98 results on '"Hedman, Asa K"'
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2. Plasma Protein Biomarkers of Spirometry Measures of Impaired Lung Function
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Aggarwal, Mohit, Hwang, Shih-Jen, Lee, Dong Heon, Huan, Tianxiao, McNeill, Jenna N., Courchesne, Paul, Joehanes, Roby, Ho, Jennifer E., Dupuis, Josée, Hedman, Åsa K., O’Connor, George, and Levy, Daniel
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- 2024
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3. Higher chylomicron remnants and LDL particle numbers associate with CD36 SNPs and DNA methylation sites that reduce CD36
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Love-Gregory, Latisha, Kraja, Aldi T., Allum, Fiona, Aslibekyan, Stella, Hedman, Åsa K., Duan, Yanan, Borecki, Ingrid B., Arnett, Donna K., McCarthy, Mark I., Deloukas, Panos, Ordovas, Jose M., Hopkins, Paul N., Grundberg, Elin, and Abumrad, Nada A.
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- 2016
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4. Genetics of circulating inflammatory proteins identifies drivers of immune-mediated 22 disease risk and therapeutic targets
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Zhao, Jing Hua, Stacey, David, Eriksson, Niclas, Macdonald-Dunlop, Erin, Hedman, Asa K, Kalnapenkis, Anette, Enroth, Stefan, Cozzetto, Domenico, Digby-Bell, Jonathan, Marten, Jonathan, Folkersen, Lasse, Herder, Christian, Jonsson, Lina, Bergen, Sarah E, Geiger, Christian, Needham, Elise J, Surendran, Praveen, Paul, Dirk S, Polasek, Ozren, Thorand, Barbara, Grallert, Harald, Roden, Michael, Võsa, Urmo, Esko, Tonu, Hayward, Caroline, Johansson, Asa, Gyllensten, Ulf, Powell, Nicholas, Hansson, Oskar, Mattsson-Carlgren, Niklas, Joshi, Peter K, Danesh, John, Padyukov, Leonid, Klareskog, Lars, Landén, Mikael, Wilson, James F, Siegbahn, Agneta, Wallentin, Lars, Mälarstig, Anders, Butterworth, Adam S, Peters, James E, and Apollo - University of Cambridge Repository
- Abstract
Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identify 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease GWAS provided insight into pathogenesis, implicating lymphotoxin-α in multiple sclerosis. Using Mendelian randomisation (MR) to assess causality in aetiology, we identify both shared and distinct effects of specific proteins across immune mediated diseases, including directionally discordant functions for CD40 in rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the aetiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets for existing drugs and provide a powerful resource to facilitate future drug target prioritisation.
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- 2023
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5. Mapping pQTLs of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and novel therapeutic targets
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Zhao, Jing Hua, Stacey, David, Eriksson, Niclas, Macdonald-Dunlop, Erin, Hedman, Asa K, Kalnapenkis, Anette, Enroth, Stefan, Cozzetto, Domenico, Digby-Bell, Jonathan, Marten, Jonathan, Folkersen, Lasse, Herder, Christian, Jonsson, Lina, Bergen, Sarah E, Geiger, Christian, J Needham, Elise, Surendran, Praveen, Pau, Dirk S, Polasek, Ozren, Thorand, Barbara, Graller, Harald, Roden, Michael, Võsa, Urmo, Esko, Tonu, Hayward, Caroline, Johansson, Asa, Gyllensten, Ulf, Powell, Nicholas, Hansson, Oskar, Mattsson-Carlgren, Niklas, Joshi, Peter K, Danesh, Josh, Padyukov, Leonid, Klareskog, Lars, Landén, Mikael, Wilson, James F, Siegbahn, Agneta, Wallentin, Lars, Mälarstig, Anders, Butterworth, Adam, Peters, James E, and Apollo - University of Cambridge Repository
- Abstract
Circulating proteins play key roles in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs, of which 50 were novel. Integration of pQTL data with eQTL and disease GWAS provided insights into pathogenesis, implicating lymphotoxin-alpha (LTA) in multiple sclerosis. Using Mendelian randomisation (MR), we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant causal roles for CD40 in rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. Our results highlight novel potential therapeutic avenues, including CXCL5 in ulcerative colitis (UC), a finding supported by elevated gut CXCL5 expression in UC patients. Our data provide a powerful resource to facilitate future drug target prioritization.
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- 2023
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6. Genome-Wide Association Studies of Obesity
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Hedman, Åsa K., Lindgren, Cecilia M., McCarthy, Mark I., and Grant, Struan F.A., editor
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- 2014
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7. Global Analysis of DNA Methylation Variation in Adipose Tissue from Twins Reveals Links to Disease-Associated Variants in Distal Regulatory Elements
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Ahmadi, Kourosh R., Ainali, Chrysanthi, Barrett, Amy, Bataille, Veronique, Bell, Jordana T., Buil, Alfonso, Deloukas, Panos, Dermitzakis, Emmanouil T., Dimas, Antigone S., Durbin, Richard, Glass, Daniel, Grundberg, Elin, Hassanali, Neelam, Hedman, Åsa K., Ingle, Catherine, Knowles, David, Krestyaninova, Maria, Lindgren, Cecilia M., Lowe, Christopher E., McCarthy, Mark I., Meduri, Eshwar, di Meglio, Paola, Min, Josine L., Montgomery, Stephen B., Nestle, Frank O., Nica, Alexandra C., Nisbet, James, O’Rahilly, Stephen, Parts, Leopold, Potter, Simon, Sandling, Johanna, Sekowska, Magdalena, Shin, So-Youn, Small, Kerrin S., Soranzo, Nicole, Spector, Tim D., Surdulescu, Gabriela, Travers, Mary E., Tsaprouni, Loukia, Tsoka, Sophia, Wilk, Alicja, Yang, Tsun-Po, Zondervan, Krina T., Sandling, Johanna K., Keildson, Sarah, Busche, Stephan, Yuan, Wei, Ge, Bing, Caron, Maxime, Lathrop, Mark, and Spector, Timothy D.
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- 2013
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8. Expression of phosphofructokinase in skeletal muscle is influenced by genetic variation and associated with insulin sensitivity
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Keildson, Sarah, Fadista, Joao, Ladenvall, Claes, Hedman, Asa K., Elgzyri, Targ, Small, Kerrin S., Grundberg, Elin, Nica, Alexandra C., Glass, Daniel, Richards, J. Brent, Barrett, Amy, Nisbet, James, Zheng, Hou-Feng, Ronn, Tina, Strom, Kristoffer, Eriksson, Karl-Fredrik, Prokopenko, Inga, Spector, Timothy D., Dermitzakis, Emmanouil T., Deloukas, Panos, McCarthy, Mark I., Rung, Johan, Groop, Leif, Franks, Paul W., Lindgren, Cecilia M., and Hansson, Ola
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Genetic research ,Musculoskeletal system -- Physiological aspects ,Genetic variation -- Research ,Phosphotransferases -- Identification and classification ,Health - Abstract
Using an integrative approach in which genetic variation, gene expression, and clinical phenotypes are assessed in relevant tissues may help functionally characterize the contribution of genetics to disease susceptibility. We sought to identify genetic variation influencing skeletal muscle gene expression (expression quantitative trait loci [eQTLs]) as well as expression associated with measures of insulin sensitivity. We investigated associations of 3,799,401 genetic variants in expression of >7,000 genes from three cohorts (n = 104). We identified 287 genes with cis-acting eQTLs (false discovery rate [FDR] DOI: 10.2337/db13-1301, Although genome-wide association studies (GWASs) have identified thousands of single nucleotide polymorphisms (SNPs) associated with traits and diseases, the molecular mechanisms underlying these associations remain largely unknown. Changes in gene [...]
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- 2014
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9. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
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Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjornsson, Gardar, Fatemifar, Ghazaleh, Hedman, Asa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Arnlov, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Doerr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engstrom, Gunnar, Esko, Tonu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Gudbjartsson, Daniel F, Gutmann, Rebecca, Haggerty, Christopher M, van der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Kober, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, Maerz, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, Stott, David J, Svensson, Per, Tammesoo, Mari-Liis, Taylor, Kent D, Teder-Laving, Maris, Teumer, Alexander, Thorgeirsson, Gudmundur, Thorsteinsdottir, Unnur, Torp-Pedersen, Christian, Trompet, Stella, Tyl, Benoit, Uitterlinden, Andre G, Veluchamy, Abirami, Voelker, Uwe, Voors, Adriaan A, Wang, Xiaosong, Wareham, Nicholas J, Waterworth, Dawn, Weeke, Peter E, Weiss, Raul, Wiggins, Kerri L, Xing, Heming, Yerges-Armstrong, Laura M, Yu, Bing, Zannad, Faiez, Zhao, Jing Hua, Hemingway, Harry, Samani, Nilesh J, McMurray, John JV, Yang, Jian, Visscher, Peter M, Newton-Cheh, Christopher, Malarstig, Anders, Holm, Hilma, Lubitz, Steven A, Sattar, Naveed, Holmes, Michael V, Cappola, Thomas P, Asselbergs, Folkert W, Hingorani, Aroon D, Kuchenbaecker, Karoline, Ellinor, Patrick T, Lang, Chim C, Stefansson, Kari, Smith, J Gustav, Vasan, Ramachandran S, Swerdlow, Daniel I, Lumbers, R Thomas, Abecasis, Goncalo, Backman, Joshua, Bai, Xiaodong, Balasubramanian, Suganthi, Banerjee, Nilanjana, Baras, Aris, Barnard, Leland, Beechert, Christina, Blumenfeld, Andrew, Cantor, Michael, Chai, Yating, Coppola, Giovanni, Damask, Amy, Dewey, Frederick, Economides, Aris, Eom, Gisu, Forsythe, Caitlin, Fuller, Erin D, Gu, Zhenhua, Gurski, Lauren, Guzzardo, Paloma M, Habegger, Lukas, Hahn, Young, Hawes, Alicia, van Hout, Cristopher, Jones, Marcus B, Khalid, Shareef, Lattari, Michael, Li, Alexander, Lin, Nan, Liu, Daren, Lopez, Alexander, Manoochehri, Kia, Marchini, Jonathan, Marcketta, Anthony, Maxwell, Evan K, McCarthy, Shane, Mitnaul, Lyndon J, O'Dushlaine, Colm, Overton, John D, Padilla, Maria Sotiropoulos, Paulding, Charles, Penn, John, Pradhan, Manasi, Reid, Jeffrey G, Schleicher, Thomas D, Schurmann, Claudia, Shuldiner, Alan, Staples, Jeffrey C, Sun, Dylan, Toledo, Karina, Ulloa, Ricardo H, Widom, Louis, Wolf, Sarah E, Yadav, Ashish, Ye, Bin, Ctr, Regeneron Genetics, Shah, Sonia [0000-0001-5860-4526], Henry, Albert [0000-0001-7422-2288], Roselli, Carolina [0000-0001-5267-6756], Lin, Honghuang [0000-0003-3043-3942], Chaffin, Mark D. [0000-0002-1234-5562], Helgadottir, Anna [0000-0002-1806-2467], Verweij, Niek [0000-0002-4303-7685], Almgren, Peter [0000-0002-0473-0241], Chen, Xu [0000-0002-7299-3238], Ghanbari, Mohsen [0000-0002-9476-7143], Giedraitis, Vilmantas [0000-0003-3423-2021], Gross, Stefan [0000-0003-4121-7161], Guðbjartsson, Daníel F. [0000-0002-5222-9857], Hyde, Craig L. [0000-0002-6939-287X], Ingelsson, Erik [0000-0003-2256-6972], Jukema, J. Wouter [0000-0002-3246-8359], Kleber, Marcus E. [0000-0003-0663-7275], Koekemoer, Andrea [0000-0001-8222-3547], Langenberg, Claudia [0000-0002-5017-7344], Lindgren, Cecilia M. [0000-0002-4903-9374], Lovering, Ruth C. [0000-0002-9791-0064], Luan, Jian’an [0000-0003-3137-6337], Magnusson, Patrik [0000-0002-7315-7899], Mahajan, Anubha [0000-0001-5585-3420], Mordi, Ify R. [0000-0002-2686-729X], Morris, Andrew D. [0000-0002-1766-0473], Nagle, Michael W. [0000-0002-4677-7582], Nelson, Christopher P. [0000-0001-8025-2897], Palmer, Colin N. A. [0000-0002-6415-6560], Rice, Kenneth M. [0000-0002-3071-7278], Rotter, Jerome I. [0000-0001-7191-1723], Salomaa, Veikko [0000-0001-7563-5324], van Setten, Jessica [0000-0002-4934-7510], Svensson, Per [0000-0003-0372-6272], Taylor, Kent D. [0000-0002-2756-4370], Teder-Laving, Maris [0000-0002-5872-1850], Teumer, Alexander [0000-0002-8309-094X], Tyl, Benoit [0000-0001-5297-8412], Uitterlinden, Andre G. [0000-0002-7276-3387], Völker, Uwe [0000-0002-5689-3448], Wiggins, Kerri L. [0000-0003-2749-1279], Hemingway, Harry [0000-0003-2279-0624], Yang, Jian [0000-0003-2001-2474], Visscher, Peter M. [0000-0002-2143-8760], Lubitz, Steven A. [0000-0002-9599-4866], Sattar, Naveed [0000-0002-1604-2593], Cappola, Thomas P. [0000-0002-9630-7204], Asselbergs, Folkert W. [0000-0002-1692-8669], Kuchenbaecker, Karoline [0000-0001-9726-603X], Ellinor, Patrick T. [0000-0002-2067-0533], Vasan, Ramachandran S. [0000-0001-7357-5970], Lumbers, R. Thomas [0000-0002-9077-4741], Apollo - University of Cambridge Repository, Chaffin, Mark D [0000-0002-1234-5562], Guðbjartsson, Daníel F [0000-0002-5222-9857], Hyde, Craig L [0000-0002-6939-287X], Jukema, J Wouter [0000-0002-3246-8359], Kleber, Marcus E [0000-0003-0663-7275], Lindgren, Cecilia M [0000-0002-4903-9374], Lovering, Ruth C [0000-0002-9791-0064], Luan, Jian'an [0000-0003-3137-6337], Mordi, Ify R [0000-0002-2686-729X], Morris, Andrew D [0000-0002-1766-0473], Nagle, Michael W [0000-0002-4677-7582], Nelson, Christopher P [0000-0001-8025-2897], Palmer, Colin NA [0000-0002-6415-6560], Rice, Kenneth M [0000-0002-3071-7278], Rotter, Jerome I [0000-0001-7191-1723], Taylor, Kent D [0000-0002-2756-4370], Uitterlinden, Andre G [0000-0002-7276-3387], Wiggins, Kerri L [0000-0003-2749-1279], Visscher, Peter M [0000-0002-2143-8760], Lubitz, Steven A [0000-0002-9599-4866], Cappola, Thomas P [0000-0002-9630-7204], Asselbergs, Folkert W [0000-0002-1692-8669], Ellinor, Patrick T [0000-0002-2067-0533], Vasan, Ramachandran S [0000-0001-7357-5970], Lumbers, R Thomas [0000-0002-9077-4741], Palmer, Colin N A [0000-0002-6415-6560], Cardiovascular Centre (CVC), University of Queensland [Brisbane], University College of London [London] (UCL), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University Medical Center Groningen [Groningen] (UMCG), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Framingham Heart Study, National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), deCODE genetics [Reykjavik], Karolinska Institutet [Stockholm], Pfizer, University of Pennsylvania [Philadelphia], University of Groningen [Groningen], Imperial College London, Lund University [Lund], Herlev and Gentofte Hospital, Massachusetts General Hospital [Boston], Department of Neurobiology, Care Sciences and Society [Stockholm, Sweden] (Division of Family Medicine), Dalarna University, Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, Department of Biostatistics, University of Washington [Seattle], Emory University School of Medicine, Emory University [Atlanta, GA], The University of Texas Medical School at Houston, Department of Molecular and Functional Genomics, Geisinger, Danville, PA, Brigham and Women's Hospital [Boston], Harvard Medical School [Boston] (HMS), Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown, NY, Novartis Institutes for BioMedical Research (NIBR), University of Liverpool, Universität Heidelberg [Heidelberg], Medizinische Fakultät Mannheim, The Alan Turing Institute, Ninewells Hospital and Medical School [Dundee], Universität Greifswald - University of Greifswald, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), University of Minnesota System, Regeneron Pharmaceuticals [Tarrytown], Department of Clinical Sciences, Cardiovascular Epidemiology, Skane University Hospital [Lund], Institute of Genomics [Tartu, Estonia], University of Tartu, Robertson Centre for Biostatistics, University of Glasgow, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Uppsala University, Brigham & Women’s Hospital [Boston] (BWH), University of Maryland School of Medicine, University of Maryland System, School of Science and Engineering (Reykjavik University), Carver College of Medicine, University of Iowa, Geisinger Health System [Danville, PA, USA], Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford Cardiovascular Institute, Uppsala Universitet [Uppsala], Leiden University Medical Center (LUMC), Einthoven Laboratory for Experimental Vascular Medicine (ELEVM - LEIDEN), Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Glenfield Hospital, University Hospitals Leicester, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Big Data Institute, University of Oxford [Oxford], University of Iowa [Iowa City], The Wellcome Trust Centre for Human Genetics [Oxford], Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Medical University Graz, Skane University Hospital [Malmo], Vanderbilt University School of Medicine [Nashville], University of Edinburgh, Université médicale de Vienne, Autriche, National Institute for Health and Welfare [Helsinki], University of Turku, Birmingham Women's and Children's NHS Foundation Trust, Kaiser Permanente, Harbor UCLA Medical Center [Torrance, Ca.], Los Angeles Biomedical Research Institute (LA BioMed), University Medical Center [Utrecht], University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Seattle Epidemiologic Research and Information Center [Seattle], Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Department of Cardiology, Södersjukhuset, Stockholm, Estonian Genome and Medicine, Landspitali National University Hospital of Iceland, University of Iceland [Reykjavik], Aalborg University [Denmark] (AAU), Institut de Recherches SERVIER (IRS), Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-Universität Greifswald, GlaxoSmithKline, Glaxo Smith Kline, Northeastern Ohio Medical University (NEOMED), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Department of Cardiovascular Sciences [Leicester], University of Leicester, Queensland Brain Institute, Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, University of Dundee, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Atherosclerosis Risk in Communities Study (ARIC)The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC- 55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694 and RC2 HL102419, National Human Genome Research Institute contract U01HG004402, and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT- CHF)This project was funded by a grant from the European Commission (FP7‐242209‐ BIOSTAT‐CHF, EudraCT 2010–020808–29). Cardiovascular Health Study (CHS) This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. deCODE Heart Failure Study (deCODE) We at deCODE thank the women and men of Iceland that have participated in our studies and our colleagues that contributed to data collection and processing. DiscovEHR We acknowledge and thank all participants in Geisinger’s MyCode Community Health Initiative for their support and permission to use their health and genomic information in the DiscovEHR collaboration. This work was supported by the Regeneron Genetics Center and Geisinger. Estonian Genome Center at the University of Tartu (EGCUT) This study was supported by Estonian Research Council Grant IUT20-60, EU, H2020 grant 692145, European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012) GENTRANSMED. Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) The EPHESUS was supported by Pfizer, Inc. The European Prospective Investigation of Cancer, Norfolk study (EPIC-Norfolk) The EPIC-Norfolk Study is supported by programme grants from the Medical Research Council UK (G1000143) and Cancer Research UK (C864/A14136) and with additional support from the European Union, Stroke Association, British Heart Foundation, Research into Ageing, Department of Health, The Wellcome Trust and the Food Standards Agency. NJW and CL also acknowledge support from the Medical Research Council, UK (MC_UU_12015/1, MC_PC_13048). We thank all EPIC participants and staff for their contribution to the study, and thank staff from the Technical, Field Epidemiology and Data Functional Group Teams of the Medical Research Council Epidemiology Unit in Cambridge, UK, for carrying out sample preparation, DNA provision and quality control, genotyping and data handling work. Framingham Heart Study (FHS) This work was conducted using data and resources from the Framingham Heart Study (FHS) of the National Heart Lung and Blood Institute and Boston University School of Medicine. The study was supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contract No. N01-HC-25195 and HHSN268201500001I) and its contract with Affymetrix, Inc for genotyping services (Contract No.N02-HL-6-4278). The work was also supported by R01 HL093328, R01 HL105993, and R01 HL71039 (PI: Ramachandran). FINRISK V.S. has been supported by the Finnish Foundation for Cardiovascular Research. Genetics of Diabetes Audit and Research Tayside Scotland GoDARTS) The Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection (supporting GoDARTS) was funded by the Wellcome Trust (072960/Z/03/Z, 084726/Z/08/Z, 084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the EU IMI-SUMMIT programme. We acknowledge the support of the Health Informatics Centre, University of Dundee, for managing and supplying the anonymized data and NHS Tayside, the original data owner. The Genetic Risk Assessment of Defibrillator Events (GRADE) NIH-NHLBI R01 HL77398 (Genetic Modulators of Sudden Death). S.L. is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. The LUdwigshafen RIsk and Cardiovascular Health (LURIC) study We extend our appreciation to the participants of the LURIC study, without their collaboration, this article would not have been written. We thank the LURIC study team who were either temporarily or permanently involved in patient recruitment as well as sample and data handling, in addition to the laboratory staff at the Ludwigshafen General Hospital and the Universities of Freiburg and Ulm, Germany. LURIC has received funding from the 7th Framework Program (RiskyCAD, grant agreement number 305739 and Atheroremo, grant agreement number 201668) of the European Union. Malmö Diet and Cancer Study (MDCS) J. Gustav Smith was supported by grants from the Swedish Heart-Lung Foundation (2016- 0134 and 2016-0315), the Swedish Research Council (2017-02554), the European Research Council (ERC-STG-2015-679242), the Crafoord Foundation, Skåne University Hospital, the Scania county, governmental funding of clinical research within the Swedish National Health Service, a generous donation from the Knut and Alice Wallenberg foundation to the Wallenberg Center for Molecular Medicine in Lund, and funding from the Swedish Research Council (Linnaeus grant Dnr 349-2006-237, Strategic Research Area Exodiab Dnr 2009-1039) and Swedish Foundation for Strategic Research (Dnr IRC15- 0067) to the Lund University Diabetes Center. The Malmo Diet and Cancer Study was made possible by grants from the Swedish Cancer Society, the Swedish Medical Research Council, the Swedish Dairy Association, and the Malmo city council. Penn Heart Failure Study (PHFS) The study was supported by NIH grants (NIH R01L088577 and NIH R01H105993). Prevention of REnal and Vascular ENd-stage Disease (PREVEND) The Prevention of Renal and Vascular Endstage Disease Study (PREVEND) genetics is supported by the Dutch Kidney Foundation (Grant E033), the EU project grant GENECURE (FP-6 LSHM CT 2006 037697), the National Institutes of Health (grant LM010098), the Netherlands organisation for health research and development (NWO VENI grant 916.761.70), and the Dutch Inter University Cardiology Institute Netherlands (ICIN). Niek Verweij was supported by NWO VENI grant 016.186.125. PROspective Study of Pravastatin in the Elderly at Risk for vascular disease (PROSPER)The PROSPER study was supported by an investigator-initiated grant obtained from Bristol- Myers Squibb. Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). J.W.J. is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Study of Health in Pomerania (SHIP) SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network ‘Greifswald Approach to Individualized Medicine (GANI_MED)’ funded by the Federal Ministry of Education and Research (grant 03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg- West Pomerania. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. Stabilization of Plaque using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID)SOLID-TIMI 52 was funded by GlaxoSmithKline. TwinGene (TwinGene) TwinGene received funding from the Swedish Research Council (M-2005-1112), GenomEUtwin (EU/QLRT-2001-01254, QLG2-CT-2002-01254), NIH DK U01-066134, The Swedish Foundation for Strategic Research (SSF) and the Heart and Lung foundation no. 20070481. TwinGene is part of the Swedish Twin Registry which is managed by Karolinska Institutet and receives funding through the Swedish Research Council (2017–00641). UK Biobank (UKBiobank) This research has been conducted using the UK Biobank Resource under Application Number 15422. This work was supported in part by grants to R.T.L. from the EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking BigData@Heart grant no. 116074, MRC Proximity to Discovery Award Scheme, the American Heart Association Institute for Precision Mecidine, Pfizer Ltd, the University College London British Heart Foundation Research Accelerator (AA/18/6/34223), and was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. A. H. is supported by the British Heart Foundation Cardiovascular Biomedicine PhD studentship. R.T.L is supported by a UK Research and Innovation Rutherford Fellowship and was previously supported by a National Institutes of Health Research Clinical Lectureship. Uppsala Longitudinal Study of Adult Men (ULSAM) J.Ä. is supported by the Swedish Research Council and the Swedish Heart Lung foundation. C.M.L is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds and by the NIHR Biomedical Research Centre, Oxford, by Widenlife and NIH (5P50HD028138- 27). Women’s Genome Health Study (WGHS) The WGHS is supported by the National Heart, Lung, and Blood Institute (HL043851 and HL080467, HL099355) and the National Cancer Institute (CA047988 and UM1CA182913), with collaborative scientific support and funding for genotyping provided by Amgen., Epidemiology, Internal Medicine, Læknadeild (HÍ), Faculty of Medicine (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, and University of Iceland
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0301 basic medicine ,Dánartíðni ,Epidemiology ,LOCI ,45/43 ,General Physics and Astronomy ,Muscle Proteins ,Genome-wide association study ,Disease ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Bioinformatics ,Genome-wide association studies ,DISEASE ,Ventricular Function, Left ,Coronary artery disease ,0302 clinical medicine ,Risk Factors ,Atrial Fibrillation ,IMPUTATION ,Medicine ,Blóðrásarsjúkdómar ,692/308/174 ,lcsh:Science ,2. Zero hunger ,RISK ,Multidisciplinary ,Microfilament Proteins ,article ,Atrial fibrillation ,Mendelian Randomization Analysis ,CATALOG ,3. Good health ,OBESITY ,Erfðarannsóknir ,Cardiomyopathies ,Medical Genetics ,Cyclin-Dependent Kinase Inhibitor p21 ,Science ,631/208/205/2138 ,Heart failure ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,631/443/592/2727 ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,RESOURCE ,Humans ,Mortality ,METAANALYSIS ,Genetic association ,Medicinsk genetik ,Adaptor Proteins, Signal Transducing ,Heart Failure ,HYPERTENSION ,business.industry ,Case-control study ,Klinisk medicin ,692/699/75/230 ,General Chemistry ,Cardiovascular genetics ,medicine.disease ,R1 ,030104 developmental biology ,Case-Control Studies ,lcsh:Q ,Morbidity ,Clinical Medicine ,business ,Apoptosis Regulatory Proteins ,Carrier Proteins ,Genome-Wide Association Study - Abstract
Publisher's version (útgefin grein), Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies., We acknowledge the contribution from the EchoGen Consortium.
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- 2020
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10. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI
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Da Silva Couto Alves, Alexessander, De Silva, N. Maneka G., Karhunen, Ville, Sovio, Ulla, Das, Shikta, Taal, H. Rob, Warrington, Nicole M., Lewin, Alexandra M., Kaakinen, Marika, Cousminer, Diana L., Thiering, Elisabeth, Timpson, Nicholas J., Bond, Tom A., Lowry, Estelle, Brown, Christopher D., Estivill, Xavier, Lindi, Virpi, Bradfield, Jonathan P., Geller, Frank, Speed, Doug, Coin, Lachlan J. M., Loh, Marie, Barton, Sheila J., Beilin, Lawrence J., Bisgaard, Hans, Bonnelykke, Klaus, Alili, Rohia, Hatoum, Ida J., Schramm, Katharina, Cartwright, Rufus, Charles, Marie-Aline, Salerno, Vincenzo, Clement, Karine, Claringbould, Annique A.J, Consortium, BIOS, van Duijin, Cornelia M., Moltchanova, Elena, Eriksson, Johan G., Elks, Cathy, Feenstra, Bjarke, Flexeder, Claudia, Franks, Stephen, Frayling, Timothy M., Freathy, Rachel M., Elliot, Paul, Widen, Elisabeth, Hakonarson, Hakon, Hattersley, Andrew T., Rodriguez, Alina, Banterle, Marco, Heinrich, Joachim, Heude, Barbara, Holloway, John W., Hofman, Albert, Hypponen, Elina, Inskip, Hazel, Kaplan, Lee M., Hedman, Asa K., Laara, Esa, Prokisch, Holger, Grallert, Harald, Lakka, Timo A., Lawlor, Debbie A., Melbye, Mads, Ahluwalia, Tarunveer S., Marinelli, Marcella, Millwood, Iona Y., Palmer, Lyle J., Pennell, Craig E., Perry, John R., Ring, Susan M., Savolainen, Markku J., Rivadeneira, Fernando, Standl, Marie, Sunyer, Jordi, Tiesler, Carla M.T, Uitterlinden, Andre G., Schierding, William, O'Sullivan, Justin M., Prokopenko, Inga, Herzig, Karl-Heinz, Smith, George Davey, O'Reilly, Paul, Felix, Janine F., Buxton, Jessica L., Blakemore, Alexandra L. F, Ong, Ken K., Jaddoe, Vincent W.V, Grant, Struan F.A, Sebert, Sylvain, McCarthy, Mark L., and Jarvelin, Marjo-Riitta
- Abstract
Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.
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- 2019
11. Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants
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Allum, Fiona, Guénard, Frédéric, Shao, Xiaojian, Vohl, Marie-Claude, Lessard, Julie., Simon, Marie-Michelle, Tchernof, André, Busche, Stephan, Caron, Maxime, Lambourn, John, Tandre, Karolina, Hedman, Asa K., Kwan, Tony, Ge, Bing, Rönnblom, Lars, McCarthy, Mark I., Deloukas, Panos, Richmond, Todd, Burgess, Daniel, Spector, T. D. (Timothy David), Marceau, Simon, Lathrop, Mark, Pastinen, Tomi, Grundberg, Elin, Allum, Fiona, Guénard, Frédéric, Shao, Xiaojian, Vohl, Marie-Claude, Lessard, Julie., Simon, Marie-Michelle, Tchernof, André, Busche, Stephan, Caron, Maxime, Lambourn, John, Tandre, Karolina, Hedman, Asa K., Kwan, Tony, Ge, Bing, Rönnblom, Lars, McCarthy, Mark I., Deloukas, Panos, Richmond, Todd, Burgess, Daniel, Spector, T. D. (Timothy David), Marceau, Simon, Lathrop, Mark, Pastinen, Tomi, and Grundberg, Elin
- Abstract
Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targetedarrays or enrichment methodologies preferentially covering CpG-dense regions, tocharacterize sufficiently large samples. To overcome this limitation, we present here a newcustomizable, cost-effective approach, methylC-capture sequencing (MCC-Seq), forsequencing functional methylomes, while simultaneously providing genetic variationinformation. To illustrate MCC-Seq, we use whole-genome bisulfite sequencing on adiposetissue (AT) samples and public databases to design AT-specific panels. We establish itsefficiency for high-density interrogation of methylome variability by systematic comparisonswith other approaches and demonstrate its applicability by identifying novel methylationvariation within enhancers strongly correlated to plasma triglyceride and HDL-cholesterol,including atCD36. Our more comprehensive AT panel assesses tissue methylation andgenotypes in parallel atB4 andB3 M sites, respectively. Our study demonstrates thatMCC-Seq provides comparable accuracy to alternative approaches but enables more efficientcataloguing of functional and disease-relevant epigenetic and genetic variants for large-scale EWAS.
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- 2020
12. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI
- Author
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Couto Alves, Alexessander, De Silva, N Maneka G, Karhunen, Ville, Sovio, Ulla, Das, Shikta, Taal, H Rob, Warrington, Nicole M, Lewin, Alexandra M, Kaakinen, Marika, Cousminer, Diana L, Thiering, Elisabeth, Timpson, Nicholas J, Bond, Tom A, Lowry, Estelle, Brown, Christopher D, Estivill, Xavier, Lindi, Virpi, Bradfield, Jonathan P, Geller, Frank, Speed, Doug, Coin, Lachlan J M, Loh, Marie, Barton, Sheila J, Beilin, Lawrence J, Bisgaard, Hans, Bønnelykke, Klaus, Alili, Rohia, Hatoum, Ida J, Schramm, Katharina, Cartwright, Rufus, Charles, Marie-Aline, Salerno, Vincenzo, Clément, Karine, Claringbould, Annique A J, Van Duijn, Cornelia M, Moltchanova, Elena, Eriksson, Johan G, Elks, Cathy, Feenstra, Bjarke, Flexeder, Claudia, Franks, Stephen, Frayling, Timothy M, Freathy, Rachel M, Elliott, Paul, Widén, Elisabeth, Hakonarson, Hakon, Hattersley, Andrew T, Rodriguez, Alina, Banterle, Marco, Heinrich, Joachim, Heude, Barbara, Holloway, John W, Hofman, Albert, Hyppönen, Elina, Inskip, Hazel, Kaplan, Lee M, Hedman, Asa K, Läärä, Esa, Prokisch, Holger, Grallert, Harald, Lakka, Timo A, Lawlor, Debbie A, Melbye, Mads, Ahluwalia, Tarunveer S, Marinelli, Marcella, Millwood, Iona Y, Palmer, Lyle J, Pennell, Craig E, Perry, John R, Ring, Susan M, Savolainen, Markku J, Rivadeneira, Fernando, Standl, Marie, Sunyer, Jordi, Tiesler, Carla M T, Uitterlinden, Andre G, Schierding, William, O'Sullivan, Justin M, Prokopenko, Inga, Herzig, Karl-Heinz, Smith, George Davey, O'Reilly, Paul, Felix, Janine F, Buxton, Jessica L, Blakemore, Alexandra I F, Ong, Ken K, Jaddoe, Vincent W V, Grant, Struan F A, Sebert, Sylvain, McCarthy, Mark I, Järvelin, Marjo-Riitta, Erasmus MC other, Epidemiology, Internal Medicine, Pediatrics, Medical Research Council (MRC), Sovio, Ulla [0000-0002-0799-1105], Perry, John [0000-0001-6483-3771], Ong, Kenneth [0000-0003-4689-7530], Apollo - University of Cambridge Repository, Warrington, Nicole M [0000-0003-4195-775X], Lewin, Alexandra M [0000-0003-0081-7582], Kaakinen, Marika [0000-0002-9228-0462], Cousminer, Diana L [0000-0001-8864-7893], Timpson, Nicholas J [0000-0002-7141-9189], Lowry, Estelle [0000-0002-4655-416X], Brown, Christopher D [0000-0002-3785-5008], Estivill, Xavier [0000-0002-0723-2256], Geller, Frank [0000-0002-9238-3269], Speed, Doug [0000-0002-0096-9765], Coin, Lachlan J M [0000-0002-4300-455X], Loh, Marie [0000-0003-3626-8466], Barton, Sheila J [0000-0003-4963-4242], Alili, Rohia [0000-0002-0158-4250], Schramm, Katharina [0000-0002-8809-3170], Charles, Marie-Aline [0000-0003-4025-4390], Claringbould, Annique A J [0000-0002-9201-6557], van Duijn, Cornelia M [0000-0002-2374-9204], Feenstra, Bjarke [0000-0003-1478-649X], Frayling, Timothy M [0000-0001-8362-2603], Freathy, Rachel M [0000-0003-4152-2238], Widén, Elisabeth [0000-0001-7108-2806], Hakonarson, Hakon [0000-0003-2814-7461], Rodriguez, Alina [0000-0003-1209-8802], Heude, Barbara [0000-0002-1565-1629], Holloway, John W [0000-0001-9998-0464], Hofman, Albert [0000-0002-9865-121X], Hyppönen, Elina [0000-0003-3670-9399], Inskip, Hazel [0000-0001-8897-1749], Kaplan, Lee M [0000-0002-6301-2696], Prokisch, Holger [0000-0003-2379-6286], Lakka, Timo A [0000-0002-9199-2871], Lawlor, Debbie A [0000-0002-6793-2262], Melbye, Mads [0000-0001-8264-6785], Ahluwalia, Tarunveer S [0000-0002-7464-3354], Marinelli, Marcella [0000-0002-5450-3960], Palmer, Lyle J [0000-0002-1628-3055], Pennell, Craig E [0000-0002-0937-6165], Perry, John R [0000-0001-6483-3771], Ring, Susan M [0000-0003-3103-9330], Savolainen, Markku J [0000-0002-2557-6423], Rivadeneira, Fernando [0000-0001-9435-9441], Sunyer, Jordi [0000-0002-2602-4110], Schierding, William [0000-0001-5659-2701], O'Sullivan, Justin M [0000-0003-2927-450X], Prokopenko, Inga [0000-0003-1624-7457], Smith, George Davey [0000-0002-1407-8314], Felix, Janine F [0000-0002-9801-5774], Ong, Ken K [0000-0003-4689-7530], Jaddoe, Vincent W V [0000-0003-2939-0041], Sebert, Sylvain [0000-0001-6681-6983], McCarthy, Mark I [0000-0002-4393-0510], and Järvelin, Marjo-Riitta [0000-0002-2149-0630]
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Adult ,Male ,Pharmacogenomic Variants ,Quantitative Trait Loci ,BLOOD-PRESSURE ,030209 endocrinology & metabolism ,Polymorphism, Single Nucleotide ,Body Mass Index ,EARLY-LIFE ,03 medical and health sciences ,AGE ,Quantitative Trait, Heritable ,0302 clinical medicine ,Humans ,Genetic Predisposition to Disease ,Longitudinal Studies ,030212 general & internal medicine ,GENOME-WIDE ASSOCIATION ,METABOLIC RISK ,Growth Charts ,FTO GENE ,Child ,Research Articles ,Genetic Association Studies ,Adaptor Proteins, Signal Transducing ,2. Zero hunger ,Science & Technology ,BIRTH COHORT ,Intracellular Signaling Peptides and Proteins ,nutritional and metabolic diseases ,SciAdv r-articles ,Infant ,Human Genetics ,Genomics ,3. Good health ,Multidisciplinary Sciences ,BODY-MASS INDEX ,OBESITY ,Science & Technology - Other Topics ,Receptors, Leptin ,ADIPOSITY ,Female ,biological ,Research Article ,Genome-Wide Association Study - Abstract
Longitudinal data find a new variant controlling BMI in infancy and reveal genetic differences between infant and adult BMI., Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.
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- 2019
13. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI
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Couto Alves, Alexessander, De Silva, N. Maneka G., Karhunen, Ville, Sovio, Ulla, Das, Shikta, Taal, H. Rob, Warrington, Nicole M., Lewin, Alexandra M., Kaakinen, Marika, Cousminer, Diana L., Thiering, Elisabeth, Timpson, Nicholas J., Bond, Tom A., Lowry, Estelle, Brown, Christopher D., Estivill, Xavier, Lindi, Virpi, Bradfield, Jonathan P., Geller, Frank, Speed, Doug, Coin, Lachlan J. M., Loh, Marie, Barton, Sheila J., Beilin, Lawrence J., Bisgaard, Hans, Bønnelykke, Klaus, Alili, Rohia, Hatoum, Ida J., Schramm, Katharina, Cartwright, Rufus, Charles, Marie-Aline, Salerno, Vincenzo, Clément, Karine, Claringbould, Annique A. J., van Duijn, Cornelia M., Moltchanova, Elena, Eriksson, Johan G., Elks, Cathy, Feenstra, Bjarke, Flexeder, Claudia, Franks, Stephen, Frayling, Timothy M., Freathy, Rachel M., Elliott, Paul, Widén, Elisabeth, Hakonarson, Hakon, Hattersley, Andrew T., Rodriguez, Alina, Banterle, Marco, Heinrich, Joachim, Heude, Barbara, Holloway, John W., Hofman, Albert, Hyppönen, Elina, Inskip, Hazel, Kaplan, Lee M., Hedman, Asa K., Läärä, Esa, Prokisch, Holger, Grallert, Harald, Lakka, Timo A., Lawlor, Debbie A., Melbye, Mads, Ahluwalia, Tarunveer S., Marinelli, Marcella, Millwood, Iona Y., Palmer, Lyle J., Pennell, Craig E., Perry, John R., Ring, Susan M., Savolainen, Markku J., Rivadeneira, Fernando, Standl, Marie, Sunyer, Jordi, Tiesler, Carla M. T., Uitterlinden, Andre G., Schierding, William, O’Sullivan, Justin M., Prokopenko, Inga, Herzig, Karl-Heinz, Smith, George Davey, O'Reilly, Paul, Felix, Janine F., Buxton, Jessica L., Blakemore, Alexandra I. F., Ong, Ken K., Jaddoe, Vincent W. V., Grant, Struan F. A., Sebert, Sylvain, McCarthy, Mark I., and Järvelin, Marjo-Riitta
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ddc - Published
- 2018
14. RELEVANCE AND SIGNIFICANCE OF LEFT VENTRICULAR EJECTION FRACTION IN CHRONIC HEART FAILURE PHENOTYPES IN A LARGE COHORT OF HEART FAILURE PATIENTS: RESULTS FROM THE PINNACLE REGISTRY AND PLANNED VALIDATION WITH LINKED MEDICARE DATA AND SWEDISH HEART FAILURE REGISTRY
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Gaggin, Hanna Kim, primary, Hedman, Asa K., additional, Song, Yang, additional, Shah, Sanjiv, additional, Lund, Lars, additional, Gao, Qi, additional, Ibrahim, Nasrien, additional, Savarese, Gianluigi, additional, Doros, Gheorghe, additional, Dahlstrom, Ulf, additional, and Januzzi, James, additional
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- 2019
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15. Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements
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Allum, Fiona, Hedman, Asa K., Shaol, Xiaojian, Cheung, Warren A., Vijay, Jinchu, Guenard, Frederic, Kwan, Tony, Simon, Marie-Michelle, Ge, Bing, Moura, Cristiano, Boulier, Elodie, Rönnblom, Lars, Bernatsky, Sasha, Lathropl, Mark, McCarthy, Mark, I, Deloukas, Panos, Tchernof, Andre, Pastinen, Tomi, Vohl, Marie-Claude, Grundberg, Elin, Allum, Fiona, Hedman, Asa K., Shaol, Xiaojian, Cheung, Warren A., Vijay, Jinchu, Guenard, Frederic, Kwan, Tony, Simon, Marie-Michelle, Ge, Bing, Moura, Cristiano, Boulier, Elodie, Rönnblom, Lars, Bernatsky, Sasha, Lathropl, Mark, McCarthy, Mark, I, Deloukas, Panos, Tchernof, Andre, Pastinen, Tomi, Vohl, Marie-Claude, and Grundberg, Elin
- Abstract
Sparse profiling of CpG methylation in blood by microarrays has identified epigenetic links to common diseases. Here we apply methylC-capture sequencing (MCC-Seq) in a clinical population of similar to 200 adipose tissue and matched blood samples (N-total similar to 400), providing high- resolution methylation profiling (>1.3 M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in similar to 800 independent adipose tissue and blood samples from the general population. We follow-up on adipose-specific regulatory regions under (1) genetic and (2) epigenetic (environmental) regulation via integrational studies. Overall, the comprehensive sequencing of regulatory element methylomes reveals a rich landscape of functional variants linked genetically as well as epigenetically to plasma lipid traits.
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- 2019
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16. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
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Kilpelainen, Tuomas O., Martin-Carli, Jayne Frances, Skowronski, Alicja Anna, Sun, Qi, Kriebel, Jennifer, Feitosa, Mary F., Hedman, Asa K., Drong, Alexander W., Hayes, James E., Zhao, Jinghua, Pers, Tune H., Schick, Ursula, Grarup, Niels, Kutalik, Zolt��n, Trompet, Stella, Mangino, Massimo, Kristiansson, Kati, Beekman, Marian, Lyytik��inen, Leo-Pekka, Eriksson, Joel, Henneman, Peter, Lahti, Jari, Tanaka, Toshiko, Luan, Jian���an, Del Greco M, Fabiola, Pasko, Dorota, Renstr��m, Frida, Willems, Sara M., Mahajan, Anubha, Rose, Lynda M., Guo, Xiuqing, Liu, Yongmei, Kleber, Marcus E., P��russe, Louis, Gaunt, Tom, Ahluwalia, Tarunveer S., Sung, Yun Ju, Ramos, Yolande F., Amin, Najaf, Amuzu, Antoinette, Barroso, In��s, Bellis, Claire, Blangero, John, Buckley, Brendan M., B��hringer, Stefan, Chen, Yii-Der I., de Craen, Anton J. N., Crosslin, David R., Dale, Caroline E., Dastani, Zari, Day, Felix R., Deelen, Joris, Delgado, Graciela E., Demirkan, Ayse, Finucane, Francis M., Ford, Ian, Garcia, Melissa E., Gieger, Christian, Gustafsson, Stefan, Hallmans, G��ran, Hankinson, Susan E., Havulinna, Aki S., Herder, Christian, Hernandez, Dena, Hicks, Andrew A., Hunter, David J., Illig, Thomas, Ingelsson, Erik, Ioan-Facsinay, Andreea, Jansson, John-Olov, Jenny, Nancy S., J��rgensen, Marit E., J��rgensen, Torben, Karlsson, Magnus, Koenig, Wolfgang, Kraft, Peter, Kwekkeboom, Joanneke, Laatikainen, Tiina, Ladwig, Karl-Heinz, LeDuc, Charles A., Lowe, Gordon, Lu, Yingchang, Marques-Vidal, Pedro, Meisinger, Christa, Menni, Cristina, Morris, Andrew P., Myers, Richard H., M��nnist��, Satu, Nalls, Mike A., Paternoster, Lavinia, Peters, Annette, Pradhan, Aruna D., Rankinen, Tuomo, Rasmussen-Torvik, Laura J., Rathmann, Wolfgang, Rice, Treva K., Richards, J. Brent, Ridker, Paul M., Sattar, Naveed, Savage, David B., S��derberg, Stefan, Timpson, Nicholas J., Vandenput, Liesbeth, van Heemst, Diana, Uh, Hae-Won, Vohl, Marie-Claude, Walker, Mark, Wichmann, Heinz-Erich, Wid��n, Elisabeth, Wood, Andrew R., Yao, Jie, Zeller, Tanja, Zhang, Yiying, Meulenbelt, Ingrid, Kloppenburg, Margreet, Astrup, Arne, S��rensen, Thorkild I. A., Sarzynski, Mark A., Rao, D. C., Jousilahti, Pekka, Vartiainen, Erkki, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andr�� G., Kajantie, Eero, Osmond, Clive, Palotie, Aarno, Eriksson, Johan G., Heli��vaara, Markku, Knekt, Paul B., Koskinen, Seppo, Jula, Antti, Perola, Markus, Huupponen, Risto K., Viikari, Jorma S., K��h��nen, Mika, Lehtim��ki, Terho, Raitakari, Olli T., Mellstr��m, Dan, Lorentzon, Mattias, Casas, Juan P., Bandinelli, Stefanie, M��rz, Winfried, Isaacs, Aaron, van Dijk, Ko W., van Duijn, Cornelia M., Harris, Tamara B., Bouchard, Claude, Allison, Matthew A., Chasman, Daniel I., Ohlsson, Claes, Lind, Lars, Scott, Robert A., Langenberg, Claudia, Wareham, Nicholas J., Ferrucci, Luigi, Frayling, Timothy M., Pramstaller, Peter P., Borecki, Ingrid B., Waterworth, Dawn M., Bergmann, Sven, Waeber, G��rard, and Vollenweider, Peter
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Leptin ,Meta-analysis ,Molecular biology ,FOS: Biological sciences ,digestive, oral, and skin physiology ,Genetics ,hormones, hormone substitutes, and hormone antagonists - Abstract
Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P
- Published
- 2016
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17. Genetic architecture of early childhood growth phenotypes gives insights into their link with later obesity
- Author
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De Silva, N. Maneka G., primary, Sebert, Sylvain, additional, Alves, Alexessander Couto, additional, Sovio, Ulla, additional, Das, Shikta, additional, Taal, Rob, additional, Warrington, Nicole M., additional, Lewin, Alexandra M., additional, Kaakinen, Marika, additional, Cousminer, Diana, additional, Thiering, Elisabeth, additional, Timpson, Nicholas J., additional, Karhunen, Ville, additional, Bond, Tom, additional, Estivill, Xavier, additional, Lindi, Virpi, additional, Bradfield, Jonathan P., additional, Geller, Frank, additional, Coin, Lachlan J.M., additional, Loh, Marie, additional, Barton, Sheila J., additional, Beilin, Lawrence J., additional, Bisgaard, Hans, additional, Bønnelykke, Klaus, additional, Alili, Rohia, additional, Hatoum, Ida J., additional, Schramm, Katharina, additional, Cartwright, Rufus, additional, Charles, Marie-Aline, additional, Salerno, Vincenzo, additional, Clément, Karine, additional, van Duijn, Cornelia M., additional, Moltchanova, Elena, additional, Eriksson, Johan G., additional, Elks, Cathy, additional, Feenstra, Bjarke, additional, Flexeder, Claudia, additional, Franks, Stephen, additional, Frayling, Timothy M., additional, Freathy, Rachel M., additional, Elliott, Paul, additional, Widén, Elisabeth, additional, Hakonarson, Hakon, additional, Hattersley, Andrew T., additional, Rodriguez, Alina, additional, Banterle, Marco, additional, Heinrich, Joachim, additional, Heude, Barbara, additional, Holloway, John W., additional, Hofman, Albert, additional, Hyppönen, Elina, additional, Inskip, Hazel, additional, Kaplan, Lee M., additional, Hedman, Asa K., additional, Läärä, Esa, additional, Prokisch, Holger, additional, Grallert, Harald, additional, Lakka, Timo A., additional, Lawlor, Debbie A., additional, Melbye, Mads, additional, Ahluwalia, Tarunveer S., additional, Marinelli, Marcella, additional, Millwood, Iona Y., additional, Palmer, Lyle J., additional, Pennell, Craig E., additional, Perry, John R., additional, Ring, Susan M., additional, Savolainen, Markku, additional, Stefansson, Kari, additional, Thorleifsson, Gudmar, additional, Rivadeneira, Fernando, additional, Standl, Marie, additional, Sunyer, Jordi, additional, Tiesler, Carla M.T., additional, Uitterlinden, Andre G., additional, Prokopenko, Inga, additional, Herzig, Karl-Heinz, additional, Smith, George Davey, additional, O'Reilly, Paul, additional, Felix, Janine F., additional, Buxton, Jessica L., additional, Blakemore, Alexandra I.F., additional, Ong, Ken K., additional, Grant, Struan F.A., additional, Jaddoe, Vincent W.V., additional, McCarthy, Mark I., additional, and Järvelin, Marjo-Riitta, additional
- Published
- 2017
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18. Genetic studies of body mass index yield new insights for obesity biology
- Author
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Locke, Adam E., Kahali, Bratati, Berndt, Sonja I., Justice, Anne E., Pers, Tune H., Day, Felix R., Powell, Corey, Vedantam, Sailaja, Buchkovich, Martin L., Yang, Jian, Croteau-Chonka, Damien C., Esko, Tonu, Fall, Tove, Ferreira, Teresa, Gustafsson, Stefan, Kutalik, Zoltan, Luan, Jian'an, Maegi, Reedik, Randall, Joshua C., Winkler, Thomas W., Wood, Andrew R., Workalemahu, Tsegaselassie, Faul, Jessica D., Smith, Jennifer A., Zhao, Jing Hua, Zhao, Wei, Chen, Jin, Fehrmann, Rudolf, Hedman, Asa K., Karjalainen, Juha, Schmidt, Ellen M., Absher, Devin, Amin, Najaf, Anderson, Denise, van der Laan, Sander W., van Setten, Jessica, Uh, Hae-Won, den Ruijter, Hester M., Moll, Frans L., Pasterkamp, Gerard, Asselbergs, Folkert W., de Bakker, Paul I. W., Zanen, Pieter, LifeLines Cohort Study, ADIPOGen Consortium, AGEN-BMI Working Grp, CARDIOGRAMplusC4D Consortium, CKDGen Consortium, GLGC, ICBP, MAGIC Investigators, MuTHER Consortium, MIGen Consortium, PAGE Consortium, ReproGen Consortium, GENIE Consortium, and Int Endogene Consortium
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EXPRESSION ,ARCHITECTURE ,PROVIDES INSIGHTS ,GLYCEMIC TRAITS ,LOCI ,PATHWAYS ,GENOME-WIDE ASSOCIATION ,VARIANTS ,HUMAN HEIGHT ,METAANALYSIS - Abstract
Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in upto 339,224 individuals. This analysis identifies 97 BMI-associated loci (P 20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous systemin obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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- 2015
19. New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- Author
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Lu, Yingchang, Day, Felix R., Gustafsson, Stefan, Buchkovich, Martin L., Na, Jianbo, Bataille, Veronique, Cousminer, Diana L., Dastani, Zari, Drong, Alexander W., Esko, Tonu, Evans, David M., Falchi, Mario, Feitosa, Mary F., Ferreira, Teresa, Hedman, Asa K., Haring, Robin, Hysi, Pirro G., Iles, Mark M., Justice, Anne E., Kanoni, Stavroula, Lagou, Vasiliki, Li, Rui, Li, Xin, Locke, Adam, Lu, Chen, Magi, Reedik, Perry, John R. B., Pers, Tune H., Qi, Qibin, Sanna, Marianna, Schmidt, Ellen M., Scott, William R., Shungin, Dmitry, Teumer, Alexander, Vinkhuyzen, Anna A. E., Walker, Ryan W., Westra, Harm-Jan, Zhang, Mingfeng, Zhang, Weihua, Zhao, Jing Hua, Zhu, Zhihong, Afzal, Uzma, Ahluwalia, Tarunveer Singh, Bakker, Stephan J. L., Bellis, Claire, Bonnefond, Amelie, Borodulin, Katja, Buchman, Aron S., Cederholm, Tommy, Choh, Audrey C., Choi, Hyung Jin, Curran, Joanne E., de Groot, Lisette C. P. G. M., De Jager, Philip L., Dhonukshe-Rutten, Rosalie A. M., Enneman, Anke W., Eury, Elodie, Evans, Daniel S., Forsen, Tom, Friedrich, Nele, Fumeron, Frederic, Garcia, Melissa E., Gartner, Simone, Han, Bok-Ghee, Havulinna, Aki S., Hayward, Caroline, Hernandez, Dena, Hillege, Hans, Ittermann, Till, Kent, Jack W., Kolcic, Ivana, Laatikainen, Tiina, Lahti, Jari, Leach, Irene Mateo, Lee, Christine G., Lee, Jong-Young, Liu, Tian, Liu, Youfang, Lobbens, Stephane, Loh, Marie, Lyytikainen, Leo-Pekka, Medina-Gomez, Carolina, Michaelsson, Karl, Nalls, Mike A., Nielson, Carrie M., Oozageer, Laticia, Pascoe, Laura, Paternoster, Lavinia, Polasek, Ozren, Ripatti, Samuli, Sarzynski, Mark A., Shin, Chan Soo, Narancic, Nina Smolej, Spira, Dominik, Srikanth, Priya, Steinhagen-Thiessen, Elisabeth, Sung, Yun Ju, Swart, Karin M. A., Taittonen, Leena, Tanaka, Toshiko, Tikkanen, Emmi, van der Velde, Nathalie, van Schoor, Natasja M., Verweij, Niek, Wright, Alan F., Yu, Lei, Zmuda, Joseph M., Eklund, Niina, Forrester, Terrence, Grarup, Niels, Jackson, Anne U., Kristiansson, Kati, Kuulasmaa, Teemu, Kuusisto, Johanna, Lichtner, Peter, Luan, Jian'an, Mahajan, Anubha, Mannisto, Satu, Palmer, Cameron D., Ried, Janina S., Scott, Robert A., Stancakova, Alena, Wagner, Peter J., Demirkan, Ayse, Doring, Angela, Gudnason, Vilmundur, Kiel, Douglas P., Kuhnel, Brigitte, Mangino, Massimo, Mcknight, Barbara, Menni, Cristina, O'Connell, Jeffrey R., Oostra, Ben A., Shuldiner, Alan R., Song, Kijoung, Vandenput, Liesbeth, van Duijn, Cornelia M., Vollenweider, Peter, White, Charles C., Boehnke, Michael, Boettcher, Yvonne, Cooper, Richard S., Forouhi, Nita G., Gieger, Christian, Grallert, Harald, Hingorani, Aroon, Jorgensen, Torben, Jousilahti, Pekka, Kivimaki, Mika, Kumari, Meena, Laakso, Markku, Langenberg, Claudia, Linneberg, Allan, Luke, Amy, Mckenzie, Colin A., Palotie, Aarno, Pedersen, Oluf, Peters, Annette, Strauch, Konstantin, Tayo, Bamidele O., Wareham, Nicholas J., Bennett, David A., Bertram, Lars, Blangero, John, Bluher, Matthias, Bouchard, Claude, Campbell, Harry, Cho, Nam H., Cummings, Steven R., Czerwinski, Stefan A., Demuth, Ilja, Eckardt, Rahel, Eriksson, Johan G., Ferrucci, Luigi, Franco, Oscar H., Froguel, Philippe, Gansevoort, Ron T., Hansen, Torben, Harris, Tamara B., Hastie, Nicholas, Heliovaara, Markku, Hofman, Albert, Jordan, Joanne M., Jula, Antti, Kahonen, Mika, Kajantie, Eero, Knekt, Paul B., Koskinen, Seppo, Kovacs, Peter, Lehtimaki, Terho, Lind, Lars, Liu, Yongmei, Orwoll, Eric S., Osmond, Clive, Perola, Markus, Perusse, Louis, Raitakari, Olli T., Rankinen, Tuomo, Rao, D. C., Rice, Treva K., Rivadeneira, Fernando, Rudan, Igor, Salomaa, Veikko, Sorensen, Thorkild I. A., Stumvoll, Michael, Tonjes, Anke, Towne, Bradford, Tranah, Gregory J., Tremblay, Angelo, Uitterlinden, Andre G., van der Harst, Pim, Vartiainen, Erkki, Viikari, Jorma S., Vitart, Veronique, Vohl, Marie-Claude, Volzke, Henry, Walker, Mark, Wallaschofski, Henri, Wild, Sarah, Wilson, James F., Yengo, Loic, Bishop, D. Timothy, Borecki, Ingrid B., Chambers, John C., Cupples, L. Adrienne, Dehghan, Abbas, Deloukas, Panos, Fatemifar, Ghazaleh, Fox, Caroline, Furey, Terrence S., Franke, Lude, Han, Jiali, Hunter, David J., Karjalainen, Juha, Karpe, Fredrik, Kaplan, Robert C., Kooner, Jaspal S., McCarthy, Mark I., Murabito, Joanne M., Morris, Andrew P., Bishop, Julia A. N., North, Kari E., Ohlsson, Claes, Ong, Ken K., Prokopenko, Inga, Richards, J. Brent, Schadt, Eric E., Spector, Tim D., Widen, Elisabeth, Willer, Cristen J., Yang, Jian, Ingelsson, Erik, Mohlke, Karen L., Hirschhorn, Joel N., Pospisilik, John Andrew, Zillikens, M. Carola, Lindgren, Cecilia, Kilpelainen, Tuomas Oskari, Loos, Ruth J. F., Lu, Yingchang, Day, Felix R., Gustafsson, Stefan, Buchkovich, Martin L., Na, Jianbo, Bataille, Veronique, Cousminer, Diana L., Dastani, Zari, Drong, Alexander W., Esko, Tonu, Evans, David M., Falchi, Mario, Feitosa, Mary F., Ferreira, Teresa, Hedman, Asa K., Haring, Robin, Hysi, Pirro G., Iles, Mark M., Justice, Anne E., Kanoni, Stavroula, Lagou, Vasiliki, Li, Rui, Li, Xin, Locke, Adam, Lu, Chen, Magi, Reedik, Perry, John R. B., Pers, Tune H., Qi, Qibin, Sanna, Marianna, Schmidt, Ellen M., Scott, William R., Shungin, Dmitry, Teumer, Alexander, Vinkhuyzen, Anna A. E., Walker, Ryan W., Westra, Harm-Jan, Zhang, Mingfeng, Zhang, Weihua, Zhao, Jing Hua, Zhu, Zhihong, Afzal, Uzma, Ahluwalia, Tarunveer Singh, Bakker, Stephan J. L., Bellis, Claire, Bonnefond, Amelie, Borodulin, Katja, Buchman, Aron S., Cederholm, Tommy, Choh, Audrey C., Choi, Hyung Jin, Curran, Joanne E., de Groot, Lisette C. P. G. M., De Jager, Philip L., Dhonukshe-Rutten, Rosalie A. M., Enneman, Anke W., Eury, Elodie, Evans, Daniel S., Forsen, Tom, Friedrich, Nele, Fumeron, Frederic, Garcia, Melissa E., Gartner, Simone, Han, Bok-Ghee, Havulinna, Aki S., Hayward, Caroline, Hernandez, Dena, Hillege, Hans, Ittermann, Till, Kent, Jack W., Kolcic, Ivana, Laatikainen, Tiina, Lahti, Jari, Leach, Irene Mateo, Lee, Christine G., Lee, Jong-Young, Liu, Tian, Liu, Youfang, Lobbens, Stephane, Loh, Marie, Lyytikainen, Leo-Pekka, Medina-Gomez, Carolina, Michaelsson, Karl, Nalls, Mike A., Nielson, Carrie M., Oozageer, Laticia, Pascoe, Laura, Paternoster, Lavinia, Polasek, Ozren, Ripatti, Samuli, Sarzynski, Mark A., Shin, Chan Soo, Narancic, Nina Smolej, Spira, Dominik, Srikanth, Priya, Steinhagen-Thiessen, Elisabeth, Sung, Yun Ju, Swart, Karin M. A., Taittonen, Leena, Tanaka, Toshiko, Tikkanen, Emmi, van der Velde, Nathalie, van Schoor, Natasja M., Verweij, Niek, Wright, Alan F., Yu, Lei, Zmuda, Joseph M., Eklund, Niina, Forrester, Terrence, Grarup, Niels, Jackson, Anne U., Kristiansson, Kati, Kuulasmaa, Teemu, Kuusisto, Johanna, Lichtner, Peter, Luan, Jian'an, Mahajan, Anubha, Mannisto, Satu, Palmer, Cameron D., Ried, Janina S., Scott, Robert A., Stancakova, Alena, Wagner, Peter J., Demirkan, Ayse, Doring, Angela, Gudnason, Vilmundur, Kiel, Douglas P., Kuhnel, Brigitte, Mangino, Massimo, Mcknight, Barbara, Menni, Cristina, O'Connell, Jeffrey R., Oostra, Ben A., Shuldiner, Alan R., Song, Kijoung, Vandenput, Liesbeth, van Duijn, Cornelia M., Vollenweider, Peter, White, Charles C., Boehnke, Michael, Boettcher, Yvonne, Cooper, Richard S., Forouhi, Nita G., Gieger, Christian, Grallert, Harald, Hingorani, Aroon, Jorgensen, Torben, Jousilahti, Pekka, Kivimaki, Mika, Kumari, Meena, Laakso, Markku, Langenberg, Claudia, Linneberg, Allan, Luke, Amy, Mckenzie, Colin A., Palotie, Aarno, Pedersen, Oluf, Peters, Annette, Strauch, Konstantin, Tayo, Bamidele O., Wareham, Nicholas J., Bennett, David A., Bertram, Lars, Blangero, John, Bluher, Matthias, Bouchard, Claude, Campbell, Harry, Cho, Nam H., Cummings, Steven R., Czerwinski, Stefan A., Demuth, Ilja, Eckardt, Rahel, Eriksson, Johan G., Ferrucci, Luigi, Franco, Oscar H., Froguel, Philippe, Gansevoort, Ron T., Hansen, Torben, Harris, Tamara B., Hastie, Nicholas, Heliovaara, Markku, Hofman, Albert, Jordan, Joanne M., Jula, Antti, Kahonen, Mika, Kajantie, Eero, Knekt, Paul B., Koskinen, Seppo, Kovacs, Peter, Lehtimaki, Terho, Lind, Lars, Liu, Yongmei, Orwoll, Eric S., Osmond, Clive, Perola, Markus, Perusse, Louis, Raitakari, Olli T., Rankinen, Tuomo, Rao, D. C., Rice, Treva K., Rivadeneira, Fernando, Rudan, Igor, Salomaa, Veikko, Sorensen, Thorkild I. A., Stumvoll, Michael, Tonjes, Anke, Towne, Bradford, Tranah, Gregory J., Tremblay, Angelo, Uitterlinden, Andre G., van der Harst, Pim, Vartiainen, Erkki, Viikari, Jorma S., Vitart, Veronique, Vohl, Marie-Claude, Volzke, Henry, Walker, Mark, Wallaschofski, Henri, Wild, Sarah, Wilson, James F., Yengo, Loic, Bishop, D. Timothy, Borecki, Ingrid B., Chambers, John C., Cupples, L. Adrienne, Dehghan, Abbas, Deloukas, Panos, Fatemifar, Ghazaleh, Fox, Caroline, Furey, Terrence S., Franke, Lude, Han, Jiali, Hunter, David J., Karjalainen, Juha, Karpe, Fredrik, Kaplan, Robert C., Kooner, Jaspal S., McCarthy, Mark I., Murabito, Joanne M., Morris, Andrew P., Bishop, Julia A. N., North, Kari E., Ohlsson, Claes, Ong, Ken K., Prokopenko, Inga, Richards, J. Brent, Schadt, Eric E., Spector, Tim D., Widen, Elisabeth, Willer, Cristen J., Yang, Jian, Ingelsson, Erik, Mohlke, Karen L., Hirschhorn, Joel N., Pospisilik, John Andrew, Zillikens, M. Carola, Lindgren, Cecilia, Kilpelainen, Tuomas Oskari, and Loos, Ruth J. F.
- Abstract
To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P < 5 x 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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- 2016
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- View/download PDF
20. New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- Author
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University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Clinicum, University of Helsinki, Institute of Behavioural Sciences, University of Helsinki, Hospital for Children and Adolescents, Lu, Yingchang, Day, Felix R., Gustafsson, Stefan, Buchkovich, Martin L., Na, Jianbo, Bataille, Veronique, Cousminer, Diana L., Dastani, Zari, Drong, Alexander W., Esko, Tonu, Evans, David M., Falchi, Mario, Feitosa, Mary F., Ferreira, Teresa, Hedman, Asa K., Haring, Robin, Hysi, Pirro G., Iles, Mark M., Justice, Anne E., Kanoni, Stavroula, Lagou, Vasiliki, Li, Rui, Li, Xin, Locke, Adam, Lu, Chen, Magi, Reedik, Perry, John R. B., Pers, Tune H., Qi, Qibin, Sanna, Marianna, Schmidt, Ellen M., Scott, William R., Shungin, Dmitry, Teumer, Alexander, Vinkhuyzen, Anna A. E., Walker, Ryan W., Westra, Harm-Jan, Zhang, Mingfeng, Zhang, Weihua, Zhao, Jing Hua, Zhu, Zhihong, Afzal, Uzma, Ahluwalia, Tarunveer Singh, Bakker, Stephan J. L., Bellis, Claire, Bonnefond, Amelie, Borodulin, Katja, Buchman, Aron S., Cederholm, Tommy, Choh, Audrey C., Choi, Hyung Jin, Curran, Joanne E., de Groot, Lisette C. P. G. M., De Jager, Philip L., Dhonukshe-Rutten, Rosalie A. M., Enneman, Anke W., Eury, Elodie, Evans, Daniel S., Forsen, Tom, Friedrich, Nele, Fumeron, Frederic, Garcia, Melissa E., Gartner, Simone, Han, Bok-Ghee, Havulinna, Aki S., Hayward, Caroline, Hernandez, Dena, Hillege, Hans, Ittermann, Till, Kent, Jack W., Kolcic, Ivana, Laatikainen, Tiina, Lahti, Jari, Leach, Irene Mateo, Lee, Christine G., Lee, Jong-Young, Liu, Tian, Liu, Youfang, Lobbens, Stephane, Loh, Marie, Lyytikainen, Leo-Pekka, Medina-Gomez, Carolina, Michaelsson, Karl, Nalls, Mike A., Nielson, Carrie M., Oozageer, Laticia, Pascoe, Laura, Paternoster, Lavinia, Polasek, Ozren, Ripatti, Samuli, Sarzynski, Mark A., Shin, Chan Soo, Narancic, Nina Smolej, Spira, Dominik, Srikanth, Priya, Steinhagen-Thiessen, Elisabeth, Sung, Yun Ju, Swart, Karin M. A., Taittonen, Leena, Tanaka, Toshiko, Tikkanen, Emmi, van der Velde, Nathalie, van Schoor, Natasja M., Verweij, Niek, Wright, Alan F., Yu, Lei, Zmuda, Joseph M., Pellikka, Niina, Forrester, Terrence, Grarup, Niels, Jackson, Anne U., Kristiansson, Kati, Kuulasmaa, Teemu, Kuusisto, Johanna, Lichtner, Peter, Luan, Jian'an, Mahajan, Anubha, Mannisto, Satu, Palmer, Cameron D., Ried, Janina S., Scott, Robert A., Stancakova, Alena, Wagner, Peter J., Demirkan, Ayse, Doring, Angela, Gudnason, Vilmundur, Kiel, Douglas P., Kuhnel, Brigitte, Mangino, Massimo, Mcknight, Barbara, Menni, Cristina, O'Connell, Jeffrey R., Oostra, Ben A., Shuldiner, Alan R., Song, Kijoung, Vandenput, Liesbeth, van Duijn, Cornelia M., Vollenweider, Peter, White, Charles C., Boehnke, Michael, Boettcher, Yvonne, Cooper, Richard S., Forouhi, Nita G., Gieger, Christian, Grallert, Harald, Hingorani, Aroon, Jorgensen, Torben, Jousilahti, Pekka, Kivimaki, Mika, Kumari, Meena, Laakso, Markku, Langenberg, Claudia, Linneberg, Allan, Luke, Amy, Mckenzie, Colin A., Palotie, Aarno, Pedersen, Oluf, Peters, Annette, Strauch, Konstantin, Tayo, Bamidele O., Wareham, Nicholas J., Bennett, David A., Bertram, Lars, Blangero, John, Bluher, Matthias, Bouchard, Claude, Campbell, Harry, Cho, Nam H., Cummings, Steven R., Czerwinski, Stefan A., Demuth, Ilja, Eckardt, Rahel, Eriksson, Johan G., Ferrucci, Luigi, Franco, Oscar H., Froguel, Philippe, Gansevoort, Ron T., Hansen, Torben, Harris, Tamara B., Hastie, Nicholas, Heliovaara, Markku, Hofman, Albert, Jordan, Joanne M., Jula, Antti, Kahonen, Mika, Kajantie, Eero, Knekt, Paul B., Koskinen, Seppo, Kovacs, Peter, Lehtimaki, Terho, Lind, Lars, Liu, Yongmei, Orwoll, Eric S., Osmond, Clive, Perola, Markus, Perusse, Louis, Raitakari, Olli T., Rankinen, Tuomo, Rao, D. C., Rice, Treva K., Rivadeneira, Fernando, Rudan, Igor, Salomaa, Veikko, Sorensen, Thorkild I. A., Stumvoll, Michael, Tonjes, Anke, Towne, Bradford, Tranah, Gregory J., Tremblay, Angelo, Uitterlinden, Andre G., van der Harst, Pim, Vartiainen, Erkki, Viikari, Jorma S., Vitart, Veronique, Vohl, Marie-Claude, Volzke, Henry, Walker, Mark, Wallaschofski, Henri, Wild, Sarah, Wilson, James F., Yengo, Loic, Bishop, D. Timothy, Borecki, Ingrid B., Chambers, John C., Cupples, L. Adrienne, Dehghan, Abbas, Deloukas, Panos, Fatemifar, Ghazaleh, Fox, Caroline, Furey, Terrence S., Franke, Lude, Han, Jiali, Hunter, David J., Karjalainen, Juha, Karpe, Fredrik, Kaplan, Robert C., Kooner, Jaspal S., McCarthy, Mark I., Murabito, Joanne M., Morris, Andrew P., Bishop, Julia A. N., North, Kari E., Ohlsson, Claes, Ong, Ken K., Prokopenko, Inga, Richards, J. Brent, Schadt, Eric E., Spector, Tim D., Widen, Elisabeth, Willer, Cristen J., Yang, Jian, Ingelsson, Erik, Mohlke, Karen L., Hirschhorn, Joel N., Pospisilik, John Andrew, Zillikens, M. Carola, Lindgren, Cecilia, Kilpelainen, Tuomas Oskari, Loos, Ruth J. F., University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Clinicum, University of Helsinki, Institute of Behavioural Sciences, University of Helsinki, Hospital for Children and Adolescents, Lu, Yingchang, Day, Felix R., Gustafsson, Stefan, Buchkovich, Martin L., Na, Jianbo, Bataille, Veronique, Cousminer, Diana L., Dastani, Zari, Drong, Alexander W., Esko, Tonu, Evans, David M., Falchi, Mario, Feitosa, Mary F., Ferreira, Teresa, Hedman, Asa K., Haring, Robin, Hysi, Pirro G., Iles, Mark M., Justice, Anne E., Kanoni, Stavroula, Lagou, Vasiliki, Li, Rui, Li, Xin, Locke, Adam, Lu, Chen, Magi, Reedik, Perry, John R. B., Pers, Tune H., Qi, Qibin, Sanna, Marianna, Schmidt, Ellen M., Scott, William R., Shungin, Dmitry, Teumer, Alexander, Vinkhuyzen, Anna A. E., Walker, Ryan W., Westra, Harm-Jan, Zhang, Mingfeng, Zhang, Weihua, Zhao, Jing Hua, Zhu, Zhihong, Afzal, Uzma, Ahluwalia, Tarunveer Singh, Bakker, Stephan J. L., Bellis, Claire, Bonnefond, Amelie, Borodulin, Katja, Buchman, Aron S., Cederholm, Tommy, Choh, Audrey C., Choi, Hyung Jin, Curran, Joanne E., de Groot, Lisette C. P. G. M., De Jager, Philip L., Dhonukshe-Rutten, Rosalie A. M., Enneman, Anke W., Eury, Elodie, Evans, Daniel S., Forsen, Tom, Friedrich, Nele, Fumeron, Frederic, Garcia, Melissa E., Gartner, Simone, Han, Bok-Ghee, Havulinna, Aki S., Hayward, Caroline, Hernandez, Dena, Hillege, Hans, Ittermann, Till, Kent, Jack W., Kolcic, Ivana, Laatikainen, Tiina, Lahti, Jari, Leach, Irene Mateo, Lee, Christine G., Lee, Jong-Young, Liu, Tian, Liu, Youfang, Lobbens, Stephane, Loh, Marie, Lyytikainen, Leo-Pekka, Medina-Gomez, Carolina, Michaelsson, Karl, Nalls, Mike A., Nielson, Carrie M., Oozageer, Laticia, Pascoe, Laura, Paternoster, Lavinia, Polasek, Ozren, Ripatti, Samuli, Sarzynski, Mark A., Shin, Chan Soo, Narancic, Nina Smolej, Spira, Dominik, Srikanth, Priya, Steinhagen-Thiessen, Elisabeth, Sung, Yun Ju, Swart, Karin M. A., Taittonen, Leena, Tanaka, Toshiko, Tikkanen, Emmi, van der Velde, Nathalie, van Schoor, Natasja M., Verweij, Niek, Wright, Alan F., Yu, Lei, Zmuda, Joseph M., Pellikka, Niina, Forrester, Terrence, Grarup, Niels, Jackson, Anne U., Kristiansson, Kati, Kuulasmaa, Teemu, Kuusisto, Johanna, Lichtner, Peter, Luan, Jian'an, Mahajan, Anubha, Mannisto, Satu, Palmer, Cameron D., Ried, Janina S., Scott, Robert A., Stancakova, Alena, Wagner, Peter J., Demirkan, Ayse, Doring, Angela, Gudnason, Vilmundur, Kiel, Douglas P., Kuhnel, Brigitte, Mangino, Massimo, Mcknight, Barbara, Menni, Cristina, O'Connell, Jeffrey R., Oostra, Ben A., Shuldiner, Alan R., Song, Kijoung, Vandenput, Liesbeth, van Duijn, Cornelia M., Vollenweider, Peter, White, Charles C., Boehnke, Michael, Boettcher, Yvonne, Cooper, Richard S., Forouhi, Nita G., Gieger, Christian, Grallert, Harald, Hingorani, Aroon, Jorgensen, Torben, Jousilahti, Pekka, Kivimaki, Mika, Kumari, Meena, Laakso, Markku, Langenberg, Claudia, Linneberg, Allan, Luke, Amy, Mckenzie, Colin A., Palotie, Aarno, Pedersen, Oluf, Peters, Annette, Strauch, Konstantin, Tayo, Bamidele O., Wareham, Nicholas J., Bennett, David A., Bertram, Lars, Blangero, John, Bluher, Matthias, Bouchard, Claude, Campbell, Harry, Cho, Nam H., Cummings, Steven R., Czerwinski, Stefan A., Demuth, Ilja, Eckardt, Rahel, Eriksson, Johan G., Ferrucci, Luigi, Franco, Oscar H., Froguel, Philippe, Gansevoort, Ron T., Hansen, Torben, Harris, Tamara B., Hastie, Nicholas, Heliovaara, Markku, Hofman, Albert, Jordan, Joanne M., Jula, Antti, Kahonen, Mika, Kajantie, Eero, Knekt, Paul B., Koskinen, Seppo, Kovacs, Peter, Lehtimaki, Terho, Lind, Lars, Liu, Yongmei, Orwoll, Eric S., Osmond, Clive, Perola, Markus, Perusse, Louis, Raitakari, Olli T., Rankinen, Tuomo, Rao, D. C., Rice, Treva K., Rivadeneira, Fernando, Rudan, Igor, Salomaa, Veikko, Sorensen, Thorkild I. A., Stumvoll, Michael, Tonjes, Anke, Towne, Bradford, Tranah, Gregory J., Tremblay, Angelo, Uitterlinden, Andre G., van der Harst, Pim, Vartiainen, Erkki, Viikari, Jorma S., Vitart, Veronique, Vohl, Marie-Claude, Volzke, Henry, Walker, Mark, Wallaschofski, Henri, Wild, Sarah, Wilson, James F., Yengo, Loic, Bishop, D. Timothy, Borecki, Ingrid B., Chambers, John C., Cupples, L. Adrienne, Dehghan, Abbas, Deloukas, Panos, Fatemifar, Ghazaleh, Fox, Caroline, Furey, Terrence S., Franke, Lude, Han, Jiali, Hunter, David J., Karjalainen, Juha, Karpe, Fredrik, Kaplan, Robert C., Kooner, Jaspal S., McCarthy, Mark I., Murabito, Joanne M., Morris, Andrew P., Bishop, Julia A. N., North, Kari E., Ohlsson, Claes, Ong, Ken K., Prokopenko, Inga, Richards, J. Brent, Schadt, Eric E., Spector, Tim D., Widen, Elisabeth, Willer, Cristen J., Yang, Jian, Ingelsson, Erik, Mohlke, Karen L., Hirschhorn, Joel N., Pospisilik, John Andrew, Zillikens, M. Carola, Lindgren, Cecilia, Kilpelainen, Tuomas Oskari, and Loos, Ruth J. F.
- Abstract
To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P <5 x 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
- Published
- 2016
21. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels
- Author
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University of Helsinki, Helsinki Collegium for Advanced Studies, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Hospital for Children and Adolescents, University of Helsinki, Clinicum, Kilpelainen, Tuomas O., Carli, Jayne F. Martin, Skowronski, Alicja A., Sun, Qi, Kriebel, Jennifer, Feitosa, Mary F., Hedman, Asa K., Drong, Alexander W., Hayes, James E., Zhao, Jinghua, Pers, Tune H., Schick, Ursula, Grarup, Niels, Kutalik, Zoltan, Trompet, Stella, Mangino, Massimo, Kristiansson, Kati, Beekman, Marian, Lyytikainen, Leo-Pekka, Eriksson, Joel, Henneman, Peter, Lahti, Jari, Tanaka, Toshiko, Luan, Jian'an, Del Greco M, Fabiola, Pasko, Dorota, Renstrom, Frida, Willems, Sara M., Mahajan, Anubha, Rose, Lynda M., Guo, Xiuqing, Liu, Yongmei, Kleber, Marcus E., Perusse, Louis, Gaunt, Tom, Ahluwalia, Tarunveer S., Sung, Yun Ju, Ramos, Yolande F., Amin, Najaf, Amuzu, Antoinette, Barroso, Ines, Bellis, Claire, Blangero, John, Buckley, Brendan M., Boehringer, Stefan, Chen, Yii-Der I., de Craen, Anton J. N., Crosslin, David R., Dale, Caroline E., Dastani, Zari, Day, Felix R., Deelen, Joris, Delgado, Graciela E., Demirkan, Ayse, Finucane, Francis M., Ford, Ian, Garcia, Melissa E., Gieger, Christian, Gustafsson, Stefan, Hallmans, Goran, Hankinson, Susan E., Havulinna, Aki S., Herder, Christian, Hernandez, Dena, Hicks, Andrew A., Hunter, David J., Illig, Thomas, Ingelsson, Erik, Ioan-Facsinay, Andreea, Jansson, John-Olov, Jenny, Nancy S., Jorgensen, Marit E., Jorgensen, Torben, Karlsson, Magnus, Koenig, Wolfgang, Kraft, Peter, Kwekkeboom, Joanneke, Laatikainen, Tiina, Ladwig, Karl-Heinz, LeDuc, Charles A., Lowe, Gordon, Lu, Yingchang, Marques-Vidal, Pedro, Meisinger, Christa, Menni, Cristina, Morris, Andrew P., Myers, Richard H., Mannisto, Satu, Nalls, Mike A., Paternoster, Lavinia, Peters, Annette, Pradhan, Aruna D., Rankinen, Tuomo, Rasmussen-Torvik, Laura J., Rathmann, Wolfgang, Rice, Treva K., Richards, J. Brent, Ridker, Paul M., Sattar, Naveed, Savage, David B., Soderberg, Stefan, Timpson, Nicholas J., Vandenput, Liesbeth, van Heemst, Diana, Uh, Hae-Won, Vohl, Marie-Claude, Walker, Mark, Wichmann, Heinz-Erich, Widen, Elisabeth, Wood, Andrew R., Yao, Jie, Zeller, Tanja, Zhang, Yiying, Meulenbelt, Ingrid, Kloppenburg, Margreet, Astrup, Arne, Sorensen, Thorkild I. A., Sarzynski, Mark A., Rao, D. C., Jousilahti, Pekka, Vartiainen, Erkki, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andre G., Kajantie, Eero, Osmond, Clive, Palotie, Aarno, Eriksson, Johan G., Heliovaara, Markku, Knekt, Paul B., Koskinen, Seppo, Jula, Antti, Perola, Markus, Huupponen, Risto K., Viikari, Jorma S., Kahonen, Mika, Lehtimaki, Terho, Raitakari, Olli T., Mellstrom, Dan, Lorentzon, Mattias, Casas, Juan P., Bandinelli, Stefanie, Maerz, Winfried, Isaacs, Aaron, van Dijk, Ko W., van Duijn, Cornelia M., Harris, Tamara B., Bouchard, Claude, Allison, Matthew A., Chasman, Daniel I., Ohlsson, Claes, Lind, Lars, Scott, Robert A., Langenberg, Claudia, Wareham, Nicholas J., Ferrucci, Luigi, Frayling, Timothy M., Pramstaller, Peter P., Borecki, Ingrid B., Waterworth, Dawn M., Bergmann, Sven, Waeber, Gerard, Vollenweider, Peter, Vestergaard, Henrik, Hansen, Torben, Pedersen, Oluf, Hu, Frank B., Slagboom, P. Eline, Grallert, Harald, Spector, Tim D., Jukema, J. W., Klein, Robert J., Schadt, Erik E., Franks, Paul W., Lindgren, Cecilia M., Leibel, Rudolph L., Loos, Ruth J. F., University of Helsinki, Helsinki Collegium for Advanced Studies, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Hospital for Children and Adolescents, University of Helsinki, Clinicum, Kilpelainen, Tuomas O., Carli, Jayne F. Martin, Skowronski, Alicja A., Sun, Qi, Kriebel, Jennifer, Feitosa, Mary F., Hedman, Asa K., Drong, Alexander W., Hayes, James E., Zhao, Jinghua, Pers, Tune H., Schick, Ursula, Grarup, Niels, Kutalik, Zoltan, Trompet, Stella, Mangino, Massimo, Kristiansson, Kati, Beekman, Marian, Lyytikainen, Leo-Pekka, Eriksson, Joel, Henneman, Peter, Lahti, Jari, Tanaka, Toshiko, Luan, Jian'an, Del Greco M, Fabiola, Pasko, Dorota, Renstrom, Frida, Willems, Sara M., Mahajan, Anubha, Rose, Lynda M., Guo, Xiuqing, Liu, Yongmei, Kleber, Marcus E., Perusse, Louis, Gaunt, Tom, Ahluwalia, Tarunveer S., Sung, Yun Ju, Ramos, Yolande F., Amin, Najaf, Amuzu, Antoinette, Barroso, Ines, Bellis, Claire, Blangero, John, Buckley, Brendan M., Boehringer, Stefan, Chen, Yii-Der I., de Craen, Anton J. N., Crosslin, David R., Dale, Caroline E., Dastani, Zari, Day, Felix R., Deelen, Joris, Delgado, Graciela E., Demirkan, Ayse, Finucane, Francis M., Ford, Ian, Garcia, Melissa E., Gieger, Christian, Gustafsson, Stefan, Hallmans, Goran, Hankinson, Susan E., Havulinna, Aki S., Herder, Christian, Hernandez, Dena, Hicks, Andrew A., Hunter, David J., Illig, Thomas, Ingelsson, Erik, Ioan-Facsinay, Andreea, Jansson, John-Olov, Jenny, Nancy S., Jorgensen, Marit E., Jorgensen, Torben, Karlsson, Magnus, Koenig, Wolfgang, Kraft, Peter, Kwekkeboom, Joanneke, Laatikainen, Tiina, Ladwig, Karl-Heinz, LeDuc, Charles A., Lowe, Gordon, Lu, Yingchang, Marques-Vidal, Pedro, Meisinger, Christa, Menni, Cristina, Morris, Andrew P., Myers, Richard H., Mannisto, Satu, Nalls, Mike A., Paternoster, Lavinia, Peters, Annette, Pradhan, Aruna D., Rankinen, Tuomo, Rasmussen-Torvik, Laura J., Rathmann, Wolfgang, Rice, Treva K., Richards, J. Brent, Ridker, Paul M., Sattar, Naveed, Savage, David B., Soderberg, Stefan, Timpson, Nicholas J., Vandenput, Liesbeth, van Heemst, Diana, Uh, Hae-Won, Vohl, Marie-Claude, Walker, Mark, Wichmann, Heinz-Erich, Widen, Elisabeth, Wood, Andrew R., Yao, Jie, Zeller, Tanja, Zhang, Yiying, Meulenbelt, Ingrid, Kloppenburg, Margreet, Astrup, Arne, Sorensen, Thorkild I. A., Sarzynski, Mark A., Rao, D. C., Jousilahti, Pekka, Vartiainen, Erkki, Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andre G., Kajantie, Eero, Osmond, Clive, Palotie, Aarno, Eriksson, Johan G., Heliovaara, Markku, Knekt, Paul B., Koskinen, Seppo, Jula, Antti, Perola, Markus, Huupponen, Risto K., Viikari, Jorma S., Kahonen, Mika, Lehtimaki, Terho, Raitakari, Olli T., Mellstrom, Dan, Lorentzon, Mattias, Casas, Juan P., Bandinelli, Stefanie, Maerz, Winfried, Isaacs, Aaron, van Dijk, Ko W., van Duijn, Cornelia M., Harris, Tamara B., Bouchard, Claude, Allison, Matthew A., Chasman, Daniel I., Ohlsson, Claes, Lind, Lars, Scott, Robert A., Langenberg, Claudia, Wareham, Nicholas J., Ferrucci, Luigi, Frayling, Timothy M., Pramstaller, Peter P., Borecki, Ingrid B., Waterworth, Dawn M., Bergmann, Sven, Waeber, Gerard, Vollenweider, Peter, Vestergaard, Henrik, Hansen, Torben, Pedersen, Oluf, Hu, Frank B., Slagboom, P. Eline, Grallert, Harald, Spector, Tim D., Jukema, J. W., Klein, Robert J., Schadt, Erik E., Franks, Paul W., Lindgren, Cecilia M., Leibel, Rudolph L., and Loos, Ruth J. F.
- Abstract
Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P <10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P <5 x 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
- Published
- 2016
22. Differential methylation of the TRPA1 promoter in pain sensitivity
- Author
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Bell, J.T., Loomis, A.K., Butcher, L.M., Gao, F., Zhang, B., Hyde, C.L., Sun, J., Wu, H., Ward, K., Harris, J., Scollen, S., Davies, M.N., Schalkwyk, L.C., Mill, J., Ahmadi, Kourosh R., Ainali, Chrysanthi, Barrett, Amy, Bataille, Veronique, Bell, Jordana T., Buil, Alfonso, Deloukas, Panos, Dermitzakis, Emmanoil T., Dimas, Antigone S., Durbin, Richard, Glass, Daniel, Grundberg, Elin, Hassanali, Neelam, Hedman, Asa K., Ingle, Catherine, Knowles, David, Krestyaninova, Maria, Lindgren, Cecilia M., Lowe, Christopher E., McCarthy, Mark I., Meduri, Eshwar, di Meglio, Paola, Min, Josine L., Montgomery, Stephen B., Nestle, Frank O., Nica, Alexandra C., Nisbet, James, O’Rahilly, Stephen, Parts, Leopold, Potter, Simon, Sekowska, Magdalena, Shin, So-Youn, Small, Kerrin S., Soranzo, Nicole, Spector, Tim D., Surdulescu, Gabriela, Travers, Mary E., Tsaprouni, Loukia, Tsoka, Sophia, Wilk, Alicja, Yang, Tsun-Po, Zondervan, Krina T., Williams, F.M.K., Li, N., Deloukas, P., Beck, S., McMahon, S.B., Wang, J., John, S.L., and Spector, T.D.
- Subjects
Male ,Candidate gene ,Gene Expression ,General Physics and Astronomy ,Genome-wide association study ,Bioinformatics ,Epigenesis, Genetic ,ACTIVATION ,Transient Receptor Potential Channels ,0302 clinical medicine ,Promoter Regions, Genetic ,DNA METHYLATION ,TRPA1 Cation Channel ,Aged, 80 and over ,Genetics ,SITES ,0303 health sciences ,Multidisciplinary ,Chronic pain ,BIPOLAR DISORDER ,Methylation ,Middle Aged ,3. Good health ,Hyperalgesia ,DNA methylation ,Female ,SUSCEPTIBILITY LOCI ,Nerve Tissue Proteins ,Biology ,INDIVIDUAL-DIFFERENCES ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,medicine ,Humans ,Methylated DNA immunoprecipitation ,Epigenetics ,GENOME-WIDE ASSOCIATION ,METAANALYSIS ,Aged ,030304 developmental biology ,HEAT-PAIN ,Twins, Monozygotic ,General Chemistry ,DNA Methylation ,medicine.disease ,Differentially methylated regions ,Case-Control Studies ,Calcium Channels ,030217 neurology & neurosurgery ,RESPONSES ,Genome-Wide Association Study - Abstract
Chronic pain is a global public health problem, but the underlying molecular mechanisms are not fully understood. Here we examine genome-wide DNA methylation, first in 50 identical twins discordant for heat pain sensitivity and then in 50 further unrelated individuals. Whole-blood DNA methylation was characterized at 5.2 million loci by MeDIP sequencing and assessed longitudinally to identify differentially methylated regions associated with high or low pain sensitivity (pain DMRs). Nine meta-analysis pain DMRs show robust evidence for association (false discovery rate 5%) with the strongest signal in the pain gene TRPA1 (P=1.2 × 10−13). Several pain DMRs show longitudinal stability consistent with susceptibility effects, have similar methylation levels in the brain and altered expression in the skin. Our approach identifies epigenetic changes in both novel and established candidate genes that provide molecular insights into pain and may generalize to other complex traits., Genetically identical twins provide a valuable resource to identify epigenetic factors associated with complex traits. Here the authors adopt this approach and find that differential methylation of the pain gene TRPA1 is associated with pain sensitivity in humans.
- Published
- 2014
- Full Text
- View/download PDF
23. Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians
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Park, Kyong Soo, Wu, Ying, Tay, Wan Ting, Chang, Tien-Jyun, Kim, Hyung-Lae, Ma, Ronald C.W., Chan, Juliana C.N., McCarthy, Mark I., Seielstad, Mark, Morris, Andrew P., Long, Jirong, Go, Min Jin, Chang, Yi-Cheng, Kato, Norihiro, Takeuchi, Fumihiko, Cho, Young Min, Takayanagi, Ryoichi, Hu, Frank B., Adair, Linda, Tai, E. Shyong, Yamauchi, Toshimasa, Chang, Li-Ching, Yokota, Mitsuhiro, DIAGRAM Consortium, Mohlke, Karen, Yamamoto, Ken, Wu, Jer-Yuarn, Chen, Chien-Hsiun, So, Wing Yee, Cho, Nam H., Wong, Tien Yin, Nakamura, Jirong, Li, Yun, Nakashima, Eitaro, Teo, Yik Ying, Jia, Weiping, Gao, Yutang, Kwak, Soo Heon, Cho, Yoon Shin, Wang, Congrong, Cai, Qiuyin, MuTHER Consortium, Sim, Xueling, Zheng, Wei, Ong, Rick Twee Hee, Shu, Xiao Ou, Liu, Jian Jun, Kim, Sangsoo, Bao, Yuqian, Aung, Tin, Kim, Young Jin, Zhang, Rong, Hara, Kazuo, Lee, Jong-Young, Han, Bok-Ghee, Lee, Nanette R., Chuang, Lee-Ming, Hu, Cheng, Maeda, Shiro, Tsai, Fuu-Jen, Ohnaka, Keizo, Hedman, Asa K., Lee, Jeannette Jen-Mai, Lu, Wei, Kadowaki, Takashi, Ikegami, Hiroshi, Chen, Yuan-Tsong, and Ng, Daniel Peng-Keat
- Subjects
endocrine system diseases - Abstract
We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression1,2, is known for its association with fasting glucose levels3,4. The evidence of an association with T2D for PEPD5 and HNF4A6,7 has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D.
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- 2012
- Full Text
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24. Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci
- Author
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Rahmioglu, Nilufer, Macgregor, Stuart, Drong, Alexander W, Hedman, Asa K, Harris, Holly R, Randall, Joshua C, Prokopenko, Inga, Nyholt, Dale R, Morris, Andrew P, Montgomery, Grant W, Missmer, Stacey A, Lindgren, Cecilia M, Zondervan, Krina T, Hallmans, Göran, Shungin, Dmitry, Rahmioglu, Nilufer, Macgregor, Stuart, Drong, Alexander W, Hedman, Asa K, Harris, Holly R, Randall, Joshua C, Prokopenko, Inga, Nyholt, Dale R, Morris, Andrew P, Montgomery, Grant W, Missmer, Stacey A, Lindgren, Cecilia M, Zondervan, Krina T, Hallmans, Göran, and Shungin, Dmitry
- Abstract
Endometriosis is a chronic inflammatory condition in women that results in pelvic pain and subfertility, and has been associated with decreased body mass index (BMI). Genetic variants contributing to the heritable component have started to emerge from genome-wide association studies (GWAS), although the majority remain unknown. Unexpectedly, we observed an intergenic locus on 7p15.2 that was genome-wide significantly associated with both endometriosis and fat distribution (waist-to-hip ratio adjusted for BMI; WHRadjBMI) in an independent meta-GWAS of European ancestry individuals. This led us to investigate the potential overlap in genetic variants underlying the aetiology of endometriosis, WHRadjBMI and BMI using GWAS data. Our analyses demonstrated significant enrichment of common variants between fat distribution and endometriosis (P = 3.7 × 10(-3)), which was stronger when we restricted the investigation to more severe (Stage B) cases (P = 4.5 × 10(-4)). However, no genetic enrichment was observed between endometriosis and BMI (P = 0.79). In addition to 7p15.2, we identify four more variants with statistically significant evidence of involvement in both endometriosis and WHRadjBMI (in/near KIFAP3, CAB39L, WNT4, GRB14); two of these, KIFAP3 and CAB39L, are novel associations for both traits. KIFAP3, WNT4 and 7p15.2 are associated with the WNT signalling pathway; formal pathway analysis confirmed a statistically significant (P = 6.41 × 10(-4)) overrepresentation of shared associations in developmental processes/WNT signalling between the two traits. Our results demonstrate an example of potential biological pleiotropy that was hitherto unknown, and represent an opportunity for functional follow-up of loci and further cross-phenotype comparisons to assess how fat distribution and endometriosis pathogenesis research fields can inform each other., G. Hallmans ingår i ett konsortsie som står som medförfattare.
- Published
- 2015
- Full Text
- View/download PDF
25. New genetic loci link adipose and insulin biology to body fat distribution
- Author
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Shungin, Dmitry, Winkler, Thomas W., Croteau-Chonka, Damien C., Ferreira, Teresa, Lockes, Adam E., Maegi, Reedik, Strawbridge, Rona J., Pers, Tune H., Fischer, Krista, Justice, Anne E., Workalemahu, Tsegaselassie, Wu, Joseph M. W., Buchkovich, Martin L., Heard-Costa, Nancy L., Roman, Tamara S., Drong, Alexander W., Song, Ci, Gustafsson, Stefan, Day, Felix R., Esko, Tonu, Fall, Tove, Kutalik, Zoltan, Luan, Jian'an, Randall, Joshua C., Scherag, Andre, Vedantam, Sailaja, Wood, Andrew R., Chen, Jin, Fehrmann, Rudolf, Karjalainen, Juha, Kahali, Bratati, Liu, Ching-Ti, Schmidt, Ellen M., Absher, Devin, Amin, Najaf, Anderson, Denise, Beekman, Marian, Bragg-Gresham, Jennifer L., Buyske, Steven, Demirkan, Ayse, Ehret, Georg B., Feitosa, Mary F., Goel, Anuj, Jackson, Anne U., Johnson, Toby, Kleber, Marcus E., Kristiansson, Kati, Mangino, Massimo, Leach, Irene Mateo, Medina-Gomez, Carolina, Palmer, Cameron D., Pasko, Dorota, Pechlivaniss, Sonali, Peters, Marjolein J., Prokopenko, Inga, Stancakova, Alena, Sung, Yun Ju, Tanakam, Toshiko, Teumer, Alexander, Van Vliet-Ostaptchouk, Jana V., Yengo, Loic, Zhang, Weihua, Albrecht, Eva, Arnlov, Johan, Arscott, Gillian M., Bandinelli, Stefania, Barrett, Amy, Bellis, Claire, Bennett, Amanda J., Berne, Christian, Blueher, Matthias, Buhringer, Stefan, Bonnet, Fabrice, Boettcher, Yvonne, Bruinenberg, Marcel, Carba, Delia B., Caspersen, Ida H., Clarke, Robert, Daw, E. Warwick, Deelen, Joris, Deelman, Ewa, Delgado, Graciela, Doney, Alex S. F., Eklund, Niina, Erdos, Michael R., Estrada, Karol, Eury, Elodie, Friedrichs, Nele, Garcia, Melissa E., Giedraitis, Vilmantas, Gigante, Bruna, Go, Alan S., Golay, Alain, Grallert, Harald, Grammer, Tanja B., Graessler, Juergen, Grewal, Jagvir, Groves, Christopher J., Haller, Toomas, Hallmans, Göran, Hartman, Catharina A., Hassinen, Maija, Hayward, Caroline, Heikkila, Kauko, Herzig, Karl-Heinz, Helmer, Quinta, Hillege, Hans L., Holmen, Oddgeir, Hunt, Steven C., Isaacs, Aaron, Ittermann, Till, James, Alan L., Johansson, Ingegerd, Juliusdottir, Thorhildur, Kalafati, Ioanna-Panagiota, Kinnunen, Leena, Koenig, Wolfgang, Kooner, Ishminder K., Kratzer, Wolfgang, Lamina, Claudia, Leander, Karin, Lee, Nanette R., Lichtner, Peter, Lind, Lars, Lindstrom, Jaana, Lobbens, Stephane, Lorentzon, Mattias, Mach, Francois, Magnusson, Patrik K. E., Mahajan, Anubha, McArdle, Wendy L., Menni, Cristina, Merger, Sigrun, Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Moayyeri, Alireza, Monda, Ken L., Mooijaart, Simon P., Muehleisen, Thomas W., Mulas, Antonella, Mueller, Gabriele, Mueller-Nurasyid, Martina, Nagaraja, Ramaiah, Nalls, Michael A., Narisu, Narisu, Glorioso, Nicola, Nolte, Ilja M., Olden, Matthias, Rayner, Nigel W., Renstrom, Frida, Ried, Janina S., Robertson, Neil R., Rose, Lynda M., Sanna, Serena, Scharnagl, Hubert, Scholtens, Salome, Sennblad, Bengt, Seufferlein, Thomas, Sitlani, Colleen M., Smith, Albert Vernon, Stirrups, Kathleen, Stringham, Heather M., Sundstrom, Johan, Swertz, Morris A., Swift, Amy J., Syvanen, Ann-Christine, Tayo, Bamidele O., Thorand, Barbara, Thorleifsson, Gudmar, Tomaschitz, Andreas, Troffa, Chiara, van Oort, Floor V. A., Verweij, Niek, Vonk, Judith M., Waite, Lindsay L., Wennauer, Roman, Wilsgaard, Tom, Wojczynski, Mary K., Wong, Andrew, Zhang, Qunyuan, Zhao, Jing Hua, Brennan, Eoin P., Choi, Murim, Eriksson, Per, Folkersen, Lasse, Franco-Cereceda, Anders, Gharavi, Ali G., Hedman, Asa K., Hivert, Marie-France, Huang, Jinyan, Kanoni, Stavroula, Karpe, Fredrik, Keildson, Sarah, Kiryluk, Krzysztof, Liang, Liming, Lifton, Richard P., Ma, Baoshan, McKnight, Amy J., McPherson, Ruth, Metspalu, Andres, Min, Josine L., Moffatt, Miriam F., Montgomery, Grant W., Murabito, Joanne M., Nicholson, George, Nyholt, Dale R., Olsson, Christian, Perry, John R. B., Reinmaa, Eva, Salem, Rany M., Sandholm, Niina, Schadt, Eric E., Scott, Robert A., Stolk, Lisette, Vallejo, Edgar E., Westra, Harm-Jan, Zondervan, Krina T., Amouyel, Philippe, Arveiler, Dominique, Bakker, Stephan J. L., Beilby, John, Bergman, Richard N., Blangero, John, Brown, Morris J., Burnier, Michel, Campbell, Harry, Chakravarti, Aravinda, Chiness, Peter S., Claudi-Boehmi, Simone, Collins, Francis S., Crawford, Dana C., Danesh, John, de Faire, Ulf, de Geusl, Eco J. C., Doerr, Marcus, Erbel, Raimund, Eriksson, Johan G., Farrall, Martin, Ferrannini, Ele, Ferrieres, Jean, Forouhi, Nita G., Forrester, Terrence, Franco, Oscar H., Gansevoort, Ron T., Gieger, Christian, Gudnason, Vilmundur, Haiman, Christopher A., Harris, Tamara B., Hattersley, Andrew T., Heliovaara, Markku, Hicks, Andrew A., Hingorani, Aroon D., Hoffmann, Wolfgang, Hofman, Albert, Homuth, Georg, Humphries, Steve E., Hyppoenen, Elina, Illig, Thomas, Jarvelin, Marjo-Riitta, Johansen, Berit, Jousilahti, Pekka, Jula, Antti M., Kaprio, Jaakko, Kee, Frank, Keinanen-Kiukaanniemi, Sirkka M., Kooner, Jaspal S., Kooperberg, Charles, Kovacs, Peter, Kraja, Aldi T., Kumari, Meena, Kuulasmaa, Kari, Kuusisto, Johanna, Lakka, Timo A., Langenberg, Claudia, Le Marchand, Loic, Lehtimaki, Terho, Lyssenko, Valeriya, Mannisto, Satu, Marette, Andre, Matise, Tara C., McKenzie, Colin A., McKnight, Barbara, Musk, Arthur W., Mohlenkamp, Stefan, Morris, Andrew D., Nelis, Mari, Ohlsson, Claes, Oldehinkel, Albertine J., Ong, Ken K., Palmer, Lyle J., Penninx, Brenda W., Peters, Annette, Pramstaller, Peter P., Raitakari, Olli T., Rankinen, Tuomo, Rao, D. C., Rice, Treva K., Ridker, Paul M., Ritchie, Marylyn D., Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J., Saramies, Jouko, Sarzynski, Mark A., Schwarz, Peter E. H., Shuldiner, Alan R., Staessen, Jan A., Steinthorsdottir, Valgerdur, Stolk, Ronald P., Strauch, Konstantin, Toenjes, Anke, Tremblay, Angelo, Tremoli, Elena, Vohl, Marie-Claude, Voelker, Uwe, Vollenweider, Peter, Wilson, James F., Witteman, Jacqueline C., Adair, Linda S., Bochud, Murielle, Boehm, Bernhard O., Bornstein, Stefan R., Bouchard, Claude, Cauchi, Stephane, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Cooper, Richard S., Dedoussis, George, Ferrucci, Luigi, Froguel, Philippe, Grabe, Hans-Joergen, Hamsten, Anders, Hui, Jennie, Hveem, Kristian, Joeckel, Karl-Heinz, Kivimaki, Mika, Kuh, Diana, Laakso, Markku, Liu, Yongmei, Maerz, Winfried, Munroe, Patricia B., Njolstad, Inger, Oostra, Ben A., Palmer, Colin N. A., Pedersen, Nancy L., Perola, Markus, Perusse, Louis, Peters, Ulrike, Power, Chris, Quertermous, Thomas, Rauramaa, Rainer, Rivadeneira, Fernando, Saaristo, Timo E., Saleheen, Danish, Sinisalo, Juha, Slagboom, P. Eline, Snieder, Harold, Spector, Tim D., Thorsteinsdottir, Unnur R., Stumvoll, Michael, Tuomilehto, Jaakko, Uitterlinden, Andre G., Uusitupa, Math, van der Harst, Pim, Veronesi, Giovanni, Walker, Mark, Wareham, Nicholas J., Watkins, Hugh, Wichmann, H-Erich, Abecasis, Goncalo R., Assimes, Themistocles L., Berndt, Sonja I., Boehnkes, Michael, Borecki, Ingrid B., Deloukas, Panos, Franke, Lude, Frayling, Timothy M., Groop, Leif C., Hunter, David J., Kaplan, Robert C., O'Connell, Jeffrey R., Qi, Lu, Schlessinger, David, Strachan, David P., Stefansson, Kari, van Dujin, Cornelia M., Willer, Cristen J., Visscher, Peter M., Yang, Jian, Hirschhorn, Joel N., Zillikens, M. Carola, McCarthy, Mark I., Speliotes, Elizabeth K., North, Kari E., Fox, Caroline S., Barroso, Ines, Franks, Paul W., Ingelsson, Erik, Heid, Iris M., Loos, Ruth J. F., Cupples, L. Adrienne, Morris, Andrew P., Lindgren, Cecilia M., Mohlke, Karen L., Shungin, Dmitry, Winkler, Thomas W., Croteau-Chonka, Damien C., Ferreira, Teresa, Lockes, Adam E., Maegi, Reedik, Strawbridge, Rona J., Pers, Tune H., Fischer, Krista, Justice, Anne E., Workalemahu, Tsegaselassie, Wu, Joseph M. W., Buchkovich, Martin L., Heard-Costa, Nancy L., Roman, Tamara S., Drong, Alexander W., Song, Ci, Gustafsson, Stefan, Day, Felix R., Esko, Tonu, Fall, Tove, Kutalik, Zoltan, Luan, Jian'an, Randall, Joshua C., Scherag, Andre, Vedantam, Sailaja, Wood, Andrew R., Chen, Jin, Fehrmann, Rudolf, Karjalainen, Juha, Kahali, Bratati, Liu, Ching-Ti, Schmidt, Ellen M., Absher, Devin, Amin, Najaf, Anderson, Denise, Beekman, Marian, Bragg-Gresham, Jennifer L., Buyske, Steven, Demirkan, Ayse, Ehret, Georg B., Feitosa, Mary F., Goel, Anuj, Jackson, Anne U., Johnson, Toby, Kleber, Marcus E., Kristiansson, Kati, Mangino, Massimo, Leach, Irene Mateo, Medina-Gomez, Carolina, Palmer, Cameron D., Pasko, Dorota, Pechlivaniss, Sonali, Peters, Marjolein J., Prokopenko, Inga, Stancakova, Alena, Sung, Yun Ju, Tanakam, Toshiko, Teumer, Alexander, Van Vliet-Ostaptchouk, Jana V., Yengo, Loic, Zhang, Weihua, Albrecht, Eva, Arnlov, Johan, Arscott, Gillian M., Bandinelli, Stefania, Barrett, Amy, Bellis, Claire, Bennett, Amanda J., Berne, Christian, Blueher, Matthias, Buhringer, Stefan, Bonnet, Fabrice, Boettcher, Yvonne, Bruinenberg, Marcel, Carba, Delia B., Caspersen, Ida H., Clarke, Robert, Daw, E. Warwick, Deelen, Joris, Deelman, Ewa, Delgado, Graciela, Doney, Alex S. F., Eklund, Niina, Erdos, Michael R., Estrada, Karol, Eury, Elodie, Friedrichs, Nele, Garcia, Melissa E., Giedraitis, Vilmantas, Gigante, Bruna, Go, Alan S., Golay, Alain, Grallert, Harald, Grammer, Tanja B., Graessler, Juergen, Grewal, Jagvir, Groves, Christopher J., Haller, Toomas, Hallmans, Göran, Hartman, Catharina A., Hassinen, Maija, Hayward, Caroline, Heikkila, Kauko, Herzig, Karl-Heinz, Helmer, Quinta, Hillege, Hans L., Holmen, Oddgeir, Hunt, Steven C., Isaacs, Aaron, Ittermann, Till, James, Alan L., Johansson, Ingegerd, Juliusdottir, Thorhildur, Kalafati, Ioanna-Panagiota, Kinnunen, Leena, Koenig, Wolfgang, Kooner, Ishminder K., Kratzer, Wolfgang, Lamina, Claudia, Leander, Karin, Lee, Nanette R., Lichtner, Peter, Lind, Lars, Lindstrom, Jaana, Lobbens, Stephane, Lorentzon, Mattias, Mach, Francois, Magnusson, Patrik K. E., Mahajan, Anubha, McArdle, Wendy L., Menni, Cristina, Merger, Sigrun, Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Moayyeri, Alireza, Monda, Ken L., Mooijaart, Simon P., Muehleisen, Thomas W., Mulas, Antonella, Mueller, Gabriele, Mueller-Nurasyid, Martina, Nagaraja, Ramaiah, Nalls, Michael A., Narisu, Narisu, Glorioso, Nicola, Nolte, Ilja M., Olden, Matthias, Rayner, Nigel W., Renstrom, Frida, Ried, Janina S., Robertson, Neil R., Rose, Lynda M., Sanna, Serena, Scharnagl, Hubert, Scholtens, Salome, Sennblad, Bengt, Seufferlein, Thomas, Sitlani, Colleen M., Smith, Albert Vernon, Stirrups, Kathleen, Stringham, Heather M., Sundstrom, Johan, Swertz, Morris A., Swift, Amy J., Syvanen, Ann-Christine, Tayo, Bamidele O., Thorand, Barbara, Thorleifsson, Gudmar, Tomaschitz, Andreas, Troffa, Chiara, van Oort, Floor V. A., Verweij, Niek, Vonk, Judith M., Waite, Lindsay L., Wennauer, Roman, Wilsgaard, Tom, Wojczynski, Mary K., Wong, Andrew, Zhang, Qunyuan, Zhao, Jing Hua, Brennan, Eoin P., Choi, Murim, Eriksson, Per, Folkersen, Lasse, Franco-Cereceda, Anders, Gharavi, Ali G., Hedman, Asa K., Hivert, Marie-France, Huang, Jinyan, Kanoni, Stavroula, Karpe, Fredrik, Keildson, Sarah, Kiryluk, Krzysztof, Liang, Liming, Lifton, Richard P., Ma, Baoshan, McKnight, Amy J., McPherson, Ruth, Metspalu, Andres, Min, Josine L., Moffatt, Miriam F., Montgomery, Grant W., Murabito, Joanne M., Nicholson, George, Nyholt, Dale R., Olsson, Christian, Perry, John R. B., Reinmaa, Eva, Salem, Rany M., Sandholm, Niina, Schadt, Eric E., Scott, Robert A., Stolk, Lisette, Vallejo, Edgar E., Westra, Harm-Jan, Zondervan, Krina T., Amouyel, Philippe, Arveiler, Dominique, Bakker, Stephan J. L., Beilby, John, Bergman, Richard N., Blangero, John, Brown, Morris J., Burnier, Michel, Campbell, Harry, Chakravarti, Aravinda, Chiness, Peter S., Claudi-Boehmi, Simone, Collins, Francis S., Crawford, Dana C., Danesh, John, de Faire, Ulf, de Geusl, Eco J. C., Doerr, Marcus, Erbel, Raimund, Eriksson, Johan G., Farrall, Martin, Ferrannini, Ele, Ferrieres, Jean, Forouhi, Nita G., Forrester, Terrence, Franco, Oscar H., Gansevoort, Ron T., Gieger, Christian, Gudnason, Vilmundur, Haiman, Christopher A., Harris, Tamara B., Hattersley, Andrew T., Heliovaara, Markku, Hicks, Andrew A., Hingorani, Aroon D., Hoffmann, Wolfgang, Hofman, Albert, Homuth, Georg, Humphries, Steve E., Hyppoenen, Elina, Illig, Thomas, Jarvelin, Marjo-Riitta, Johansen, Berit, Jousilahti, Pekka, Jula, Antti M., Kaprio, Jaakko, Kee, Frank, Keinanen-Kiukaanniemi, Sirkka M., Kooner, Jaspal S., Kooperberg, Charles, Kovacs, Peter, Kraja, Aldi T., Kumari, Meena, Kuulasmaa, Kari, Kuusisto, Johanna, Lakka, Timo A., Langenberg, Claudia, Le Marchand, Loic, Lehtimaki, Terho, Lyssenko, Valeriya, Mannisto, Satu, Marette, Andre, Matise, Tara C., McKenzie, Colin A., McKnight, Barbara, Musk, Arthur W., Mohlenkamp, Stefan, Morris, Andrew D., Nelis, Mari, Ohlsson, Claes, Oldehinkel, Albertine J., Ong, Ken K., Palmer, Lyle J., Penninx, Brenda W., Peters, Annette, Pramstaller, Peter P., Raitakari, Olli T., Rankinen, Tuomo, Rao, D. C., Rice, Treva K., Ridker, Paul M., Ritchie, Marylyn D., Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J., Saramies, Jouko, Sarzynski, Mark A., Schwarz, Peter E. H., Shuldiner, Alan R., Staessen, Jan A., Steinthorsdottir, Valgerdur, Stolk, Ronald P., Strauch, Konstantin, Toenjes, Anke, Tremblay, Angelo, Tremoli, Elena, Vohl, Marie-Claude, Voelker, Uwe, Vollenweider, Peter, Wilson, James F., Witteman, Jacqueline C., Adair, Linda S., Bochud, Murielle, Boehm, Bernhard O., Bornstein, Stefan R., Bouchard, Claude, Cauchi, Stephane, Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Cooper, Richard S., Dedoussis, George, Ferrucci, Luigi, Froguel, Philippe, Grabe, Hans-Joergen, Hamsten, Anders, Hui, Jennie, Hveem, Kristian, Joeckel, Karl-Heinz, Kivimaki, Mika, Kuh, Diana, Laakso, Markku, Liu, Yongmei, Maerz, Winfried, Munroe, Patricia B., Njolstad, Inger, Oostra, Ben A., Palmer, Colin N. A., Pedersen, Nancy L., Perola, Markus, Perusse, Louis, Peters, Ulrike, Power, Chris, Quertermous, Thomas, Rauramaa, Rainer, Rivadeneira, Fernando, Saaristo, Timo E., Saleheen, Danish, Sinisalo, Juha, Slagboom, P. Eline, Snieder, Harold, Spector, Tim D., Thorsteinsdottir, Unnur R., Stumvoll, Michael, Tuomilehto, Jaakko, Uitterlinden, Andre G., Uusitupa, Math, van der Harst, Pim, Veronesi, Giovanni, Walker, Mark, Wareham, Nicholas J., Watkins, Hugh, Wichmann, H-Erich, Abecasis, Goncalo R., Assimes, Themistocles L., Berndt, Sonja I., Boehnkes, Michael, Borecki, Ingrid B., Deloukas, Panos, Franke, Lude, Frayling, Timothy M., Groop, Leif C., Hunter, David J., Kaplan, Robert C., O'Connell, Jeffrey R., Qi, Lu, Schlessinger, David, Strachan, David P., Stefansson, Kari, van Dujin, Cornelia M., Willer, Cristen J., Visscher, Peter M., Yang, Jian, Hirschhorn, Joel N., Zillikens, M. Carola, McCarthy, Mark I., Speliotes, Elizabeth K., North, Kari E., Fox, Caroline S., Barroso, Ines, Franks, Paul W., Ingelsson, Erik, Heid, Iris M., Loos, Ruth J. F., Cupples, L. Adrienne, Morris, Andrew P., Lindgren, Cecilia M., and Mohlke, Karen L.
- Abstract
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 x 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
- Published
- 2015
- Full Text
- View/download PDF
26. Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants
- Author
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Allum, Fiona, Shao, Xiaojian, Guénard, Frédéric, Simon, Marie-Michelle, Busche, Stephan, Caron, Maxime, Lambourn, John, Lessard, Julie, Tandre, Karolina, Hedman, Asa K., Kwan, Tony, Ge, Bing, Rönnblom, Lars, McCarthy, Mark I., Deloukas, Panos, Richmond, Todd, Burgess, Daniel, Spector, T. D. (Timothy David), Tchernof, André, Marceau, Simon, Lathrop, Mark, Vohl, Marie-Claude, Pastinen, Tomi, Grundberg, Elin, Allum, Fiona, Shao, Xiaojian, Guénard, Frédéric, Simon, Marie-Michelle, Busche, Stephan, Caron, Maxime, Lambourn, John, Lessard, Julie, Tandre, Karolina, Hedman, Asa K., Kwan, Tony, Ge, Bing, Rönnblom, Lars, McCarthy, Mark I., Deloukas, Panos, Richmond, Todd, Burgess, Daniel, Spector, T. D. (Timothy David), Tchernof, André, Marceau, Simon, Lathrop, Mark, Vohl, Marie-Claude, Pastinen, Tomi, and Grundberg, Elin
- Abstract
Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targetedarrays or enrichment methodologies preferentially covering CpG-dense regions, tocharacterize sufficiently large samples. To overcome this limitation, we present here a newcustomizable, cost-effective approach, methylC-capture sequencing (MCC-Seq), forsequencing functional methylomes, while simultaneously providing genetic variationinformation. To illustrate MCC-Seq, we use whole-genome bisulfite sequencing on adiposetissue (AT) samples and public databases to design AT-specific panels. We establish itsefficiency for high-density interrogation of methylome variability by systematic comparisonswith other approaches and demonstrate its applicability by identifying novel methylationvariation within enhancers strongly correlated to plasma triglyceride and HDL-cholesterol,including atCD36. Our more comprehensive AT panel assesses tissue methylation andgenotypes in parallel atB4 andB3 M sites, respectively. Our study demonstrates thatMCC-Seq provides comparable accuracy to alternative approaches but enables more efficientcataloguing of functional and disease-relevant epigenetic and genetic variants for large-scale EWAS.
- Published
- 2015
27. Genetic studies of body mass index yield new insights for obesity biology
- Author
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Experimentele Afd. Cardiologie 1, Onderzoek Vrouw Hart & Vaatziekten, Circulatory Health, CMM Groep Kaaij, Brain, JC onderzoeksprogramma Methodologie, Cancer, Afdeling Longfunctie, Epi Kanker Team 1, JC onderzoeksprogramma Kanker, MS VPG/Gynaecologie, Child Health, Epi Kanker Team A, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Cardiovasculaire Epidemiologie, Cardiovasculaire Epi Team 4, Cardiovasculaire Epi Team 5, Locke, Adam E., Kahali, Bratati, Berndt, Sonja I., Justice, Anne E., Pers, Tune H., Day, Felix R., Powell, Corey, Vedantam, Sailaja, Buchkovich, Martin L., Yang, Jian, Croteau-Chonka, Damien C., Esko, Tonu, Fall, Tove, Ferreira, Teresa, Gustafsson, Stefan, Kutalik, Zoltan, Luan, Jian'an, Maegi, Reedik, Randall, Joshua C., Winkler, Thomas W., Wood, Andrew R., Workalemahu, Tsegaselassie, Faul, Jessica D., Smith, Jennifer A., Zhao, Jing Hua, Zhao, Wei, Chen, Jin, Fehrmann, Rudolf, Hedman, Asa K., Karjalainen, Juha, Schmidt, Ellen M., Absher, Devin, Amin, Najaf, Anderson, Denise, van der Laan, Sander W., van Setten, Jessica, Uh, Hae-Won, den Ruijter, Hester M., Moll, Frans L., Pasterkamp, Gerard, Asselbergs, Folkert W., de Bakker, Paul I. W., Zanen, Pieter, LifeLines Cohort Study, ADIPOGen Consortium, AGEN-BMI Working Grp, CARDIOGRAMplusC4D Consortium, CKDGen Consortium, GLGC, ICBP, MAGIC Investigators, MuTHER Consortium, MIGen Consortium, PAGE Consortium, ReproGen Consortium, GENIE Consortium, Int Endogene Consortium, Experimentele Afd. Cardiologie 1, Onderzoek Vrouw Hart & Vaatziekten, Circulatory Health, CMM Groep Kaaij, Brain, JC onderzoeksprogramma Methodologie, Cancer, Afdeling Longfunctie, Epi Kanker Team 1, JC onderzoeksprogramma Kanker, MS VPG/Gynaecologie, Child Health, Epi Kanker Team A, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Cardiovasculaire Epidemiologie, Cardiovasculaire Epi Team 4, Cardiovasculaire Epi Team 5, Locke, Adam E., Kahali, Bratati, Berndt, Sonja I., Justice, Anne E., Pers, Tune H., Day, Felix R., Powell, Corey, Vedantam, Sailaja, Buchkovich, Martin L., Yang, Jian, Croteau-Chonka, Damien C., Esko, Tonu, Fall, Tove, Ferreira, Teresa, Gustafsson, Stefan, Kutalik, Zoltan, Luan, Jian'an, Maegi, Reedik, Randall, Joshua C., Winkler, Thomas W., Wood, Andrew R., Workalemahu, Tsegaselassie, Faul, Jessica D., Smith, Jennifer A., Zhao, Jing Hua, Zhao, Wei, Chen, Jin, Fehrmann, Rudolf, Hedman, Asa K., Karjalainen, Juha, Schmidt, Ellen M., Absher, Devin, Amin, Najaf, Anderson, Denise, van der Laan, Sander W., van Setten, Jessica, Uh, Hae-Won, den Ruijter, Hester M., Moll, Frans L., Pasterkamp, Gerard, Asselbergs, Folkert W., de Bakker, Paul I. W., Zanen, Pieter, LifeLines Cohort Study, ADIPOGen Consortium, AGEN-BMI Working Grp, CARDIOGRAMplusC4D Consortium, CKDGen Consortium, GLGC, ICBP, MAGIC Investigators, MuTHER Consortium, MIGen Consortium, PAGE Consortium, ReproGen Consortium, GENIE Consortium, and Int Endogene Consortium
- Published
- 2015
28. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility
- Author
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Mahajan, Anubha, Go, Min Jin, Zhang, Weihua, Below, Jennifer E, Gaulton, Kyle J, Ferreira, Teresa, Horikoshi, Momoko, Johnson, Andrew D, Ng, Maggie C Y, Prokopenko, Inga, Saleheen, Danish, Wang, Xu, Zeggini, Eleftheria, Abecasis, Goncalo R, Adair, Linda S, Almgren, Peter, Atalay, Mustafa, Aung, Tin, Baldassarre, Damiano, Balkau, Beverley, Bao, Yuqian, Barnett, Anthony H, Barroso, Ines, Basit, Abdul, Been, Latonya F, Beilby, John, Bell, Graeme I, Benediktsson, Rafn, Bergman, Richard N, Boehm, Bernhard O, Boerwinkle, Eric, Bonnycastle, Lori L, Burtt, Noel, Cai, Qiuyin, Campbell, Harry, Carey, Jason, Cauchi, Stephane, Caulfield, Mark, Chan, Juliana C N, Chang, Li-Ching, Chang, Tien-Jyun, Chang, Yi-Cheng, Charpentier, Guillaume, Chen, Chien-Hsiun, Chen, Han, Chen, Yuan-Tsong, Chia, Kee-Seng, Chidambaram, Manickam, Chines, Peter S, Cho, Nam H, Cho, Young Min, Chuang, Lee-Ming, Collins, Francis S, Cornelis, Marilyn C, Couper, David J, Crenshaw, Andrew T, van Dam, Rob M, Danesh, John, Das, Debashish, de Faire, Ulf, Dedoussis, George, Deloukas, Panos, Dimas, Antigone S, Dina, Christian, Doney, Alex S F, Donnelly, Peter J, Dorkhan, Mozhgan, van Duijn, Cornelia, Dupuis, Josee, Edkins, Sarah, Elliott, Paul, Emilsson, Valur, Erbel, Raimund, Eriksson, Johan G, Escobedo, Jorge, Esko, Tonu, Eury, Elodie, Florez, Jose C, Fontanillas, Pierre, Forouhi, Nita G, Forsen, Tom, Fox, Caroline, Fraser, Ross M, Frayling, Timothy M, Froguel, Philippe, Frossard, Philippe, Gao, Yutang, Gertow, Karl, Gieger, Christian, Gigante, Bruna, Grallert, Harald, Grant, George B, Groop, Leif C, Groves, Christopher J, Grundberg, Elin, Guiducci, Candace, Hamsten, Anders, Han, Bok-Ghee, Hara, Kazuo, Hassanali, Neelam, Hattersley, Andrew T, Hayward, Caroline, Hedman, Asa K, Herder, Christian, Hofman, Albert, Holmen, Oddgeir L, Hovingh, Kees, Hreidarsson, Astradur B, Hu, Cheng, Hu, Frank B, Hui, Jennie, Humphries, Steve E, Hunt, Sarah E, Hunter, David J, Hveem, Kristian, Hydrie, Zafar I, Ikegami, Hiroshi, Illig, Thomas, Ingelsson, Erik, Islam, Muhammed, Isomaa, Bo, Jackson, Anne U, Jafar, Tazeen, James, Alan, Jia, Weiping, Jockel, Karl-Heinz, Jonsson, Anna, Jowett, Jeremy B M, Kadowaki, Takashi, Kang, Hyun Min, Kanoni, Stavroula, Kao, Wen Hong L, Kathiresan, Sekar, Kato, Norihiro, Katulanda, Prasad, Keinanen-Kiukaanniemi, Sirkka M, Kelly, Ann M, Khan, Hassan, Khaw, Kay-Tee, Khor, Chiea-Chuen, Kim, Hyung-Lae, Kim, Sangsoo, Kim, Young Jin, Kinnunen, Leena, Klopp, Norman, Kong, Augustine, Korpi-Hyovalti, Eeva, Kowlessur, Sudhir, Kraft, Peter, Kravic, Jasmina, Kristensen, Malene M, Krithika, S, Kumar, Ashish, Kumate, Jesus, Kuusisto, Johanna, Kwak, Soo Heon, Laakso, Markku, Lagou, Vasiliki, Lakka, Timo A, Langenberg, Claudia, Langford, Cordelia, Lawrence, Robert, Leander, Karin, Lee, Jen-Mai, Lee, Nanette R, Li, Man, Li, Xinzhong, Li, Yun, Liang, Junbin, Liju, Samuel, Lim, Wei-Yen, Lind, Lars, Lindgren, Cecilia M, Lindholm, Eero, Liu, Ching-Ti, Liu, Jian Jun, Lobbens, Stephane, Long, Jirong, Loos, Ruth J F, Lu, Wei, Luan, Jian'an, Lyssenko, Valeriya, Ma, Ronald C W, Maeda, Shiro, Magi, Reedik, Mannisto, Satu, Matthews, David R, Meigs, James B, Melander, Olle, Metspalu, Andres, Meyer, Julia, Mirza, Ghazala, Mihailov, Evelin, Moebus, Susanne, Mohan, Viswanathan, Mohlke, Karen L, Morris, Andrew D, Muhleisen, Thomas W, Muller-Nurasyid, Martina, Musk, Bill, Nakamura, Jiro, Nakashima, Eitaro, Navarro, Pau, Ng, Peng-Keat, Nica, Alexandra C, Nilsson, Peter M, Njolstad, Inger, Nothen, Markus M, Ohnaka, Keizo, Ong, Twee Hee, Owen, Katharine R, Palmer, Colin N A, Pankow, James S, Park, Kyong Soo, Parkin, Melissa, Pechlivanis, Sonali, Pedersen, Nancy L, Peltonen, Leena, Perry, John R B, Peters, Annette, Pinidiyapathirage, Janani M, Platou, Carl G P, Potter, Simon, Price, Jackie F, Qi, Lu, Radha, Venkatesan, Rallidis, Loukianos, Rasheed, Asif, Rathmann, Wolfgang, Rauramaa, Rainer, Raychaudhuri, Soumya, Rayner, N William, Rees, Simon D, Rehnberg, Emil, Ripatti, Samuli, Robertson, Neil, Roden, Michael, Rossin, Elizabeth J, Rudan, Igor, Rybin, Denis, Saaristo, Timo E, Salomaa, Veikko, Saltevo, Juha, Samuel, Maria, Sanghera, Dharambir K, Saramies, Jouko, Scott, James, Scott, Laura J, Scott, Robert A, Segre, Ayellet V, Sehmi, Joban, Sennblad, Bengt, Shah, Nabi, Shah, Sonia, Shera, A Samad, Shu, Xiao Ou, Shuldiner, Alan R, Sigurðsson, Gunnar, Sijbrands, Eric, Silveira, Angela, Sim, Xueling, Sivapalaratnam, Suthesh, Small, Kerrin S, So, Wing Yee, Stancakova, Alena, Stefansson, Kari, Steinbach, Gerald, Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Strawbridge, Rona J, Stringham, Heather M, Sun, Qi, Suo, Chen, Syvänen, Ann-Christine, Takayanagi, Ryoichi, Takeuchi, Fumihiko, Tay, Wan Ting, Teslovich, Tanya M, Thorand, Barbara, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tikkanen, Emmi, Trakalo, Joseph, Tremoli, Elena, Trip, Mieke D, Tsai, Fuu Jen, Tuomi, Tiinamaija, Tuomilehto, Jaakko, Uitterlinden, Andre G, Valladares-Salgado, Adan, Vedantam, Sailaja, Veglia, Fabrizio, Voight, Benjamin F, Wang, Congrong, Wareham, Nicholas J, Wennauer, Roman, Wickremasinghe, Ananda R, Wilsgaard, Tom, Wilson, James F, Wiltshire, Steven, Winckler, Wendy, Wong, Tien Yin, Wood, Andrew R, Wu, Jer-Yuarn, Wu, Ying, Yamamoto, Ken, Yamauchi, Toshimasa, Yang, Mingyu, Yengo, Loic, Yokota, Mitsuhiro, Young, Robin, Zabaneh, Delilah, Zhang, Fan, Zhang, Rong, Zheng, Wei, Zimmet, Paul Z, Altshuler, David, Bowden, Donald W, Cho, Yoon Shin, Cox, Nancy J, Cruz, Miguel, Hanis, Craig L, Kooner, Jaspal, Lee, Jong-Young, Seielstad, Mark, Teo, Yik Ying, Boehnke, Michael, Parra, Esteban J, Chambers, John C, Tai, E Shyong, McCarthy, Mark I, Morris, Andrew P, Mahajan, Anubha, Go, Min Jin, Zhang, Weihua, Below, Jennifer E, Gaulton, Kyle J, Ferreira, Teresa, Horikoshi, Momoko, Johnson, Andrew D, Ng, Maggie C Y, Prokopenko, Inga, Saleheen, Danish, Wang, Xu, Zeggini, Eleftheria, Abecasis, Goncalo R, Adair, Linda S, Almgren, Peter, Atalay, Mustafa, Aung, Tin, Baldassarre, Damiano, Balkau, Beverley, Bao, Yuqian, Barnett, Anthony H, Barroso, Ines, Basit, Abdul, Been, Latonya F, Beilby, John, Bell, Graeme I, Benediktsson, Rafn, Bergman, Richard N, Boehm, Bernhard O, Boerwinkle, Eric, Bonnycastle, Lori L, Burtt, Noel, Cai, Qiuyin, Campbell, Harry, Carey, Jason, Cauchi, Stephane, Caulfield, Mark, Chan, Juliana C N, Chang, Li-Ching, Chang, Tien-Jyun, Chang, Yi-Cheng, Charpentier, Guillaume, Chen, Chien-Hsiun, Chen, Han, Chen, Yuan-Tsong, Chia, Kee-Seng, Chidambaram, Manickam, Chines, Peter S, Cho, Nam H, Cho, Young Min, Chuang, Lee-Ming, Collins, Francis S, Cornelis, Marilyn C, Couper, David J, Crenshaw, Andrew T, van Dam, Rob M, Danesh, John, Das, Debashish, de Faire, Ulf, Dedoussis, George, Deloukas, Panos, Dimas, Antigone S, Dina, Christian, Doney, Alex S F, Donnelly, Peter J, Dorkhan, Mozhgan, van Duijn, Cornelia, Dupuis, Josee, Edkins, Sarah, Elliott, Paul, Emilsson, Valur, Erbel, Raimund, Eriksson, Johan G, Escobedo, Jorge, Esko, Tonu, Eury, Elodie, Florez, Jose C, Fontanillas, Pierre, Forouhi, Nita G, Forsen, Tom, Fox, Caroline, Fraser, Ross M, Frayling, Timothy M, Froguel, Philippe, Frossard, Philippe, Gao, Yutang, Gertow, Karl, Gieger, Christian, Gigante, Bruna, Grallert, Harald, Grant, George B, Groop, Leif C, Groves, Christopher J, Grundberg, Elin, Guiducci, Candace, Hamsten, Anders, Han, Bok-Ghee, Hara, Kazuo, Hassanali, Neelam, Hattersley, Andrew T, Hayward, Caroline, Hedman, Asa K, Herder, Christian, Hofman, Albert, Holmen, Oddgeir L, Hovingh, Kees, Hreidarsson, Astradur B, Hu, Cheng, Hu, Frank B, Hui, Jennie, Humphries, Steve E, Hunt, Sarah E, Hunter, David J, Hveem, Kristian, Hydrie, Zafar I, Ikegami, Hiroshi, Illig, Thomas, Ingelsson, Erik, Islam, Muhammed, Isomaa, Bo, Jackson, Anne U, Jafar, Tazeen, James, Alan, Jia, Weiping, Jockel, Karl-Heinz, Jonsson, Anna, Jowett, Jeremy B M, Kadowaki, Takashi, Kang, Hyun Min, Kanoni, Stavroula, Kao, Wen Hong L, Kathiresan, Sekar, Kato, Norihiro, Katulanda, Prasad, Keinanen-Kiukaanniemi, Sirkka M, Kelly, Ann M, Khan, Hassan, Khaw, Kay-Tee, Khor, Chiea-Chuen, Kim, Hyung-Lae, Kim, Sangsoo, Kim, Young Jin, Kinnunen, Leena, Klopp, Norman, Kong, Augustine, Korpi-Hyovalti, Eeva, Kowlessur, Sudhir, Kraft, Peter, Kravic, Jasmina, Kristensen, Malene M, Krithika, S, Kumar, Ashish, Kumate, Jesus, Kuusisto, Johanna, Kwak, Soo Heon, Laakso, Markku, Lagou, Vasiliki, Lakka, Timo A, Langenberg, Claudia, Langford, Cordelia, Lawrence, Robert, Leander, Karin, Lee, Jen-Mai, Lee, Nanette R, Li, Man, Li, Xinzhong, Li, Yun, Liang, Junbin, Liju, Samuel, Lim, Wei-Yen, Lind, Lars, Lindgren, Cecilia M, Lindholm, Eero, Liu, Ching-Ti, Liu, Jian Jun, Lobbens, Stephane, Long, Jirong, Loos, Ruth J F, Lu, Wei, Luan, Jian'an, Lyssenko, Valeriya, Ma, Ronald C W, Maeda, Shiro, Magi, Reedik, Mannisto, Satu, Matthews, David R, Meigs, James B, Melander, Olle, Metspalu, Andres, Meyer, Julia, Mirza, Ghazala, Mihailov, Evelin, Moebus, Susanne, Mohan, Viswanathan, Mohlke, Karen L, Morris, Andrew D, Muhleisen, Thomas W, Muller-Nurasyid, Martina, Musk, Bill, Nakamura, Jiro, Nakashima, Eitaro, Navarro, Pau, Ng, Peng-Keat, Nica, Alexandra C, Nilsson, Peter M, Njolstad, Inger, Nothen, Markus M, Ohnaka, Keizo, Ong, Twee Hee, Owen, Katharine R, Palmer, Colin N A, Pankow, James S, Park, Kyong Soo, Parkin, Melissa, Pechlivanis, Sonali, Pedersen, Nancy L, Peltonen, Leena, Perry, John R B, Peters, Annette, Pinidiyapathirage, Janani M, Platou, Carl G P, Potter, Simon, Price, Jackie F, Qi, Lu, Radha, Venkatesan, Rallidis, Loukianos, Rasheed, Asif, Rathmann, Wolfgang, Rauramaa, Rainer, Raychaudhuri, Soumya, Rayner, N William, Rees, Simon D, Rehnberg, Emil, Ripatti, Samuli, Robertson, Neil, Roden, Michael, Rossin, Elizabeth J, Rudan, Igor, Rybin, Denis, Saaristo, Timo E, Salomaa, Veikko, Saltevo, Juha, Samuel, Maria, Sanghera, Dharambir K, Saramies, Jouko, Scott, James, Scott, Laura J, Scott, Robert A, Segre, Ayellet V, Sehmi, Joban, Sennblad, Bengt, Shah, Nabi, Shah, Sonia, Shera, A Samad, Shu, Xiao Ou, Shuldiner, Alan R, Sigurðsson, Gunnar, Sijbrands, Eric, Silveira, Angela, Sim, Xueling, Sivapalaratnam, Suthesh, Small, Kerrin S, So, Wing Yee, Stancakova, Alena, Stefansson, Kari, Steinbach, Gerald, Steinthorsdottir, Valgerdur, Stirrups, Kathleen, Strawbridge, Rona J, Stringham, Heather M, Sun, Qi, Suo, Chen, Syvänen, Ann-Christine, Takayanagi, Ryoichi, Takeuchi, Fumihiko, Tay, Wan Ting, Teslovich, Tanya M, Thorand, Barbara, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tikkanen, Emmi, Trakalo, Joseph, Tremoli, Elena, Trip, Mieke D, Tsai, Fuu Jen, Tuomi, Tiinamaija, Tuomilehto, Jaakko, Uitterlinden, Andre G, Valladares-Salgado, Adan, Vedantam, Sailaja, Veglia, Fabrizio, Voight, Benjamin F, Wang, Congrong, Wareham, Nicholas J, Wennauer, Roman, Wickremasinghe, Ananda R, Wilsgaard, Tom, Wilson, James F, Wiltshire, Steven, Winckler, Wendy, Wong, Tien Yin, Wood, Andrew R, Wu, Jer-Yuarn, Wu, Ying, Yamamoto, Ken, Yamauchi, Toshimasa, Yang, Mingyu, Yengo, Loic, Yokota, Mitsuhiro, Young, Robin, Zabaneh, Delilah, Zhang, Fan, Zhang, Rong, Zheng, Wei, Zimmet, Paul Z, Altshuler, David, Bowden, Donald W, Cho, Yoon Shin, Cox, Nancy J, Cruz, Miguel, Hanis, Craig L, Kooner, Jaspal, Lee, Jong-Young, Seielstad, Mark, Teo, Yik Ying, Boehnke, Michael, Parra, Esteban J, Chambers, John C, Tai, E Shyong, McCarthy, Mark I, and Morris, Andrew P
- Abstract
To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry., Consortium, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM)Consortium, Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D)Consortium, South Asian Type 2 Diabetes (SAT2D)Consortium, Mexican American Type 2 Diabetes (MAT2D)Consortium, Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples (T2D-GENES)
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- 2014
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29. Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease
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Ganna, Andrea, Salihovic, Samira, Sundström, Johan, Broeckling, Corey D, Hedman, Asa K, Magnusson, Patrik K E, Pedersen, Nancy L, Larsson, Anders, Ärnlöv, Johan, Ingelsson, Erik, Ganna, Andrea, Salihovic, Samira, Sundström, Johan, Broeckling, Corey D, Hedman, Asa K, Magnusson, Patrik K E, Pedersen, Nancy L, Larsson, Anders, Ärnlöv, Johan, and Ingelsson, Erik
- Abstract
Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18∶1 (hazard ratio [HR] per standard deviation [SD] increment = 0.77, P-value<0.001), lysophosphatidylcholine 18∶2 (HR = 0.81, P-value<0.001), monoglyceride 18∶2 (MG 18∶2; HR = 1.18, P-value = 0.011) and sphingomyelin 28∶1 (HR = 0.85, P-value = 0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addition to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18∶2 was associated with CHD independently of triglycerides. Lysophosphatidylcholines were negatively associated with body mass index, C-reactive protein and with less evidence of subclinical cardiovascular disease in additional 970 participants; a reverse pattern was observed for MG 18∶2. MG 18∶2 showed an enrichment (P-value = 0.002) of significant associations with CHD-associated SNPs (P-value = 1.2×10-7 for association with rs964184 in the ZNF259/APOA5 region) and a weak, but positive causal effect (odds ratio = 1.05 per SD increment in MG 18∶2, P-value = 0.05) on CHD, as suggested by Mendelian randomization analysis. In conclusion, we identified four lipid-related metabolites with evidence for clinical utility, as well as a causal role in CHD development.
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- 2014
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30. Global Analysis of DNA Methylation Variation in Adipose Tissue from Twins Reveals Links to Disease-Associated Variants in Distal Regulatory Elements
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Grundberg, Elin, Meduri, Eshwar, Sandling, Johanna K., Hedman, Asa K., Keildson, Sarah, Buil, Alfonso, Busche, Stephan, Yuan, Wei, Nisbet, James, Sekowska, Magdalena, Wilk, Alicja, Barrett, Amy, Small, Kerrin S., Ge, Bing, Caron, Maxime, Shin, So-Youn, Lathrop, Mark, Dermitzakis, Emmanouil T., McCarthy, Mark I., Spector, Timothy D., Bell, Jordana T., Deloukas, Panos, Grundberg, Elin, Meduri, Eshwar, Sandling, Johanna K., Hedman, Asa K., Keildson, Sarah, Buil, Alfonso, Busche, Stephan, Yuan, Wei, Nisbet, James, Sekowska, Magdalena, Wilk, Alicja, Barrett, Amy, Small, Kerrin S., Ge, Bing, Caron, Maxime, Shin, So-Youn, Lathrop, Mark, Dermitzakis, Emmanouil T., McCarthy, Mark I., Spector, Timothy D., Bell, Jordana T., and Deloukas, Panos
- Abstract
Epigenetic modifications such as DNA methylation play a key role in gene regulation and disease susceptibility. However, little is known about the genome-wide frequency, localization, and function of methylation variation and how it is regulated by genetic and environmental factors. We utilized the Multiple Tissue Human Expression Resource (MuTHER) and generated Illumina 450K adipose methylome data from 648 twins. We found that individual CpGs had low variance and that variability was suppressed in promoters. We noted that DNA methylation variation was highly heritable (h(median)(2) = 0.34) and that shared environmental effects correlated with metabolic phenotype-associated CpGs. Analysis of methylation quantitative-trait loci (metQTL) revealed that 28% of CpGs were associated with nearby SNPs, and when overlapping them with adipose expression quantitative-trait loci (eQTL) from the same individuals, we found that 6% of the loci played a role in regulating both gene expression and DNA methylation. These associations were bidirectional, but there were pronounced negative associations for promoter CpGs. Integration of metQTL with adipose reference epigenomes and disease associations revealed significant enrichment of metQTL overlapping metabolic-trait or disease loci in enhancers (the strongest effects were for high-density lipoprotein cholesterol and body mass index [BMI]). We followed up with the BMI SNP rs713586, a cg01884057 metQTL that overlaps an enhancer upstream of ADCY3, and used bisulphite sequencing to refine this region. Our results showed widespread population invariability yet sequence dependence on adipose DNA methylation but that incorporating maps of regulatory elements aid in linking CpG variation to gene regulation and disease risk in a tissue-dependent manner.
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- 2013
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31. Transcriptional profiling of serogroup B Neisseria meningitidis growing in human blood : an approach to vaccine antigen discovery
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Hedman, Asa K, Li, Ming-Shi, Langford, Paul R, Kroll, J Simon, Hedman, Asa K, Li, Ming-Shi, Langford, Paul R, and Kroll, J Simon
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- 2012
32. Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population.
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Bell, Jordana T, Tsai, Pei-Chien, Yang, Tsun-Po, Pidsley, Ruth, Nisbet, James, Glass, Daniel, Mangino, Massimo, Zhai, Guangju, Zhang, Feng, Valdes, Ana, Shin, So-Youn, Dempster, Emma L, Murray, Robin M, Grundberg, Elin, Hedman, Asa K, Nica, Alexandra, Small, Kerrin S, Dermitzakis, Emmanouil T, McCarthy, Mark I, Mill, Jonathan, Spector, Tim D, Deloukas, Panos, Bell, Jordana T, Tsai, Pei-Chien, Yang, Tsun-Po, Pidsley, Ruth, Nisbet, James, Glass, Daniel, Mangino, Massimo, Zhai, Guangju, Zhang, Feng, Valdes, Ana, Shin, So-Youn, Dempster, Emma L, Murray, Robin M, Grundberg, Elin, Hedman, Asa K, Nica, Alexandra, Small, Kerrin S, Dermitzakis, Emmanouil T, McCarthy, Mark I, Mill, Jonathan, Spector, Tim D, and Deloukas, Panos
- Abstract
Age-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role of age-related epigenetic changes in healthy ageing and potential longevity, we tested for association between whole-blood DNA methylation patterns in 172 female twins aged 32 to 80 with age and age-related phenotypes. Twin-based DNA methylation levels at 26,690 CpG-sites showed evidence for mean genome-wide heritability of 18%, which was supported by the identification of 1,537 CpG-sites with methylation QTLs in cis at FDR 5%. We performed genome-wide analyses to discover differentially methylated regions (DMRs) for sixteen age-related phenotypes (ap-DMRs) and chronological age (a-DMRs). Epigenome-wide association scans (EWAS) identified age-related phenotype DMRs (ap-DMRs) associated with LDL (STAT5A), lung function (WT1), and maternal longevity (ARL4A, TBX20). In contrast, EWAS for chronological age identified hundreds of predominantly hyper-methylated age DMRs (490 a-DMRs at FDR 5%), of which only one (TBX20) was also associated with an age-related phenotype. Therefore, the majority of age-related changes in DNA methylation are not associated with phenotypic measures of healthy ageing in later life. We replicated a large proportion of a-DMRs in a sample of 44 younger adult MZ twins aged 20 to 61, suggesting that a-DMRs may initiate at an earlier age. We next explored potential genetic and environmental mechanisms underlying a-DMRs and ap-DMRs. Genome-wide overlap across cis-meQTLs, genotype-phenotype associations, and EWAS ap-DMRs identified CpG-sites that had cis-meQTLs with evidence for genotype-phenotype association, where the CpG-site was also an ap-DMR for the same phenotype. Monozygotic twin methylation difference analyses identified one potential environmentally-mediated ap-DMR associated with total cholesterol and LDL (CSMD1). Our results suggest that in a smal
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- 2012
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33. Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms.
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Zhai, Guangju, Teumer, Alexander, Stolk, Lisette, Perry, John R B, Vandenput, Liesbeth, Coviello, Andrea D, Koster, Annemarie, Bell, Jordana T, Bhasin, Shalender, Eriksson, Joel, Eriksson, Anna, Ernst, Florian, Ferrucci, Luigi, Frayling, Timothy M, Glass, Daniel, Grundberg, Elin, Haring, Robin, Hedman, Asa K, Hofman, Albert, Kiel, Douglas P, Kroemer, Heyo K, Liu, Yongmei, Lunetta, Kathryn L, Maggio, Marcello, Lorentzon, Mattias, Mangino, Massimo, Melzer, David, Miljkovic, Iva, Nica, Alexandra, Penninx, Brenda W J H, Vasan, Ramachandran S, Rivadeneira, Fernando, Small, Kerrin S, Soranzo, Nicole, Uitterlinden, André G, Völzke, Henry, Wilson, Scott G, Xi, Li, Zhuang, Wei Vivian, Harris, Tamara B, Murabito, Joanne M, Ohlsson, Claes, Murray, Anna, de Jong, Frank H, Spector, Tim D, Wallaschofski, Henri, Zhai, Guangju, Teumer, Alexander, Stolk, Lisette, Perry, John R B, Vandenput, Liesbeth, Coviello, Andrea D, Koster, Annemarie, Bell, Jordana T, Bhasin, Shalender, Eriksson, Joel, Eriksson, Anna, Ernst, Florian, Ferrucci, Luigi, Frayling, Timothy M, Glass, Daniel, Grundberg, Elin, Haring, Robin, Hedman, Asa K, Hofman, Albert, Kiel, Douglas P, Kroemer, Heyo K, Liu, Yongmei, Lunetta, Kathryn L, Maggio, Marcello, Lorentzon, Mattias, Mangino, Massimo, Melzer, David, Miljkovic, Iva, Nica, Alexandra, Penninx, Brenda W J H, Vasan, Ramachandran S, Rivadeneira, Fernando, Small, Kerrin S, Soranzo, Nicole, Uitterlinden, André G, Völzke, Henry, Wilson, Scott G, Xi, Li, Zhuang, Wei Vivian, Harris, Tamara B, Murabito, Joanne M, Ohlsson, Claes, Murray, Anna, de Jong, Frank H, Spector, Tim D, and Wallaschofski, Henri
- Abstract
Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands--yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15 × 10(-36)), SULT2A1 (rs2637125; p = 2.61 × 10(-19)), ARPC1A (rs740160; p = 1.56 × 10(-16)), TRIM4 (rs17277546; p = 4.50 × 10(-11)), BMF (rs7181230; p = 5.44 × 10(-11)), HHEX (rs2497306; p = 4.64 × 10(-9)), BCL2L11 (rs6738028; p = 1.72 × 10(-8)), and CYP2C9 (rs2185570; p = 2.29 × 10(-8)). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.
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- 2011
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34. The architecture of gene regulatory variation across multiple human tissues : the MuTHER study.
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Nica, Alexandra C, Parts, Leopold, Glass, Daniel, Nisbet, James, Barrett, Amy, Sekowska, Magdalena, Travers, Mary, Potter, Simon, Grundberg, Elin, Small, Kerrin, Hedman, Asa K, Bataille, Veronique, Tzenova Bell, Jordana, Surdulescu, Gabriela, Dimas, Antigone S, Ingle, Catherine, Nestle, Frank O, di Meglio, Paola, Min, Josine L, Wilk, Alicja, Hammond, Christopher J, Hassanali, Neelam, Yang, Tsun-Po, Montgomery, Stephen B, O'Rahilly, Steve, Lindgren, Cecilia M, Zondervan, Krina T, Soranzo, Nicole, Barroso, Inês, Durbin, Richard, Ahmadi, Kourosh, Deloukas, Panos, McCarthy, Mark I, Dermitzakis, Emmanouil T, Spector, Timothy D, Nica, Alexandra C, Parts, Leopold, Glass, Daniel, Nisbet, James, Barrett, Amy, Sekowska, Magdalena, Travers, Mary, Potter, Simon, Grundberg, Elin, Small, Kerrin, Hedman, Asa K, Bataille, Veronique, Tzenova Bell, Jordana, Surdulescu, Gabriela, Dimas, Antigone S, Ingle, Catherine, Nestle, Frank O, di Meglio, Paola, Min, Josine L, Wilk, Alicja, Hammond, Christopher J, Hassanali, Neelam, Yang, Tsun-Po, Montgomery, Stephen B, O'Rahilly, Steve, Lindgren, Cecilia M, Zondervan, Krina T, Soranzo, Nicole, Barroso, Inês, Durbin, Richard, Ahmadi, Kourosh, Deloukas, Panos, McCarthy, Mark I, Dermitzakis, Emmanouil T, and Spector, Timothy D
- Abstract
While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis--MCTA) permits immediate replication of eQTLs using co-twins (93%-98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%-20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits.
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- 2011
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35. Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci.
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Kooner, Jaspal S, Saleheen, Danish, Sim, Xueling, Sehmi, Joban, Zhang, Weihua, Frossard, Philippe, Been, Latonya F, Chia, Kee-Seng, Dimas, Antigone S, Hassanali, Neelam, Jafar, Tazeen, Jowett, Jeremy B M, Li, Xinzhong, Radha, Venkatesan, Rees, Simon D, Takeuchi, Fumihiko, Young, Robin, Aung, Tin, Basit, Abdul, Chidambaram, Manickam, Das, Debashish, Grundberg, Elin, Hedman, Asa K, Hydrie, Zafar I, Islam, Muhammed, Khor, Chiea-Chuen, Kowlessur, Sudhir, Kristensen, Malene M, Liju, Samuel, Lim, Wei-Yen, Matthews, David R, Liu, Jianjun, Morris, Andrew P, Nica, Alexandra C, Pinidiyapathirage, Janani M, Prokopenko, Inga, Rasheed, Asif, Samuel, Maria, Shah, Nabi, Shera, A Samad, Small, Kerrin S, Suo, Chen, Wickremasinghe, Ananda R, Wong, Tien Yin, Yang, Mingyu, Zhang, Fan, Abecasis, Goncalo R, Barnett, Anthony H, Caulfield, Mark, Deloukas, Panos, Frayling, Timothy M, Froguel, Philippe, Kato, Norihiro, Katulanda, Prasad, Kelly, M Ann, Liang, Junbin, Mohan, Viswanathan, Sanghera, Dharambir K, Scott, James, Seielstad, Mark, Zimmet, Paul Z, Elliott, Paul, Teo, Yik Ying, McCarthy, Mark I, Danesh, John, Tai, E Shyong, Chambers, John C, Kooner, Jaspal S, Saleheen, Danish, Sim, Xueling, Sehmi, Joban, Zhang, Weihua, Frossard, Philippe, Been, Latonya F, Chia, Kee-Seng, Dimas, Antigone S, Hassanali, Neelam, Jafar, Tazeen, Jowett, Jeremy B M, Li, Xinzhong, Radha, Venkatesan, Rees, Simon D, Takeuchi, Fumihiko, Young, Robin, Aung, Tin, Basit, Abdul, Chidambaram, Manickam, Das, Debashish, Grundberg, Elin, Hedman, Asa K, Hydrie, Zafar I, Islam, Muhammed, Khor, Chiea-Chuen, Kowlessur, Sudhir, Kristensen, Malene M, Liju, Samuel, Lim, Wei-Yen, Matthews, David R, Liu, Jianjun, Morris, Andrew P, Nica, Alexandra C, Pinidiyapathirage, Janani M, Prokopenko, Inga, Rasheed, Asif, Samuel, Maria, Shah, Nabi, Shera, A Samad, Small, Kerrin S, Suo, Chen, Wickremasinghe, Ananda R, Wong, Tien Yin, Yang, Mingyu, Zhang, Fan, Abecasis, Goncalo R, Barnett, Anthony H, Caulfield, Mark, Deloukas, Panos, Frayling, Timothy M, Froguel, Philippe, Kato, Norihiro, Katulanda, Prasad, Kelly, M Ann, Liang, Junbin, Mohan, Viswanathan, Sanghera, Dharambir K, Scott, James, Seielstad, Mark, Zimmet, Paul Z, Elliott, Paul, Teo, Yik Ying, McCarthy, Mark I, Danesh, John, Tai, E Shyong, and Chambers, John C
- Abstract
We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10(-8) to P = 1.9 × 10(-11)). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10(-4)), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D.
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- 2011
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36. Correction: Transcriptional Profiling of Serogroup B Neisseria meningitidis Growing in Human Blood: An Approach to Vaccine Antigen Discovery
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Hedman, Asa K., primary, Li, Ming-Shi, additional, Langford, Paul R., additional, and Kroll, J. Simon, additional
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- 2012
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37. Transcriptional Profiling of Serogroup B Neisseria meningitidis Growing in Human Blood: An Approach to Vaccine Antigen Discovery
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Hedman, Asa K., primary, Li, Ming-Shi, additional, Langford, Paul R., additional, and Kroll, J. Simon, additional
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- 2012
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38. Epigenetic Patterns in Blood Associated With Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results From Genome-Wide Association Studies
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Hedman, Åsa K., Mendelson, Michael M., Marioni, Riccardo E., Gustafsson, Stefan, Joehanes, Roby, Irvin, Marguerite R., Zhi, Degui, Sandling, Johanna K., Yao, Chen, Liu, Chunyu, Liang, Liming, Huan, Tianxiao, McRae, Allan F., Demissie, Serkalem, Shah, Sonia, Starr, John M., Cupples, L. Adrienne, Deloukas, Panos, Spector, Timothy D., Sundström, Johan, Krauss, Ronald M., Arnett, Donna K., Deary, Ian J., Lind, Lars, Levy, Daniel, and Ingelsson, Erik
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cardiovascular diseases ,DNA Methylation ,epigenomics ,gene expression ,lipids - Abstract
Background— Genome-wide association studies have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways, and biology may be gained through studies of epigenetic modifications. Methods and Results— To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine–guanine dinucleotides (CpGs) in whole blood from 2306 individuals from 2 population-based cohorts, with replication of findings in 2025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage (P<1.08E-07) and replicated 33 (at Bonferroni-corrected P<0.05), including 25 novel CpGs not previously associated with lipids. Genes at lipid-associated CpGs were enriched in lipid and amino acid metabolism processes. A differentially methylated locus associated with triglycerides and high-density lipoprotein cholesterol (HDL-C; cg27243685; P=8.1E-26 and 9.3E-19) was associated with cis-expression of a reverse cholesterol transporter (ABCG1; P=7.2E-28) and incident cardiovascular disease events (hazard ratio per SD increment, 1.38; 95% confidence interval, 1.15–1.66; P=0.0007). We found significant cis-methylation quantitative trait loci at 64% of the 193 CpGs with an enrichment of signals from genome-wide association studies of lipid levels (PTC=0.004, PHDL-C=0.008 and Ptriglycerides=0.00003) and coronary heart disease (P=0.0007). For example, genome-wide significant variants associated with low-density lipoprotein cholesterol and coronary heart disease at APOB were cis-methylation quantitative trait loci for a low-density lipoprotein cholesterol–related differentially methylated locus. Conclusions— We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous genome-wide association studies discoveries, and provide evidence implicating epigenetic regulation of reverse cholesterol transport in blood in relation to occurrence of cardiovascular disease events.
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- 2017
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39. Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach
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Mendelson, Michael M., Marioni, Riccardo E., Joehanes, Roby, Liu, Chunyu, Hedman, Åsa K., Aslibekyan, Stella, Demerath, Ellen W., Guan, Weihua, Zhi, Degui, Yao, Chen, Huan, Tianxiao, Willinger, Christine, Chen, Brian, Courchesne, Paul, Multhaup, Michael, Irvin, Marguerite R., Cohain, Ariella, Schadt, Eric E., Grove, Megan L., Bressler, Jan, North, Kari, Sundström, Johan, Gustafsson, Stefan, Shah, Sonia, McRae, Allan F., Harris, Sarah E., Gibson, Jude, Redmond, Paul, Corley, Janie, Murphy, Lee, Starr, John M., Kleinbrink, Erica, Lipovich, Leonard, Visscher, Peter M., Wray, Naomi R., Krauss, Ronald M., Fallin, Daniele, Feinberg, Andrew, Absher, Devin M., Fornage, Myriam, Pankow, James S., Lind, Lars, Fox, Caroline, Ingelsson, Erik, Arnett, Donna K., Boerwinkle, Eric, Liang, Liming, Levy, Daniel, and Deary, Ian J.
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Biology and life sciences ,Cell biology ,Chromosome biology ,Chromatin ,Chromatin modification ,DNA methylation ,Genetics ,Epigenetics ,Gene expression ,DNA ,DNA modification ,Biochemistry ,Nucleic acids ,Biology and Life Sciences ,Physiology ,Physiological Parameters ,Body Weight ,Body Mass Index ,Medicine and Health Sciences ,Gene Expression ,Anatomy ,Body Fluids ,Blood ,Hematology ,Obesity ,Genetic Loci ,DNA replication - Abstract
Background: The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. Methods and Findings: We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. Conclusions: We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases.
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- 2017
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40. Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population.
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Bell, Jordana T., Pei-Chien Tsai, Tsun-Po Yang, Pidsley, Ruth, Nisbet, James, Glass, Daniel, Mangino, Massimo, Guangju Zhai, Feng Zhang, Valdes, Ana, So-Youn Shin, Dempster, Emma L., Murray, Robin M., Grundberg, Elin, Hedman, Asa K., Nica, Alexandra, Small, Kerrin S., Dermitzakis, Emmanouil T., McCarthy, Mark I., and Mill, Jonathan
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DNA methylation ,GENOMICS ,DNA replication ,PHENOTYPES ,GENETICS of aging - Abstract
Age-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role of age-related epigenetic changes in healthy ageing and potential longevity, we tested for association between whole-blood DNA methylation patterns in 172 female twins aged 32 to 80 with age and age-related phenotypes. Twin-based DNA methylation levels at 26,690 CpG-sites showed evidence for mean genome-wide heritability of 18%, which was supported by the identification of 1,537 CpG-sites with methylation QTLs in cis at FDR 5%. We performed genome-wide analyses to discover differentially methylated regions (DMRs) for sixteen age-related phenotypes (ap-DMRs) and chronological age (a-DMRs). Epigenome-wide association scans (EWAS) identified age-related phenotype DMRs (ap-DMRs) associated with LDL (STAT5A), lung function (WT1), and maternal longevity (ARL4A, TBX20). In contrast, EWAS for chronological age identified hundreds of predominantly hyper-methylated age DMRs (490 a-DMRs at FDR 5%), of which only one (TBX20) was also associated with an age-related phenotype. Therefore, the majority of age-related changes in DNA methylation are not associated with phenotypic measures of healthy ageing in later life. We replicated a large proportion of a-DMRs in a sample of 44 younger adult MZ twins aged 20 to 61, suggesting that a-DMRs may initiate at an earlier age. We next explored potential genetic and environmental mechanisms underlying a-DMRs and ap-DMRs. Genome-wide overlap across cis-meQTLs, genotype-phenotype associations, and EWAS ap-DMRs identified CpG-sites that had cis-meQTLs with evidence for genotype-phenotype association, where the CpG-site was also an ap-DMR for the same phenotype. Monozygotic twin methylation difference analyses identified one potential environmentally-mediated ap-DMR associated with total cholesterol and LDL (CSMD1). Our results suggest that in a small set of genes DNA methylation may be a candidate mechanism of mediating not only environmental, but also genetic effects on age-related phenotypes. [ABSTRACT FROM AUTHOR]
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- 2012
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41. Eight Common Genetic Variants Associated with Serum DHEAS Levels Suggest a Key Role in Ageing Mechanisms.
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Guangju Zhai, Teumer, Alexander, Stolk, Lisette, Perry, John R. B., Vandenput, Liesbeth, Coviello, Andrea D., Koster, Annemarie, Bell, Jordana T., Bhasin, Shalender, Eriksson, Joel, Eriksson, Anna, Ernst, Florian, Ferrucci, Luigi, Frayling, Timothy M., Glass, Daniel, Grundberg, Elin, Haring, Robin, Hedman, Asa K., Hofman, Albert, and Kiel, Douglas P.
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DEHYDROEPIANDROSTERONE ,AGING ,LONGEVITY ,SERUM ,GENE expression ,ZINC-finger proteins ,META-analysis ,GENETICS education - Published
- 2011
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42. The Architecture of Gene Regulatory Variation across Multiple Human Tissues: The MuTHER Study.
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Nica, Alexandra C., Parts, Leopold, Glass, Daniel, Nisbet, James, Barrett, Amy, Sekowska, Magdalena, Travers, Mary, Potter, Simon, Grundberg, Elin, Small, Kerrin, Hedman, Asa K., Bataille, Veronique, Bell, Jordana Tzenova, Surdulescu, Gabriela, Dimas, Antigone S., Ingle, Catherine, Nestle, Frank O., di Meglio, Paola, Min, Josine L., and Wilk, Alicja
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GENETIC regulation ,TISSUES ,LYMPHOBLASTOID cell lines ,PHENOTYPES ,FACTOR analysis ,GENE expression ,LATENT variables - Published
- 2011
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43. New genetic loci link adipose and insulin biology to body fat distribution
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Shungin, Dmitry, Winkler, Thomas W, Croteau-Chonka, Damien C, Ferreira, Teresa, Locke, Adam E, Mägi, Reedik, Strawbridge, Rona J, Pers, Tune H, Fischer, Krista, Justice, Anne E, Workalemahu, Tsegaselassie, Wu, Joseph M.W., Buchkovich, Martin L, Heard-Costa, Nancy L, Roman, Tamara S, Drong, Alexander W, Song, Ci, Gustafsson, Stefan, Day, Felix R, Esko, Tonu, Fall, Tove, Kutalik, Zoltán, Luan, Jian’an, Randall, Joshua C, Scherag, André, Vedantam, Sailaja, Wood, Andrew R, Chen, Jin, Fehrmann, Rudolf, Karjalainen, Juha, Kahali, Bratati, Liu, Ching-Ti, Schmidt, Ellen M, Absher, Devin, Amin, Najaf, Anderson, Denise, Beekman, Marian, Bragg-Gresham, Jennifer L, Buyske, Steven, Demirkan, Ayse, Ehret, Georg B, Feitosa, Mary F, Goel, Anuj, Jackson, Anne U, Johnson, Toby, Kleber, Marcus E, Kristiansson, Kati, Mangino, Massimo, Leach, Irene Mateo, Medina-Gomez, Carolina, Palmer, Cameron D, Pasko, Dorota, Pechlivanis, Sonali, Peters, Marjolein J, Prokopenko, Inga, Stančáková, Alena, Sung, Yun Ju, Tanaka, Toshiko, Teumer, Alexander, Van Vliet-Ostaptchouk, Jana V, Yengo, Loïc, Zhang, Weihua, Albrecht, Eva, Ärnlöv, Johan, Arscott, Gillian M, Bandinelli, Stefania, Barrett, Amy, Bellis, Claire, Bennett, Amanda J, Berne, Christian, Blüher, Matthias, Böhringer, Stefan, Bonnet, Fabrice, Böttcher, Yvonne, Bruinenberg, Marcel, Carba, Delia B, Caspersen, Ida H, Clarke, Robert, Daw, E Warwick, Deelen, Joris, Deelman, Ewa, Delgado, Graciela, Doney, Alex SF, Eklund, Niina, Erdos, Michael R, Estrada, Karol, Eury, Elodie, Friedrich, Nele, Garcia, Melissa E, Giedraitis, Vilmantas, Gigante, Bruna, Go, Alan S, Golay, Alain, Grallert, Harald, Grammer, Tanja B, Gräßler, Jürgen, Grewal, Jagvir, Groves, Christopher J, Haller, Toomas, Hallmans, Goran, Hartman, Catharina A, Hassinen, Maija, Hayward, Caroline, Heikkilä, Kauko, Herzig, Karl-Heinz, Helmer, Quinta, Hillege, Hans L, Holmen, Oddgeir, Hunt, Steven C, Isaacs, Aaron, Ittermann, Till, James, Alan L, Johansson, Ingegerd, Juliusdottir, Thorhildur, Kalafati, Ioanna-Panagiota, Kinnunen, Leena, Koenig, Wolfgang, Kooner, Ishminder K, Kratzer, Wolfgang, Lamina, Claudia, Leander, Karin, Lee, Nanette R, Lichtner, Peter, Lind, Lars, Lindström, Jaana, Lobbens, Stéphane, Lorentzon, Mattias, Mach, François, Magnusson, Patrik KE, Mahajan, Anubha, McArdle, Wendy L, Menni, Cristina, Merger, Sigrun, Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Moayyeri, Alireza, Monda, Keri L, Mooijaart, Simon P, Mühleisen, Thomas W, Mulas, Antonella, Müller, Gabriele, Müller-Nurasyid, Martina, Nagaraja, Ramaiah, Nalls, Michael A, Narisu, Narisu, Glorioso, Nicola, Nolte, Ilja M, Olden, Matthias, Rayner, Nigel W, Renstrom, Frida, Ried, Janina S, Robertson, Neil R, Rose, Lynda M, Sanna, Serena, Scharnagl, Hubert, Scholtens, Salome, Sennblad, Bengt, Seufferlein, Thomas, Sitlani, Colleen M, Smith, Albert Vernon, Stirrups, Kathleen, Stringham, Heather M, Sundström, Johan, Swertz, Morris A, Swift, Amy J, Syvänen, Ann-Christine, Tayo, Bamidele O, Thorand, Barbara, Thorleifsson, Gudmar, Tomaschitz, Andreas, Troffa, Chiara, van Oort, Floor VA, Verweij, Niek, Vonk, Judith M, Waite, Lindsay L, Wennauer, Roman, Wilsgaard, Tom, Wojczynski, Mary K, Wong, Andrew, Zhang, Qunyuan, Zhao, Jing Hua, Brennan, Eoin P., Choi, Murim, Eriksson, Per, Folkersen, Lasse, Franco-Cereceda, Anders, Gharavi, Ali G, Hedman, Åsa K, Hivert, Marie-France, Huang, Jinyan, Kanoni, Stavroula, Karpe, Fredrik, Keildson, Sarah, Kiryluk, Krzysztof, Liang, Liming, Lifton, Richard P, Ma, Baoshan, McKnight, Amy J, McPherson, Ruth, Metspalu, Andres, Min, Josine L, Moffatt, Miriam F, Montgomery, Grant W, Murabito, Joanne M, Nicholson, George, Nyholt, Dale R, Olsson, Christian, Perry, John RB, Reinmaa, Eva, Salem, Rany M, Sandholm, Niina, Schadt, Eric E, Scott, Robert A, Stolk, Lisette, Vallejo, Edgar E., Westra, Harm-Jan, Zondervan, Krina T, Amouyel, Philippe, Arveiler, Dominique, Bakker, Stephan JL, Beilby, John, Bergman, Richard N, Blangero, John, Brown, Morris J, Burnier, Michel, Campbell, Harry, Chakravarti, Aravinda, Chines, Peter S, Claudi-Boehm, Simone, Collins, Francis S, Crawford, Dana C, Danesh, John, de Faire, Ulf, de Geus, Eco JC, Dörr, Marcus, Erbel, Raimund, Eriksson, Johan G, Farrall, Martin, Ferrannini, Ele, Ferrières, Jean, Forouhi, Nita G, Forrester, Terrence, Franco, Oscar H, Gansevoort, Ron T, Gieger, Christian, Gudnason, Vilmundur, Haiman, Christopher A, Harris, Tamara B, Hattersley, Andrew T, Heliövaara, Markku, Hicks, Andrew A, Hingorani, Aroon D, Hoffmann, Wolfgang, Hofman, Albert, Homuth, Georg, Humphries, Steve E, Hyppönen, Elina, Illig, Thomas, Jarvelin, Marjo-Riitta, Johansen, Berit, Jousilahti, Pekka, Jula, Antti M, Kaprio, Jaakko, Kee, Frank, Keinanen-Kiukaanniemi, Sirkka M, Kooner, Jaspal S, Kooperberg, Charles, Kovacs, Peter, Kraja, Aldi T, Kumari, Meena, Kuulasmaa, Kari, Kuusisto, Johanna, Lakka, Timo A, Langenberg, Claudia, Le Marchand, Loic, Lehtimäki, Terho, Lyssenko, Valeriya, Männistö, Satu, Marette, André, Matise, Tara C, McKenzie, Colin A, McKnight, Barbara, Musk, Arthur W, Möhlenkamp, Stefan, Morris, Andrew D, Nelis, Mari, Ohlsson, Claes, Oldehinkel, Albertine J, Ong, Ken K, Palmer, Lyle J, Penninx, Brenda W, Peters, Annette, Pramstaller, Peter P, Raitakari, Olli T, Rankinen, Tuomo, Rao, DC, Rice, Treva K, Ridker, Paul M, Ritchie, Marylyn D., Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J, Saramies, Jouko, Sarzynski, Mark A, Schwarz, Peter EH, Shuldiner, Alan R, Staessen, Jan A, Steinthorsdottir, Valgerdur, Stolk, Ronald P, Strauch, Konstantin, Tönjes, Anke, Tremblay, Angelo, Tremoli, Elena, Vohl, Marie-Claude, Völker, Uwe, Vollenweider, Peter, Wilson, James F, Witteman, Jacqueline C, Adair, Linda S, Bochud, Murielle, Boehm, Bernhard O, Bornstein, Stefan R, Bouchard, Claude, Cauchi, Stéphane, Caulfield, Mark J, Chambers, John C, Chasman, Daniel I, Cooper, Richard S, Dedoussis, George, Ferrucci, Luigi, Froguel, Philippe, Grabe, Hans-Jörgen, Hamsten, Anders, Hui, Jennie, Hveem, Kristian, Jöckel, Karl-Heinz, Kivimaki, Mika, Kuh, Diana, Laakso, Markku, Liu, Yongmei, März, Winfried, Munroe, Patricia B, Njølstad, Inger, Oostra, Ben A, Palmer, Colin NA, Pedersen, Nancy L, Perola, Markus, Pérusse, Louis, Peters, Ulrike, Power, Chris, Quertermous, Thomas, Rauramaa, Rainer, Rivadeneira, Fernando, Saaristo, Timo E, Saleheen, Danish, Sinisalo, Juha, Slagboom, P Eline, Snieder, Harold, Spector, Tim D, Stefansson, Kari, Stumvoll, Michael, Tuomilehto, Jaakko, Uitterlinden, André G, Uusitupa, Matti, van der Harst, Pim, Veronesi, Giovanni, Walker, Mark, Wareham, Nicholas J, Watkins, Hugh, Wichmann, H-Erich, Abecasis, Goncalo R, Assimes, Themistocles L, Berndt, Sonja I, Boehnke, Michael, Borecki, Ingrid B, Deloukas, Panos, Franke, Lude, Frayling, Timothy M, Groop, Leif C, Hunter, David J., Kaplan, Robert C, O’Connell, Jeffrey R, Qi, Lu, Schlessinger, David, Strachan, David P, Thorsteinsdottir, Unnur, van Duijn, Cornelia M, Willer, Cristen J, Visscher, Peter M, Yang, Jian, Hirschhorn, Joel N, Zillikens, M Carola, McCarthy, Mark I, Speliotes, Elizabeth K, North, Kari E, Fox, Caroline S, Barroso, Inês, Franks, Paul W, Ingelsson, Erik, Heid, Iris M, Loos, Ruth JF, Cupples, L Adrienne, Morris, Andrew P, Lindgren, Cecilia M, and Mohlke, Karen L
- Abstract
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10−8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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- 2014
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44. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI
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Couto Alves, Alexessander, De Silva, N Maneka G, Karhunen, Ville, Sovio, Ulla, Das, Shikta, Taal, H Rob, Warrington, Nicole M, Lewin, Alexandra M, Kaakinen, Marika, Cousminer, Diana L, Thiering, Elisabeth, Timpson, Nicholas J, Bond, Tom A, Lowry, Estelle, Brown, Christopher D, Estivill, Xavier, Lindi, Virpi, Bradfield, Jonathan P, Geller, Frank, Speed, Doug, Coin, Lachlan JM, Loh, Marie, Barton, Sheila J, Beilin, Lawrence J, Bisgaard, Hans, Bønnelykke, Klaus, Alili, Rohia, Hatoum, Ida J, Schramm, Katharina, Cartwright, Rufus, Charles, Marie-Aline, Salerno, Vincenzo, Clément, Karine, Claringbould, Annique AJ, Van Duijn, Cornelia M, Moltchanova, Elena, Eriksson, Johan G, Elks, Cathy, Feenstra, Bjarke, Flexeder, Claudia, Franks, Stephen, Frayling, Timothy M, Freathy, Rachel M, Elliott, Paul, Widén, Elisabeth, Hakonarson, Hakon, Hattersley, Andrew T, Rodriguez, Alina, Banterle, Marco, Heinrich, Joachim, Heude, Barbara, Holloway, John W, Hofman, Albert, Hyppönen, Elina, Inskip, Hazel, Kaplan, Lee M, Hedman, Asa K, Läärä, Esa, Prokisch, Holger, Grallert, Harald, Lakka, Timo A, Lawlor, Debbie A, Melbye, Mads, Ahluwalia, Tarunveer S, Marinelli, Marcella, Millwood, Iona Y, Palmer, Lyle J, Pennell, Craig E, Perry, John R, Ring, Susan M, Savolainen, Markku J, Rivadeneira, Fernando, Standl, Marie, Sunyer, Jordi, Tiesler, Carla MT, Uitterlinden, Andre G, Schierding, William, O’Sullivan, Justin M, Prokopenko, Inga, Herzig, Karl-Heinz, Smith, George Davey, O'Reilly, Paul, Felix, Janine F, Buxton, Jessica L, Blakemore, Alexandra IF, Ong, Ken K, Jaddoe, Vincent WV, Grant, Struan FA, Sebert, Sylvain, McCarthy, Mark I, and Järvelin, Marjo-Riitta
- Subjects
2. Zero hunger ,Adult ,Male ,Pharmacogenomic Variants ,Quantitative Trait Loci ,Intracellular Signaling Peptides and Proteins ,Infant ,Genomics ,Polymorphism, Single Nucleotide ,Body Mass Index ,Quantitative Trait, Heritable ,Humans ,Receptors, Leptin ,Female ,Genetic Predisposition to Disease ,Longitudinal Studies ,Growth Charts ,Child ,Genetic Association Studies ,Adaptor Proteins, Signal Transducing ,Genome-Wide Association Study - Abstract
Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.
45. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.
- Author
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Couto Alves A, De Silva NMG, Karhunen V, Sovio U, Das S, Taal HR, Warrington NM, Lewin AM, Kaakinen M, Cousminer DL, Thiering E, Timpson NJ, Bond TA, Lowry E, Brown CD, Estivill X, Lindi V, Bradfield JP, Geller F, Speed D, Coin LJM, Loh M, Barton SJ, Beilin LJ, Bisgaard H, Bønnelykke K, Alili R, Hatoum IJ, Schramm K, Cartwright R, Charles MA, Salerno V, Clément K, Claringbould AAJ, van Duijn CM, Moltchanova E, Eriksson JG, Elks C, Feenstra B, Flexeder C, Franks S, Frayling TM, Freathy RM, Elliott P, Widén E, Hakonarson H, Hattersley AT, Rodriguez A, Banterle M, Heinrich J, Heude B, Holloway JW, Hofman A, Hyppönen E, Inskip H, Kaplan LM, Hedman AK, Läärä E, Prokisch H, Grallert H, Lakka TA, Lawlor DA, Melbye M, Ahluwalia TS, Marinelli M, Millwood IY, Palmer LJ, Pennell CE, Perry JR, Ring SM, Savolainen MJ, Rivadeneira F, Standl M, Sunyer J, Tiesler CMT, Uitterlinden AG, Schierding W, O'Sullivan JM, Prokopenko I, Herzig KH, Smith GD, O'Reilly P, Felix JF, Buxton JL, Blakemore AIF, Ong KK, Jaddoe VWV, Grant SFA, Sebert S, McCarthy MI, and Järvelin MR
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adult, Child, Female, Genetic Predisposition to Disease, Genomics, Growth Charts, Humans, Infant, Intracellular Signaling Peptides and Proteins, Longitudinal Studies, Male, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Receptors, Leptin genetics, Body Mass Index, Genetic Association Studies, Genome-Wide Association Study, Quantitative Trait Loci, Quantitative Trait, Heritable
- Abstract
Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)
- Published
- 2019
- Full Text
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46. Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease.
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Ganna A, Salihovic S, Sundström J, Broeckling CD, Hedman AK, Magnusson PK, Pedersen NL, Larsson A, Siegbahn A, Zilmer M, Prenni J, Arnlöv J, Lind L, Fall T, and Ingelsson E
- Subjects
- Aged, C-Reactive Protein metabolism, Coronary Disease genetics, Female, Follow-Up Studies, Gene Expression Profiling, Genetic Association Studies, Humans, Incidence, Linear Models, Longitudinal Studies, Lysophosphatidylcholines blood, Male, Metabolomics, Middle Aged, Monoglycerides blood, Polymorphism, Single Nucleotide, Prospective Studies, Reproducibility of Results, Risk Assessment, Risk Factors, Sphingomyelins blood, Sweden, Biomarkers blood, Coronary Disease blood, Coronary Disease epidemiology
- Abstract
Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18∶1 (hazard ratio [HR] per standard deviation [SD] increment = 0.77, P-value<0.001), lysophosphatidylcholine 18∶2 (HR = 0.81, P-value<0.001), monoglyceride 18∶2 (MG 18∶2; HR = 1.18, P-value = 0.011) and sphingomyelin 28∶1 (HR = 0.85, P-value = 0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addition to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18∶2 was associated with CHD independently of triglycerides. Lysophosphatidylcholines were negatively associated with body mass index, C-reactive protein and with less evidence of subclinical cardiovascular disease in additional 970 participants; a reverse pattern was observed for MG 18∶2. MG 18∶2 showed an enrichment (P-value = 0.002) of significant associations with CHD-associated SNPs (P-value = 1.2×10-7 for association with rs964184 in the ZNF259/APOA5 region) and a weak, but positive causal effect (odds ratio = 1.05 per SD increment in MG 18∶2, P-value = 0.05) on CHD, as suggested by Mendelian randomization analysis. In conclusion, we identified four lipid-related metabolites with evidence for clinical utility, as well as a causal role in CHD development.
- Published
- 2014
- Full Text
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47. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.
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Mahajan A, Go MJ, Zhang W, Below JE, Gaulton KJ, Ferreira T, Horikoshi M, Johnson AD, Ng MC, Prokopenko I, Saleheen D, Wang X, Zeggini E, Abecasis GR, Adair LS, Almgren P, Atalay M, Aung T, Baldassarre D, Balkau B, Bao Y, Barnett AH, Barroso I, Basit A, Been LF, Beilby J, Bell GI, Benediktsson R, Bergman RN, Boehm BO, Boerwinkle E, Bonnycastle LL, Burtt N, Cai Q, Campbell H, Carey J, Cauchi S, Caulfield M, Chan JC, Chang LC, Chang TJ, Chang YC, Charpentier G, Chen CH, Chen H, Chen YT, Chia KS, Chidambaram M, Chines PS, Cho NH, Cho YM, Chuang LM, Collins FS, Cornelis MC, Couper DJ, Crenshaw AT, van Dam RM, Danesh J, Das D, de Faire U, Dedoussis G, Deloukas P, Dimas AS, Dina C, Doney AS, Donnelly PJ, Dorkhan M, van Duijn C, Dupuis J, Edkins S, Elliott P, Emilsson V, Erbel R, Eriksson JG, Escobedo J, Esko T, Eury E, Florez JC, Fontanillas P, Forouhi NG, Forsen T, Fox C, Fraser RM, Frayling TM, Froguel P, Frossard P, Gao Y, Gertow K, Gieger C, Gigante B, Grallert H, Grant GB, Grrop LC, Groves CJ, Grundberg E, Guiducci C, Hamsten A, Han BG, Hara K, Hassanali N, Hattersley AT, Hayward C, Hedman AK, Herder C, Hofman A, Holmen OL, Hovingh K, Hreidarsson AB, Hu C, Hu FB, Hui J, Humphries SE, Hunt SE, Hunter DJ, Hveem K, Hydrie ZI, Ikegami H, Illig T, Ingelsson E, Islam M, Isomaa B, Jackson AU, Jafar T, James A, Jia W, Jöckel KH, Jonsson A, Jowett JB, Kadowaki T, Kang HM, Kanoni S, Kao WH, Kathiresan S, Kato N, Katulanda P, Keinanen-Kiukaanniemi KM, Kelly AM, Khan H, Khaw KT, Khor CC, Kim HL, Kim S, Kim YJ, Kinnunen L, Klopp N, Kong A, Korpi-Hyövälti E, Kowlessur S, Kraft P, Kravic J, Kristensen MM, Krithika S, Kumar A, Kumate J, Kuusisto J, Kwak SH, Laakso M, Lagou V, Lakka TA, Langenberg C, Langford C, Lawrence R, Leander K, Lee JM, Lee NR, Li M, Li X, Li Y, Liang J, Liju S, Lim WY, Lind L, Lindgren CM, Lindholm E, Liu CT, Liu JJ, Lobbens S, Long J, Loos RJ, Lu W, Luan J, Lyssenko V, Ma RC, Maeda S, Mägi R, Männisto S, Matthews DR, Meigs JB, Melander O, Metspalu A, Meyer J, Mirza G, Mihailov E, Moebus S, Mohan V, Mohlke KL, Morris AD, Mühleisen TW, Müller-Nurasyid M, Musk B, Nakamura J, Nakashima E, Navarro P, Ng PK, Nica AC, Nilsson PM, Njølstad I, Nöthen MM, Ohnaka K, Ong TH, Owen KR, Palmer CN, Pankow JS, Park KS, Parkin M, Pechlivanis S, Pedersen NL, Peltonen L, Perry JR, Peters A, Pinidiyapathirage JM, Platou CG, Potter S, Price JF, Qi L, Radha V, Rallidis L, Rasheed A, Rathman W, Rauramaa R, Raychaudhuri S, Rayner NW, Rees SD, Rehnberg E, Ripatti S, Robertson N, Roden M, Rossin EJ, Rudan I, Rybin D, Saaristo TE, Salomaa V, Saltevo J, Samuel M, Sanghera DK, Saramies J, Scott J, Scott LJ, Scott RA, Segrè AV, Sehmi J, Sennblad B, Shah N, Shah S, Shera AS, Shu XO, Shuldiner AR, Sigurđsson G, Sijbrands E, Silveira A, Sim X, Sivapalaratnam S, Small KS, So WY, Stančáková A, Stefansson K, Steinbach G, Steinthorsdottir V, Stirrups K, Strawbridge RJ, Stringham HM, Sun Q, Suo C, Syvänen AC, Takayanagi R, Takeuchi F, Tay WT, Teslovich TM, Thorand B, Thorleifsson G, Thorsteinsdottir U, Tikkanen E, Trakalo J, Tremoli E, Trip MD, Tsai FJ, Tuomi T, Tuomilehto J, Uitterlinden AG, Valladares-Salgado A, Vedantam S, Veglia F, Voight BF, Wang C, Wareham NJ, Wennauer R, Wickremasinghe AR, Wilsgaard T, Wilson JF, Wiltshire S, Winckler W, Wong TY, Wood AR, Wu JY, Wu Y, Yamamoto K, Yamauchi T, Yang M, Yengo L, Yokota M, Young R, Zabaneh D, Zhang F, Zhang R, Zheng W, Zimmet PZ, Altshuler D, Bowden DW, Cho YS, Cox NJ, Cruz M, Hanis CL, Kooner J, Lee JY, Seielstad M, Teo YY, Boehnke M, Parra EJ, Chambers JC, Tai ES, McCarthy MI, and Morris AP
- Subjects
- Alleles, Asian People genetics, Case-Control Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Hispanic or Latino genetics, Humans, Polymorphism, Single Nucleotide, Risk Factors, White People genetics, Diabetes Mellitus, Type 2 genetics
- Abstract
To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.
- Published
- 2014
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48. Gene expression changes with age in skin, adipose tissue, blood and brain.
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Glass D, Viñuela A, Davies MN, Ramasamy A, Parts L, Knowles D, Brown AA, Hedman AK, Small KS, Buil A, Grundberg E, Nica AC, Di Meglio P, Nestle FO, Ryten M, Durbin R, McCarthy MI, Deloukas P, Dermitzakis ET, Weale ME, Bataille V, and Spector TD
- Subjects
- Adult, Age Distribution, Aged, Aged, 80 and over, Cell Line, Databases, Genetic, Female, Genome-Wide Association Study, Genotype, Humans, Middle Aged, Polymorphism, Single Nucleotide genetics, Quantitative Trait Loci genetics, Transcription, Genetic, Adipose Tissue metabolism, Aging blood, Aging genetics, Brain metabolism, Gene Expression Regulation, Developmental, Skin metabolism
- Abstract
Background: Previous studies have demonstrated that gene expression levels change with age. These changes are hypothesized to influence the aging rate of an individual. We analyzed gene expression changes with age in abdominal skin, subcutaneous adipose tissue and lymphoblastoid cell lines in 856 female twins in the age range of 39-85 years. Additionally, we investigated genotypic variants involved in genotype-by-age interactions to understand how the genomic regulation of gene expression alters with age., Results: Using a linear mixed model, differential expression with age was identified in 1,672 genes in skin and 188 genes in adipose tissue. Only two genes expressed in lymphoblastoid cell lines showed significant changes with age. Genes significantly regulated by age were compared with expression profiles in 10 brain regions from 100 postmortem brains aged 16 to 83 years. We identified only one age-related gene common to the three tissues. There were 12 genes that showed differential expression with age in both skin and brain tissue and three common to adipose and brain tissues., Conclusions: Skin showed the most age-related gene expression changes of all the tissues investigated, with many of the genes being previously implicated in fatty acid metabolism, mitochondrial activity, cancer and splicing. A significant proportion of age-related changes in gene expression appear to be tissue-specific with only a few genes sharing an age effect in expression across tissues. More research is needed to improve our understanding of the genetic influences on aging and the relationship with age-related diseases.
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- 2013
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49. The presence of methylation quantitative trait loci indicates a direct genetic influence on the level of DNA methylation in adipose tissue.
- Author
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Drong AW, Nicholson G, Hedman AK, Meduri E, Grundberg E, Small KS, Shin SY, Bell JT, Karpe F, Soranzo N, Spector TD, McCarthy MI, Deloukas P, Rantalainen M, and Lindgren CM
- Subjects
- Adult, Aged, Cohort Studies, CpG Islands, Female, Gene Frequency, Genome-Wide Association Study, Genotype, Humans, Male, Metabolic Syndrome genetics, Middle Aged, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, RNA, Messenger genetics, RNA, Messenger metabolism, Transcriptome, DNA Methylation, Quantitative Trait Loci, Subcutaneous Fat, Abdominal metabolism
- Abstract
Genetic variants that associate with DNA methylation at CpG sites (methylation quantitative trait loci, meQTLs) offer a potential biological mechanism of action for disease associated SNPs. We investigated whether meQTLs exist in abdominal subcutaneous adipose tissue (SAT) and if CpG methylation associates with metabolic syndrome (MetSyn) phenotypes. We profiled 27,718 genomic regions in abdominal SAT samples of 38 unrelated individuals using differential methylation hybridization (DMH) together with genotypes at 5,227,243 SNPs and expression of 17,209 mRNA transcripts. Validation and replication of significant meQTLs was pursued in an independent cohort of 181 female twins. We find that, at 5% false discovery rate, methylation levels of 149 DMH regions associate with at least one SNP in a ±500 kilobase cis-region in our primary study. We sought to validate 19 of these in the replication study and find that five of these significantly associate with the corresponding meQTL SNPs from the primary study. We find that none of the 149 meQTL top SNPs is a significant expression quantitative trait locus in our expression data, but we observed association between expression levels of two mRNA transcripts and cis-methylation status. Our results indicate that DNA CpG methylation in abdominal SAT is partly under genetic control. This study provides a starting point for future investigations of DNA methylation in adipose tissue.
- Published
- 2013
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50. Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci.
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Kooner JS, Saleheen D, Sim X, Sehmi J, Zhang W, Frossard P, Been LF, Chia KS, Dimas AS, Hassanali N, Jafar T, Jowett JB, Li X, Radha V, Rees SD, Takeuchi F, Young R, Aung T, Basit A, Chidambaram M, Das D, Grundberg E, Hedman AK, Hydrie ZI, Islam M, Khor CC, Kowlessur S, Kristensen MM, Liju S, Lim WY, Matthews DR, Liu J, Morris AP, Nica AC, Pinidiyapathirage JM, Prokopenko I, Rasheed A, Samuel M, Shah N, Shera AS, Small KS, Suo C, Wickremasinghe AR, Wong TY, Yang M, Zhang F, Abecasis GR, Barnett AH, Caulfield M, Deloukas P, Frayling TM, Froguel P, Kato N, Katulanda P, Kelly MA, Liang J, Mohan V, Sanghera DK, Scott J, Seielstad M, Zimmet PZ, Elliott P, Teo YY, McCarthy MI, Danesh J, Tai ES, and Chambers JC
- Subjects
- Asian People genetics, Case-Control Studies, Female, Gene Expression Regulation, Genetics, Population, Genome, Human, Humans, Linkage Disequilibrium, London, Male, Pakistan, Polymorphism, Single Nucleotide, Singapore, Diabetes Mellitus, Type 2 genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Quantitative Trait Loci
- Abstract
We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10(-8) to P = 1.9 × 10(-11)). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10(-4)), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D.
- Published
- 2011
- Full Text
- View/download PDF
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