vaidya, D. ; Delgado, G. ; Smit, J. H. ; Grossmann, V. ; Sinisalo, J. ; Seppala, I. ; Williams, S. R. ; Holliday, E. G. ; Moed, M. ; Langenberg, C. ; Raikkonen, K. ; Ding, J. ; Campbell, H. ; Sale, M. M. ; Chen, Y. -D. I. ; James, A. L. ; Ruggiero, D. ; Soranzo, N. ; Hartman, C. A. ; Smith, E. N. ; Berenson, G. S. ; Fuchsberger, C. ; Hernandez, D. ; Tiesler, C. M. T. ; Giedraitis, V. ; Liewald, D. ; Fischer, K. ; Mellstrom, D. ; Larsson, A. ; Wang, Y. ; Scott, W. R. ; Lorentzon, M. ; Beilby, J. ; Ryan, K. A. ; Pennell, C. E. ; Vuckovic, D. ; Balkau, B. ; Concas, M. P. ; Schmidt, R. ; Mendes de Leon, C. F. ; Bottinger, E. P. ; Kloppenburg, M. ; Paternoster, L. ; Boehnke, M. ; Musk, A. W. ; Willemsen, G. ; Evans, D. M. ; Madden, P. A. F. ; Kahonen, M. ; Kutalik, Z. ; Zoledziewska, M. ; Karhunen, V. ; Kritchevsky, S. B. ; Sattar, N. ; Lachance, G. ; Clarke, R. ; Harris, T. B. ; Raitakari, O. T. ; Attia, J. R. ; van Heemst, D. ; Kajantie, E. ; Sorice, R. ; Gambaro, G. ; Scott, R. A. ; Hicks, A. A. ; Ferrucci, L. ; Standl, M. ; Lindgren, C. M. ; Starr, J. M. ; Karlsson, M. ; Lind, L. ; Li, J. Z. ; Chambers, J. C. ; Mori, T. A. ; de Geus, E. J. C. N. ; Heath, A. C. ; Martin, N. G. ; Auvinen, J. ; Buckley, B. M. ; de Craen, A. J. M. ; Waldenberger, M. ; Strauch, K. ; Meitinger, T. ; Scott, R. J. ; Mcevoy, M. ; Beekman, M. ; Bombieri, C. ; Ridker, P. M. ; Mohlke, K. L. ; Pedersen, N. L. ; Boomsma, D. I. ; Whitfield, J. B. ; Strachan, D. P. ; Hofman, A. ; Vollenweider, P. ; Cucca, F. ; Jarvelin, M. R. ; Jukema, J. W. ; Spector, T. D. ; Hamsten, A. ; Zeller, T. ; Nauck, M. ; Gudnason, V. ; Qi, L. ; Grallert, H. ; Borecki, I. B. ; Rotter, J. I. ; Marz, W. ; Wild, P. S. ; Lokki, M. L. ; Boyle, M. ; Salomaa, V. ; Melbye, M. ; Eriksson, J. G. ; Wilson, J. F. ; Penninx, B. W. J. H. ; Becker, D. M. ; Worrall, B. B. ; Gibson, G. ; Krauss, R. M. ; Ciullo, M. ; Zaza, G. ; Wareham, N. J. ; Oldehinkel, A. J. ; Palmer, L. J. ; Murray, S. S. ; Pramstaller, P. P. ; Bandinelli, S. ; Heinrich, J. ; Ingelsson, E. ; Deary, I. J. ; Magi, R. ; Vandenput, L. ; Desch, K. C. ; Kooner, J. S. ; Ohlsson, C. ; Hayward, C. ; Shuldiner, A. R. ; Arnett, D. K. ; Beilin, L. J. ; Robino, A. ; Froguel, P. ; Pirastu, M. ; Jess, T. ; Loos, R. J. F. ; Evans, D. A. ; Schmidt, H. ; Slagboom, P. E. ; Tracy, R. P. ; Visvikis-Siest, S. ; Reiner, A. P. ; Bis, J. C. ; Franco, O. H. ; Benjamin, E. J. ; AGEM - Amsterdam Gastroenterology Endocrinology Metabolism ; School, Graduate ; Epidemiology ; Medicine, Internal ; Groningen Institute for Organ Transplantation (GIOT) ; Lifestyle Medicine (LM) ; Groningen Kidney Center (GKC) ; Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE) ; Cardiovascular Centre (CVC) ; Life Course Epidemiology (LCE) ; Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI) ; Stem Cell Aging Leukemia and Lymphoma (SALL) ; Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET) ; VU University medical center ; Psychiatry ; Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep ; APH - Mental Health ; APH - Methodology ; APH - Digital Health ; Psychology, Biological ; APH - Personalized Medicine ; APH - Health Behaviors & Chronic Diseases ; Universität Heidelberg [Heidelberg] ; University of Verona (UNIVR) ; Department of Molecular and Experimental Medicine, The Scripps Research Institute ; The Scripps Research Institute ; Université Grenoble Alpes - UFR Sciences de l'Homme et de la Société (UGA UFR SHS) ; Université Grenoble Alpes [2016-2019] (UGA [2016-2019]) ; IT University of Copenhagen ; Technical University of Denmark [Lyngby] (DTU) ; Consiglio Nazionale delle Ricerche (CNR) ; University of Virginia [Charlottesville] ; Université de Lausanne (UNIL) ; University of Oxford [Oxford] ; University of Newcastle [Australia] (UoN) ; Centre d'économie industrielle i3 (CERNA i3) ; Centre National de la Recherche Scientifique (CNRS)-MINES ParisTech - École nationale supérieure des mines de Paris ; Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL) ; Helmholtz-Zentrum München (HZM) ; Laboratoire Interuniversitaire des Systèmes Atmosphériques (LISA (UMR_7583)) ; Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS) ; Universitätsmedizin der Johannes-Gutenberg Universität Mainz ; University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki] ; University of Helsinki-University of Helsinki ; Cardiff University-Medical Research Council ; University of California-University of California ; DE CARVALHO, Philippe |
| Link: | |
| Zeitschrift: | Am J Hum Genet Pool, R, de Geus, E, Hottenga, Jg. 103 Ligthart (2018-11-01), S. 691-706 |
| Veröffentlichung: | 2018 |
| Medientyp: | unknown |
| ISSN: | 0002-9297 (print) ; 1537-6605 (print) |
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