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  • 1
    Publication Date: 2015-09-15
    Description: The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF 〈/= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755714/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755714/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Hou-Feng -- Forgetta, Vincenzo -- Hsu, Yi-Hsiang -- Estrada, Karol -- Rosello-Diez, Alberto -- Leo, Paul J -- Dahia, Chitra L -- Park-Min, Kyung Hyun -- Tobias, Jonathan H -- Kooperberg, Charles -- Kleinman, Aaron -- Styrkarsdottir, Unnur -- Liu, Ching-Ti -- Uggla, Charlotta -- Evans, Daniel S -- Nielson, Carrie M -- Walter, Klaudia -- Pettersson-Kymmer, Ulrika -- McCarthy, Shane -- Eriksson, Joel -- Kwan, Tony -- Jhamai, Mila -- Trajanoska, Katerina -- Memari, Yasin -- Min, Josine -- Huang, Jie -- Danecek, Petr -- Wilmot, Beth -- Li, Rui -- Chou, Wen-Chi -- Mokry, Lauren E -- Moayyeri, Alireza -- Claussnitzer, Melina -- Cheng, Chia-Ho -- Cheung, Warren -- Medina-Gomez, Carolina -- Ge, Bing -- Chen, Shu-Huang -- Choi, Kwangbom -- Oei, Ling -- Fraser, James -- Kraaij, Robert -- Hibbs, Matthew A -- Gregson, Celia L -- Paquette, Denis -- Hofman, Albert -- Wibom, Carl -- Tranah, Gregory J -- Marshall, Mhairi -- Gardiner, Brooke B -- Cremin, Katie -- Auer, Paul -- Hsu, Li -- Ring, Sue -- Tung, Joyce Y -- Thorleifsson, Gudmar -- Enneman, Anke W -- van Schoor, Natasja M -- de Groot, Lisette C P G M -- van der Velde, Nathalie -- Melin, Beatrice -- Kemp, John P -- Christiansen, Claus -- Sayers, Adrian -- Zhou, Yanhua -- Calderari, Sophie -- van Rooij, Jeroen -- Carlson, Chris -- Peters, Ulrike -- Berlivet, Soizik -- Dostie, Josee -- Uitterlinden, Andre G -- Williams, Stephen R -- Farber, Charles -- Grinberg, Daniel -- LaCroix, Andrea Z -- Haessler, Jeff -- Chasman, Daniel I -- Giulianini, Franco -- Rose, Lynda M -- Ridker, Paul M -- Eisman, John A -- Nguyen, Tuan V -- Center, Jacqueline R -- Nogues, Xavier -- Garcia-Giralt, Natalia -- Launer, Lenore L -- Gudnason, Vilmunder -- Mellstrom, Dan -- Vandenput, Liesbeth -- Amin, Najaf -- van Duijn, Cornelia M -- Karlsson, Magnus K -- Ljunggren, Osten -- Svensson, Olle -- Hallmans, Goran -- Rousseau, Francois -- Giroux, Sylvie -- Bussiere, Johanne -- Arp, Pascal P -- Koromani, Fjorda -- Prince, Richard L -- Lewis, Joshua R -- Langdahl, Bente L -- Hermann, A Pernille -- Jensen, Jens-Erik B -- Kaptoge, Stephen -- Khaw, Kay-Tee -- Reeve, Jonathan -- Formosa, Melissa M -- Xuereb-Anastasi, Angela -- Akesson, Kristina -- McGuigan, Fiona E -- Garg, Gaurav -- Olmos, Jose M -- Zarrabeitia, Maria T -- Riancho, Jose A -- Ralston, Stuart H -- Alonso, Nerea -- Jiang, Xi -- Goltzman, David -- Pastinen, Tomi -- Grundberg, Elin -- Gauguier, Dominique -- Orwoll, Eric S -- Karasik, David -- Davey-Smith, George -- AOGC Consortium -- Smith, Albert V -- Siggeirsdottir, Kristin -- Harris, Tamara B -- Zillikens, M Carola -- van Meurs, Joyce B J -- Thorsteinsdottir, Unnur -- Maurano, Matthew T -- Timpson, Nicholas J -- Soranzo, Nicole -- Durbin, Richard -- Wilson, Scott G -- Ntzani, Evangelia E -- Brown, Matthew A -- Stefansson, Kari -- Hinds, David A -- Spector, Tim -- Cupples, L Adrienne -- Ohlsson, Claes -- Greenwood, Celia M T -- UK10K Consortium -- Jackson, Rebecca D -- Rowe, David W -- Loomis, Cynthia A -- Evans, David M -- Ackert-Bicknell, Cheryl L -- Joyner, Alexandra L -- Duncan, Emma L -- Kiel, Douglas P -- Rivadeneira, Fernando -- Richards, J Brent -- G1000143/Medical Research Council/United Kingdom -- K01 AR062655/AR/NIAMS NIH HHS/ -- MC_UU_12013/3/Medical Research Council/United Kingdom -- R01 AG005394/AG/NIA NIH HHS/ -- R01 AG005407/AG/NIA NIH HHS/ -- R01 AG027574/AG/NIA NIH HHS/ -- R01 AG027576/AG/NIA NIH HHS/ -- R01 AR035582/AR/NIAMS NIH HHS/ -- R01 AR035583/AR/NIAMS NIH HHS/ -- RC2 AR058973/AR/NIAMS NIH HHS/ -- U01 AG018197/AG/NIA NIH HHS/ -- U01 AG042140/AG/NIA NIH HHS/ -- U01 AG042143/AG/NIA NIH HHS/ -- U01 AR045580/AR/NIAMS NIH HHS/ -- U01 AR045583/AR/NIAMS NIH HHS/ -- U01 AR045614/AR/NIAMS NIH HHS/ -- U01 AR045632/AR/NIAMS NIH HHS/ -- U01 AR045647/AR/NIAMS NIH HHS/ -- U01 AR045654/AR/NIAMS NIH HHS/ -- U01 AR066160/AR/NIAMS NIH HHS/ -- England -- Nature. 2015 Oct 1;526(7571):112-7. doi: 10.1038/nature14878. Epub 2015 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal H3A 1A2, Canada. ; Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal H3T 1E2, Canada. ; Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts 02131, USA. ; Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Broad Institute of MIT and Harvard, Boston, Massachusetts 02115, USA. ; Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands. ; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Developmental Biology Program, Sloan Kettering Institute, New York, New York 10065, USA. ; The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane 4102, Australia. ; Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10065, USA. ; Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, New York 10021, USA. ; Rheumatology Divison, Hospital for Special Surgery New York, New York 10021, USA. ; School of Clinical Science, University of Bristol, Bristol BS10 5NB, UK. ; MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK. ; Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; Department of Research, 23andMe, Mountain View, California 94041, USA. ; Department of Population Genomics, deCODE Genetics, Reykjavik IS-101, Iceland. ; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA. ; Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden. ; California Pacific Medical Center Research Institute, San Francisco, California 94158, USA. ; Department of Public Health and Preventive Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Bone &Mineral Unit, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK. ; Departments of Pharmacology and Clinical Neurosciences, Umea University, Umea S-901 87, Sweden. ; Department of Public Health and Clinical Medicine, Umea University, Umea SE-901 87, Sweden. ; Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden. ; McGill University and Genome Quebec Innovation Centre, Montreal H3A 0G1, Canada. ; Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands. ; Oregon Clinical and Translational Research Institute, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Department of Medical and Clinical Informatics, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Farr Institute of Health Informatics Research, University College London, London NW1 2DA, UK. ; Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK. ; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA. ; Department of Human Genetics, McGill University, Montreal H3A 1B1, Canada. ; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden 2300RC, The Netherlands. ; Center for Musculoskeletal Research, University of Rochester, Rochester, New York 14642, USA. ; Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montreal H3G 1Y6, Canada. ; Department of Computer Science, Trinity University, San Antonio, Texas 78212, USA. ; Musculoskeletal Research Unit, University of Bristol, Bristol BS10 5NB, UK. ; Department of Radiation Sciences, Umea University, Umea S-901 87, Sweden. ; School of Public Health, University of Wisconsin, Milwaukee, Wisconsin 53726, USA. ; School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK. ; Department of Statistics, deCODE Genetics, Reykjavik IS-101, Iceland. ; Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam 1007 MB, The Netherlands. ; Department of Human Nutrition, Wageningen University, Wageningen 6700 EV, The Netherlands. ; Department of Internal Medicine, Section Geriatrics, Academic Medical Center, Amsterdam 1105, The Netherlands. ; Nordic Bioscience, Herlev 2730, Denmark. ; Cordeliers Research Centre, INSERM UMRS 1138, Paris 75006, France. ; Institute of Cardiometabolism and Nutrition, University Pierre &Marie Curie, Paris 75013, France. ; Departments of Medicine (Cardiovascular Medicine), Centre for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA. ; Department of Genetics, University of Barcelona, Barcelona 08028, Spain. ; U-720, Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona 28029, Spain. ; Department of Human Molecular Genetics, The Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain. ; Women's Health Center of Excellence Family Medicine and Public Health, University of California - San Diego, San Diego, California 92093, USA. ; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. ; Osteoporosis &Bone Biology Program, Garvan Institute of Medical Research, Sydney 2010, Australia. ; School of Medicine Sydney, University of Notre Dame Australia, Sydney 6959, Australia. ; St. Vincent's Hospital &Clinical School, NSW University, Sydney 2010, Australia. ; Musculoskeletal Research Group, Institut Hospital del Mar d'Investigacions Mediques, Barcelona 08003, Spain. ; Cooperative Research Network on Aging and Fragility (RETICEF), Institute of Health Carlos III, 28029, Spain. ; Department of Internal Medicine, Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona 08193, Spain. ; Neuroepidemiology Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Icelandic Heart Association, Kopavogur IS-201, Iceland. ; Faculty of Medicine, University of Iceland, Reykjavik IS-101, Iceland. ; Genetic epidemiology unit, Department of Epidemiology, Erasmus MC, Rotterdam 3000CA, The Netherlands. ; Department of Orthopaedics, Skane University Hospital Malmo 205 02, Sweden. ; Department of Medical Sciences, University of Uppsala, Uppsala 751 85, Sweden. ; Department of Surgical and Perioperative Sciences, Umea Unviersity, Umea 901 85, Sweden. ; Department of Molecular Biology, Medical Biochemistry and Pathology, Universite Laval, Quebec City G1V 0A6, Canada. ; Axe Sante des Populations et Pratiques Optimales en Sante, Centre de recherche du CHU de Quebec, Quebec City G1V 4G2, Canada. ; Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands 6009, Australia. ; Department of Medicine, University of Western Australia, Perth 6009, Australia. ; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C 8000, Denmark. ; Department of Endocrinology, Odense University Hospital, Odense C 5000, Denmark. ; Department of Endocrinology, Hvidovre University Hospital, Hvidovre 2650, Denmark. ; Clinical Gerontology Unit, University of Cambridge, Cambridge CB2 2QQ, UK. ; Medicine and Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK. ; Institute of Musculoskeletal Sciences, The Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK. ; Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida MSD 2080, Malta. ; Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences Malmo, Lund University, 205 02, Sweden. ; Department of Medicine and Psychiatry, University of Cantabria, Santander 39011, Spain. ; Department of Internal Medicine, Hospital U.M. Valdecilla- IDIVAL, Santander 39008, Spain. ; Department of Legal Medicine, University of Cantabria, Santander 39011, Spain. ; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK. ; Department of Reconstructive Sciences, College of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030, USA. ; Department of Medicine and Physiology, McGill University, Montreal H4A 3J1, Canada. ; Department of Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 13010, Israel. ; Laboratory of Epidemiology, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. ; School of Medicine and Pharmacology, University of Western Australia, Crawley 6009, Australia. ; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece. ; Department of Health Services, Policy and Practice, Brown University School of Public Health, Providence, Rhode Island 02903, USA. ; deCODE Genetics, Reykjavik IS-101, Iceland. ; Framingham Heart Study, Framingham, Massachusetts 01702, USA. ; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal H3A 1A2, Canada. ; Department of Oncology, Gerald Bronfman Centre, McGill University, Montreal H2W 1S6, Canada. ; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, Ohio 43210, USA. ; The Ronald O. Perelman Department of Dermatology and Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA. ; Department of Diabetes and Endocrinology, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26367794" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Density/*genetics ; Bone and Bones/metabolism ; Disease Models, Animal ; Europe/ethnology ; European Continental Ancestry Group/genetics ; Exome/genetics ; Female ; Fractures, Bone/*genetics ; Gene Frequency/genetics ; Genetic Predisposition to Disease/genetics ; Genetic Variation/genetics ; Genome, Human/*genetics ; Genomics ; Genotype ; Homeodomain Proteins/*genetics ; Humans ; Mice ; Sequence Analysis, DNA ; Wnt Proteins/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2015-02-13
    Description: 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338562/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338562/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shungin, Dmitry -- Winkler, Thomas W -- Croteau-Chonka, Damien C -- Ferreira, Teresa -- Locke, Adam E -- Magi, 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 -- Mateo Leach, Irene -- Medina-Gomez, Carolina -- Palmer, Cameron D -- Pasko, Dorota -- Pechlivanis, Sonali -- Peters, Marjolein J -- Prokopenko, Inga -- Stancakova, Alena -- Ju Sung, Yun -- Tanaka, 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 -- Bluher, Matthias -- Bohringer, Stefan -- Bonnet, Fabrice -- Bottcher, 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 -- Friedrich, Nele -- Garcia, Melissa E -- Giedraitis, Vilmantas -- Gigante, Bruna -- Go, Alan S -- Golay, Alain -- Grallert, Harald -- Grammer, Tanja B -- Grassler, Jurgen -- Grewal, Jagvir -- Groves, Christopher J -- Haller, Toomas -- Hallmans, Goran -- 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, Keri L -- Mooijaart, Simon P -- Muhleisen, Thomas W -- Mulas, Antonella -- Muller, Gabriele -- Muller-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 -- Vernon Smith, Albert -- 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 -- Hua Zhao, Jing -- 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 -- ADIPOGen Consortium -- CARDIOGRAMplusC4D Consortium -- CKDGen Consortium -- GEFOS Consortium -- GENIE Consortium -- GLGC -- ICBP -- International Endogene Consortium -- LifeLines Cohort Study -- MAGIC Investigators -- MuTHER Consortium -- PAGE Consortium -- ReproGen Consortium -- Amouyel, Philippe -- Arveiler, Dominique -- Bakker, Stephan J L -- 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 J C -- Dorr, 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 -- Hypponen, 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 -- Tonjes, Anke -- Tremblay, Angelo -- Tremoli, Elena -- Vohl, Marie-Claude -- Volker, 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-Jorgen -- Hamsten, Anders -- Hui, Jennie -- Hveem, Kristian -- Jockel, Karl-Heinz -- Kivimaki, Mika -- Kuh, Diana -- Laakso, Markku -- Liu, Yongmei -- Marz, 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 -- Stumvoll, Michael -- Tuomilehto, Jaakko -- Uitterlinden, Andre 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 -- Stefansson, Kari -- 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, 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 -- 084766/Wellcome Trust/United Kingdom -- 085235/Wellcome Trust/United Kingdom -- 097117/Wellcome Trust/United Kingdom -- 098381/Wellcome Trust/United Kingdom -- 098498/Wellcome Trust/United Kingdom -- 12/0004470/Diabetes UK/United Kingdom -- 14136/Cancer Research UK/United Kingdom -- CZB/4/710/Chief Scientist Office/United Kingdom -- G0601261/Medical Research Council/United Kingdom -- G1000143/Medical Research Council/United Kingdom -- K01 HL116770/HL/NHLBI NIH HHS/ -- K23 DK080145/DK/NIDDK NIH HHS/ -- MC_PC_U127561128/Medical Research Council/United Kingdom -- MC_U106179471/Medical Research Council/United Kingdom -- MC_UP_A620_1014/Medical Research Council/United Kingdom -- MC_UU_12011/1/Medical Research Council/United Kingdom -- MC_UU_12015/1/Medical Research Council/United Kingdom -- MC_UU_12015/2/Medical Research Council/United Kingdom -- MC_UU_12015/5/Medical Research Council/United Kingdom -- MR/K011480/1/Medical Research Council/United Kingdom -- MR/K013351/1/Medical Research Council/United Kingdom -- P20 MD006899/MD/NIMHD NIH HHS/ -- P30 DK020541/DK/NIDDK NIH HHS/ -- P30 DK020572/DK/NIDDK NIH HHS/ -- P30 GM103341/GM/NIGMS NIH HHS/ -- P60 DK020541/DK/NIDDK NIH HHS/ -- R00 HL094535/HL/NHLBI NIH HHS/ -- R01 AG041517/AG/NIA NIH HHS/ -- R01 DK062370/DK/NIDDK NIH HHS/ -- R01 DK072193/DK/NIDDK NIH HHS/ -- R01 DK075787/DK/NIDDK NIH HHS/ -- R01 DK078150/DK/NIDDK NIH HHS/ -- R01 DK089256/DK/NIDDK NIH HHS/ -- R01 DK093757/DK/NIDDK NIH HHS/ -- R01 HL109946/HL/NHLBI NIH HHS/ -- R01 HL117626/HL/NHLBI NIH HHS/ -- R21 DA027040/DA/NIDA NIH HHS/ -- T32 GM007092/GM/NIGMS NIH HHS/ -- T32 GM067553/GM/NIGMS NIH HHS/ -- T32 HL007055/HL/NHLBI NIH HHS/ -- T32 HL069768/HL/NHLBI NIH HHS/ -- U01 AG049505/AG/NIA NIH HHS/ -- U01 DK062370/DK/NIDDK NIH HHS/ -- U01 HG007416/HG/NHGRI NIH HHS/ -- U01 HG007419/HG/NHGRI NIH HHS/ -- UM1 CA182910/CA/NCI NIH HHS/ -- Z01 HG000024-14/Intramural NIH HHS/ -- England -- Nature. 2015 Feb 12;518(7538):187-96. doi: 10.1038/nature14132.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Public Health and Clinical Medicine, Unit of Medicine, Umea University, 901 87 Umea, Sweden. [2] Department of Clinical Sciences, Genetic &Molecular Epidemiology Unit, Lund University Diabetes Center, Skane University Hosptial, 205 02 Malmo, Sweden. [3] Department of Odontology, Umea University, 901 85 Umea, Sweden. ; Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, D-93053 Regensburg, Germany. ; 1] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA. [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. ; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. ; Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA. ; 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Estonian Genome Center, University of Tartu, Tartu 51010, Estonia. ; Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm 17176, Sweden. ; 1] Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA. [2] Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA. [3] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. [4] Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby 2800, Denmark. ; Estonian Genome Center, University of Tartu, Tartu 51010, Estonia. ; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. ; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA. ; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA. ; Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA. ; 1] National Heart, Lung, and Blood Institute, the Framingham Heart Study, Framingham Massachusetts 01702, USA. [2] Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, USA. ; 1] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden. [2] Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden. [3] Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala 75185, Sweden. ; 1] Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden. [2] Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala 75185, Sweden. ; MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. ; 1] Estonian Genome Center, University of Tartu, Tartu 51010, Estonia. [2] Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA. [3] Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA. [4] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne 1010, Switzerland. [2] Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland. [3] Department of Medical Genetics, University of Lausanne, Lausanne 1005, Switzerland. ; 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. ; 1] Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital Essen, Essen, 45147 Germany. [2] Clinical Epidemiology, Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena 07743, Germany. ; 1] Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA. [2] Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA. ; Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK. ; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands. ; Department of Internal Medicine, Division of Gastroenterology, and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA. ; HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA. ; Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC University Medical Center, 3015 GE Rotterdam, The Netherlands. ; Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Perth, Western Australia 6008, Australia. ; 1] Netherlands Consortium for Healthy Aging (NCHA), Leiden University Medical Center, Leiden 2300 RC, The Netherlands. [2] Department of Molecular Epidemiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. ; 1] Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA. [2] Kidney Epidemiology and Cost Center, University of Michigan, Ann Arbor, Michigan 48109, USA. ; 1] Department of Statistics &Biostatistics, Rutgers University, Piscataway, New Jersey 08854, USA. [2] Department of Genetics, Rutgers University, Piscataway, New Jersey 08854, USA. ; 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC University Medical Center, 3015 GE Rotterdam, The Netherlands. [2] Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands. ; 1] Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. [2] Cardiology, Department of Specialties of Internal Medicine, Geneva University Hospital, Geneva 1211, Switzerland. ; Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Division of Cardiovacular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK. ; 1] Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland. [2] Department of Medical Genetics, University of Lausanne, Lausanne 1005, Switzerland. [3] University Institute for Social and Preventative Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Lausanne 1005, Switzerland. ; 1] Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, D-68187 Mannheim, Germany. [2] Department of Internal Medicine II, Ulm University Medical Centre, D-89081 Ulm, Germany. ; National Institute for Health and Welfare, FI-00271 Helsinki, Finland. ; Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK. ; Department of Cardiology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands. ; 1] Netherlands Consortium for Healthy Aging (NCHA), 3015GE Rotterdam, The Netherlands. [2] Department of Epidemiology, Erasmus MC University Medical Center, 3015GE Rotterdam, The Netherlands. [3] Department of Internal Medicine, Erasmus MC University Medical Center, 3015GE Rotterdam, The Netherlands. ; Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital Essen, Essen, 45147 Germany. ; 1] Netherlands Consortium for Healthy Aging (NCHA), 3015GE Rotterdam, The Netherlands. [2] Department of Internal Medicine, Erasmus MC University Medical Center, 3015GE Rotterdam, The Netherlands. ; 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK. [3] Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. ; University of Eastern Finland, FI-70210 Kuopio, Finland. ; Division of Biostatistics, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland 21225, USA. ; Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, D-17475 Greifswald, Germany. ; Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, 9700 RB, The Netherlands. ; 1] CNRS UMR 8199, F-59019 Lille, France. [2] European Genomic Institute for Diabetes, F-59000 Lille, France. [3] Universite de Lille 2, F-59000 Lille, France. ; 1] Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK. [2] Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK. ; Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen - German Research Center for Environmental Health, D-85764 Neuherberg, Germany. ; 1] Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden. [2] Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala 75185, Sweden. [3] School of Health and Social Studies, Dalarna University, SE-791 88 Falun, Sweden. ; PathWest Laboratory Medicine of Western Australia, Nedlands, Western Australia 6009, Australia. ; Geriatric Unit, Azienda Sanitaria Firenze (ASF), 50125 Florence, Italy. ; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK. ; 1] Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas 78227, USA. [2] Genomics Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland 4001, Australia. ; Department of Medical Sciences, Endocrinology, Diabetes and Metabolism, Uppsala University, Uppsala 75185, Sweden. ; 1] Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, D-04103 Leipzig, Germany. [2] Department of Medicine, University of Leipzig, D-04103 Leipzig, Germany. ; 1] Netherlands Consortium for Healthy Aging (NCHA), Leiden University Medical Center, Leiden 2300 RC, The Netherlands. [2] Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. ; Inserm UMR991, Department of Endocrinology, University of Rennes, F-35000 Rennes, France. ; Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, D-04103 Leipzig, Germany. ; LifeLines Cohort Study, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands. ; USC-Office of Population Studies Foundation, Inc., University of San Carlos, Cebu City 6000, Philippines. ; Department of Biology, Norwegian University of Science and Technology, 7491 Trondheim, Norway. ; Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK. ; Information Sciences Institute, University of Southern California, Marina del Rey, California 90292, USA. ; Department of Public Health and Clinical Medicine, Unit of Medicine, Umea University, 901 87 Umea, Sweden. ; Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. ; 1] National Institute for Health and Welfare, FI-00271 Helsinki, Finland. [2] Institute for Molecular Medicine, University of Helsinki, FI-00014 Helsinki, Finland. ; Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA. ; 1] Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA. [2] Department of Internal Medicine, Erasmus MC University Medical Center, 3015GE Rotterdam, The Netherlands. [3] Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany. ; Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Bethesda, Maryland 20892, USA. ; Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala 75185, Sweden. ; Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, Stockholm 17177, Sweden. ; Kaiser Permanente, Division of Research, Oakland, California 94612, USA. ; Service of Therapeutic Education for Diabetes, Obesity and Chronic Diseases, Geneva University Hospital, Geneva CH-1211, Switzerland. ; 1] Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen - German Research Center for Environmental Health, D-85764 Neuherberg, Germany. [2] Research Unit of Molecular Epidemiology, Helmholtz Zentrum Munchen - German Research Center for Environmental Health, D-85764 Neuherberg, Germany. [3] German Center for Diabetes Research (DZD), D-85764 Neuherberg, Germany. ; Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universitat Dresden, D-01307 Dresden, Germany. ; Department of Public Health and Clinical Medicine, Unit of Nutritional Research, Umea University, Umea 90187, Sweden. ; Department of Psychiatry, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands. ; Kuopio Research Institute of Exercise Medicine, FI-70100 Kuopio, Finland. ; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. ; Hjelt Institute Department of Public Health, University of Helsinki, FI-00014 Helsinki, Finland. ; 1] Institute of Biomedicine, University of Oulu, FI-90014 Oulu, Finland. [2] Medical Research Center Oulu and Oulu University Hospital, FI-90014 Oulu, Finland. [3] Biocenter Oulu, University of Oulu, FI-90014 Oulu, Finland. ; 1] Netherlands Consortium for Healthy Aging (NCHA), Leiden University Medical Center, Leiden 2300 RC, The Netherlands. [2] Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. [3] Faculty of Psychology and Education, VU University Amsterdam, 1081BT Amsterdam, The Netherlands. ; 1] Department of Cardiology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands. [2] Department of Epidemiology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands. ; Department of Public Health and General Practice, Norwegian University of Science and Technology, Trondheim 7489, Norway. ; Cardiovascular Genetics Division, Department of Internal Medicine, University of Utah, Salt Lake City, Utah 84108, USA. ; 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC University Medical Center, 3015 GE Rotterdam, The Netherlands. [2] Center for Medical Sytems Biology, 2300 RC Leiden, The Netherlands. ; Institute for Community Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany. ; 1] Department of Pulmonary Physiology and Sleep Medicine, Nedlands, Western Australia 6009, Australia. [2] School of Medicine and Pharmacology, University of Western Australia, Crawley 6009, Australia. ; Department of Odontology, Umea University, 901 85 Umea, Sweden. ; Department of Dietetics-Nutrition, Harokopio University, 17671 Athens, Greece. ; Department of Internal Medicine II, Ulm University Medical Centre, D-89081 Ulm, Germany. ; Department of Internal Medicine I, Ulm University Medical Centre, D-89081 Ulm, Germany. ; Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, 6020 Innsbruck, Austria. ; Institute of Human Genetics, Helmholtz Zentrum Munchen - German Research Center for Environmental Health, D-85764 Neuherberg, Germany. ; Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala 75185, Sweden. ; Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 413 45, Sweden. ; Cardiology, Department of Specialties of Internal Medicine, Geneva University Hospital, Geneva 1211, Switzerland. ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden. ; School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK. ; Division of Endocrinology, Diabetes and Metabolism, Ulm University Medical Centre, D-89081 Ulm, Germany. ; 1] Estonian Genome Center, University of Tartu, Tartu 51010, Estonia. [2] Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia. ; 1] Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK. [2] Farr Institute of Health Informatics Research, University College London, London NW1 2DA, UK. ; 1] Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. [2] The Center for Observational Research, Amgen, Inc., Thousand Oaks, California 91320, USA. ; 1] Netherlands Consortium for Healthy Aging (NCHA), Leiden University Medical Center, Leiden 2300 RC, The Netherlands. [2] Department of Gerontology and Geriatrics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. ; 1] Department of Genomics, Life &Brain Center, University of Bonn, 53127 Bonn, Germany. [2] Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany. ; Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, Cagliari, Sardinia 09042, Italy. ; Center for Evidence-based Healthcare, University Hospital Carl Gustav Carus, Technische Universitat Dresden, D-01307 Dresden, Germany. ; 1] Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen - German Research Center for Environmental Health, D-85764 Neuherberg, Germany. [2] Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universitat, D-81377 Munich, Germany. [3] Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universitat, D-81377 Munich, Germany. [4] Deutsches Forschungszentrum fur Herz-Kreislauferkrankungen (DZHK) (German Research Centre for Cardiovascular Research), Munich Heart Alliance, D-80636 Munich, Germany. ; Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland 21224, USA. ; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Hypertension and Related Diseases Centre - AOU, University of Sassari Medical School, Sassari 07100, Italy. ; Department of Epidemiology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands. ; 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. [3] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK. ; Department of Clinical Sciences, Genetic &Molecular Epidemiology Unit, Lund University Diabetes Center, Skane University Hosptial, 205 02 Malmo, Sweden. ; 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK. ; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. ; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8036, Austria. ; 1] Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm 17176, Sweden. [2] Science for Life Laboratory, Karolinska Institutet, Stockholm 171 65, Sweden. ; Department of Medicine, University of Washington, Seattle, Washington 98101, USA. ; 1] Icelandic Heart Association, Kopavogur 201, Iceland. [2] University of Iceland, Reykjavik 101, Iceland. ; 1] Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. [2] William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK. ; 1] Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden. [2] Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala 75144, Sweden. ; Department of Public Health Sciences, Stritch School of Medicine, Loyola University of Chicago, Maywood, Illinois 61053, USA. ; 1] German Center for Diabetes Research (DZD), D-85764 Neuherberg, Germany. [2] Institute of Epidemiology II, Helmholtz Zentrum Munchen - German Research Center for Environmental Health, Neuherberg, Germany, D-85764 Neuherberg, Germany. ; deCODE Genetics, Amgen Inc., Reykjavik 101, Iceland. ; Department of Cardiology, Medical University of Graz, Graz 8036, Austria. ; Department of Child and Adolescent Psychiatry, Psychology, Erasmus MC University Medical Centre, 3000 CB Rotterdam, The Netherlands. ; Department of Clinical Chemistry, Ulm University Medical Centre, D-89081 Ulm, Germany. ; Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, 9037 Tromso, Norway. ; MRC Unit for Lifelong Health and Ageing at University College London, London WC1B 5JU, UK. ; Diabetes Complications Research Centre, Conway Institute, School of Medicine and Medical Sciences, University College Dublin, Dublin 4, Ireland. ; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea. ; Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 17176, Sweden. ; Department of Medicine, Columbia University College of Physicians and Surgeons, New York 10032, USA. ; 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden. [3] Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala 75185, Sweden. ; 1] Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, Massachusetts 02215, USA. [2] Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; 1] State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. [2] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA. ; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK. ; 1] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK. [2] NIHR Oxford Biomedical Research Centre, OUH Trust, Oxford OX3 7LE, UK. ; 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA. [2] Harvard School of Public Health, Department of Biostatistics, Harvard University, Boston, Massachusetts 02115, USA. ; Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, New Haven, Connecticut 06520, USA. ; 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA. [2] College of Information Science and Technology, Dalian Maritime University, Dalian, Liaoning 116026, China. ; Nephrology Research, Centre for Public Health, Queen's University of Belfast, Belfast, County Down BT9 7AB, UK. ; University of Ottawa Heart Institute, Ottawa K1Y 4W7, Canada. ; National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK. ; QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia. ; 1] National Heart, Lung, and Blood Institute, the Framingham Heart Study, Framingham Massachusetts 01702, USA. [2] Section of General Internal Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA. ; 1] Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK. [2] MRC Harwell, Harwell Science and Innovation Campus, Harwell OX11 0QG, UK. ; 1] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia. [2] Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland 4059, Australia. ; 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK. [3] Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK. ; 1] Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA. [2] Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA. [3] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Department of Biomedical Engineering and Computational Science, Aalto University School of Science, FI-00076 Helsinki, Finland. [2] Department of Medicine, Division of Nephrology, Helsinki University Central Hospital, FI-00290 Helsinki, Finland. [3] Folkhalsan Institute of Genetics, Folkhalsan Research Center, FI-00290 Helsinki, Finland. ; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10580, USA. ; 1] Netherlands Consortium for Healthy Aging (NCHA), Leiden University Medical Center, Leiden 2300 RC, The Netherlands. [2] Department of Internal Medicine, Erasmus MC University Medical Center, 3015GE Rotterdam, The Netherlands. ; Computer Science Department, Tecnologico de Monterrey, Atizapan de Zaragoza, 52926, Mexico. ; 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Nuffield Department of Obstetrics &Gynaecology, University of Oxford, Oxford OX3 7BN, UK. ; Institut Pasteur de Lille; INSERM, U744; Universite de Lille 2; F-59000 Lille, France. ; Department of Epidemiology and Public Health, EA3430, University of Strasbourg, Faculty of Medicine, Strasbourg, France. ; Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands. ; 1] PathWest Laboratory Medicine of Western Australia, Nedlands, Western Australia 6009, Australia. [2] Pathology and Laboratory Medicine, The University of Western Australia, Perth, Western Australia 6009, Australia. ; Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California 90048, USA. ; Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas 78227, USA. ; Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. ; Service of Nephrology, Department of Medicine, Lausanne University Hospital (CHUV), Lausanne 1005, Switzerland. ; Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK. ; Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee 37203, USA. [2] Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 37232, USA. ; Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK. ; 1] Biological Psychology, VU University Amsterdam, 1081BT Amsterdam, The Netherlands. [2] Institute for Research in Extramural Medicine, Institute for Health and Care Research, VU University, 1081BT Amsterdam, The Netherlands. ; 1] Department of Internal Medicine B, University Medicine Greifswald, D-17475 Greifswald, Germany. [2] DZHK (Deutsches Zentrum fur Herz-Kreislaufforschung - German Centre for Cardiovascular Research), partner site Greifswald, D-17475 Greifswald, Germany. ; Clinic of Cardiology, West-German Heart Centre, University Hospital Essen, 45122 Essen, Germany. ; 1] National Institute for Health and Welfare, FI-00271 Helsinki, Finland. [2] Department of General Practice and Primary Health Care, University of Helsinki, FI-00290 Helsinki, Finland. [3] Unit of General Practice, Helsinki University Central Hospital, Helsinki FI-00290, Finland. ; 1] Department of Internal Medicine, University of Pisa, Pisa 56100, Italy. [2] National Research Council Institute of Clinical Physiology, University of Pisa, Pisa 56124, Italy. ; Department of Cardiology, Toulouse University School of Medicine, Rangueil Hospital, 31400 Toulouse, France. ; UWI Solutions for Developing Countries, The University of the West Indies, Mona, Kingston 7, Jamaica. ; 1] Netherlands Consortium for Healthy Aging (NCHA), 3015GE Rotterdam, The Netherlands. [2] Department of Epidemiology, Erasmus MC University Medical Center, 3015GE Rotterdam, The Netherlands. ; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA. ; Institute of Biomedical &Clinical Science, University of Exeter, Barrack Road, Exeter EX2 5DW, UK. ; Center for Biomedicine, European Academy Bozen, Bolzano (EURAC), Bolzano 39100, Italy (affiliated Institute of the University of Lubeck, D-23562 Lubeck, Germany). ; Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK. ; 1] Institute for Community Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany. [2] DZHK (Deutsches Zentrum fur Herz-Kreislaufforschung - German Centre for Cardiovascular Research), partner site Greifswald, D-17475 Greifswald, Germany. ; Centre for Cardiovascular Genetics, Institute Cardiovascular Sciences, University College London, London WC1E 6JJ, UK. ; 1] Sansom Institute for Health Research, University of South Australia, Adelaide 5000, South Australia, Australia. [2] School of Population Health, University of South Australia, Adelaide 5000, South Australia, Australia. [3] South Australian Health and Medical Research Institute, Adelaide 5000, South Australia, Australia. [4] Population, Policy, and Practice, University College London Institute of Child Health, London WC1N 1EH, UK. ; 1] Research Unit of Molecular Epidemiology, Helmholtz Zentrum Munchen - German Research Center for Environmental Health, D-85764 Neuherberg, Germany. [2] Hannover Unified Biobank, Hannover Medical School, Hannover, D-30625 Hannover, Germany. ; 1] Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK. [2] Biocenter Oulu, University of Oulu, FI-90014 Oulu, Finland. [3] National Institute for Health and Welfare, FI-90101 Oulu, Finland. [4] MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK. [5] Unit of Primary Care, Oulu University Hospital, FI-90220 Oulu, Finland. [6] Institute of Health Sciences, University of Oulu, FI-90014 Oulu, Finland. ; 1] National Institute for Health and Welfare, FI-00271 Helsinki, Finland. [2] Institute for Molecular Medicine, University of Helsinki, FI-00014 Helsinki, Finland. [3] Hjelt Institute Department of Public Health, University of Helsinki, FI-00014 Helsinki, Finland. ; UK Clinical Research Collaboration Centre of Excellence for Public Health (NI), Queens University of Belfast, Belfast BT7 1NN, Northern Ireland, UK. ; 1] Institute of Health Sciences, Faculty of Medicine, University of Oulu, FI-90014 Oulu, Finland. [2] Unit of Primary Health Care/General Practice, Oulu University Hospital, FI-90220 Oulu, Finland. ; 1] Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK. [2] National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK. [3] Imperial College Healthcare NHS Trust, London W12 0HS, UK. ; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; 1] Department of Epidemiology and Public Health, University College London, London WC1E 6BT, UK. [2] Department of Biological and Social Epidemiology, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, UK. ; Department of Medicine, Kuopio University Hospital and University of Eastern Finland, FI-70210 Kuopio, Finland. ; 1] Kuopio Research Institute of Exercise Medicine, FI-70100 Kuopio, Finland. [2] Department of Physiology, Institute of Biomedicine, University of Eastern Finland, Kuopio Campus, FI-70211 Kuopio, Finland. [3] Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital and University of Eastern Finland, FI-70210 Kuopio, Finland. ; 1] MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. [2] Department of Epidemiology and Public Health, University College London, London WC1E 6BT, UK. ; Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA. ; Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine University of Tampere, FI-33520 Tampere, Finland. ; 1] Steno Diabetes Center A/S, Gentofte DK-2820, Denmark. [2] Lund University Diabetes Centre and Department of Clinical Science, Diabetes &Endocrinology Unit, Lund University, Malmo 221 00, Sweden. ; 1] Institut Universitaire de Cardiologie et de Pneumologie de Quebec, Faculty of Medicine, Laval University, Quebec QC G1V 0A6, Canada. [2] Institute of Nutrition and Functional Foods, Laval University, Quebec QC G1V 0A6, Canada. ; Department of Genetics, Rutgers University, Piscataway, New Jersey 08854, USA. ; Department of Biostatistics, University of Washington, Seattle, Washington 98195, USA. ; Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia. ; 1] MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. [2] MRC Unit for Lifelong Health and Ageing at University College London, London WC1B 5JU, UK. ; 1] Epidemiology and Obstetrics &Gynaecology, University of Toronto, Toronto, Ontario M5G 1E2, Canada. [2] Genetic Epidemiology &Biostatistics Platform, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada. ; 1] Institute for Research in Extramural Medicine, Institute for Health and Care Research, VU University, 1081BT Amsterdam, The Netherlands. [2] Department of Psychiatry, Neuroscience Campus, VU University Amsterdam, 1081 BT Amsterdam, The Netherlands. ; 1] Research Unit of Molecular Epidemiology, Helmholtz Zentrum Munchen - German Research Center for Environmental Health, D-85764 Neuherberg, Germany. [2] Deutsches Forschungszentrum fur Herz-Kreislauferkrankungen (DZHK) (German Research Centre for Cardiovascular Research), Munich Heart Alliance, D-80636 Munich, Germany. [3] Institute of Epidemiology II, Helmholtz Zentrum Munchen - German Research Center for Environmental Health, Neuherberg, Germany, D-85764 Neuherberg, Germany. ; 1] Center for Biomedicine, European Academy Bozen, Bolzano (EURAC), Bolzano 39100, Italy (affiliated Institute of the University of Lubeck, D-23562 Lubeck, Germany). [2] Department of Neurology, General Central Hospital, Bolzano 39100, Italy. ; 1] Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, FI-20521 Turku, Finland. [2] Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, FI-20521 Turku, Finland. ; Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808, USA. ; 1] Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63110, USA. [2] Division of Biostatistics, Washington University School of Medicine, St Louis, Missouri 63110, USA. [3] Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; 1] Division of Biostatistics, Washington University School of Medicine, St Louis, Missouri 63110, USA. [2] Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; 1] Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. [2] Harvard Medical School, Boston, Massachusetts 02115, USA. ; Center for Systems Genomics, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; 1] Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK. [2] Croatian Centre for Global Health, Faculty of Medicine, University of Split, 21000 Split, Croatia. ; 1] Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK. [2] National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK. ; South Carelia Central Hospital, 53130 Lappeenranta, Finland. ; 1] Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universitat Dresden, D-01307 Dresden, Germany. [2] Paul Langerhans Institute Dresden, German Center for Diabetes Research (DZD), 01307 Dresden, Germany. ; 1] Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. [2] Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. [3] Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland 21201, USA. ; 1] Department of Epidemiology, Maastricht University, 6229 HA Maastricht, The Netherlands. [2] Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, B-3000 Leuven, Belgium. ; 1] Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen - German Research Center for Environmental Health, D-85764 Neuherberg, Germany. [2] Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universitat, D-81377 Munich, Germany. ; Department of Kinesiology, Laval University, Quebec, QC G1V 0A6, Canada. ; Dipartimento di Scienze Farmacologiche e Biomolecolari, Universita di Milano &Centro Cardiologico Monzino, Instituto di Ricovero e Cura a Carattere Scientifico, Milan 20133, Italy. ; 1] Institute of Nutrition and Functional Foods, Laval University, Quebec QC G1V 0A6, Canada. [2] Department of Food Science and Nutrition, Laval University, Quebec, QC G1V 0A6, Canada. ; 1] Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, D-17475 Greifswald, Germany. [2] DZHK (Deutsches Zentrum fur Herz-Kreislaufforschung - German Centre for Cardiovascular Research), partner site Greifswald, D-17475 Greifswald, Germany. ; Department of Internal Medicine, University Hospital (CHUV) and University of Lausanne, 1011, Switzerland. ; Department of Epidemiology, Erasmus MC University Medical Center, 3015GE Rotterdam, The Netherlands. ; Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina 27599, USA. ; 1] Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois and University of Lausanne, 1010 Lausanne, Switzerland. [2] Ministry of Health, Victoria, Republic of Seychelles. ; 1] Lee Kong Chian School of Medicine, Imperial College London and Nanyang Technological University, Singapore, 637553 Singapore, Singapore. [2] Department of Internal Medicine I, Ulm University Medical Centre, D-89081 Ulm, Germany. ; Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK. ; 1] Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK. [2] Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK. [3] Imperial College Healthcare NHS Trust, London W12 0HS, UK. ; 1] Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. [2] CNRS UMR 8199, F-59019 Lille, France. [3] European Genomic Institute for Diabetes, F-59000 Lille, France. [4] Universite de Lille 2, F-59000 Lille, France. ; 1] Department of Psychiatry and Psychotherapy, University Medicine Greifswald, HELIOS-Hospital Stralsund, D-17475 Greifswald, Germany. [2] German Center for Neurodegenerative Diseases (DZNE), Rostock, Greifswald, D-17475 Greifswald, Germany. ; 1] PathWest Laboratory Medicine of Western Australia, Nedlands, Western Australia 6009, Australia. [2] Pathology and Laboratory Medicine, The University of Western Australia, Perth, Western Australia 6009, Australia. [3] School of Population Health, The University of Western Australia, Nedlands, Western Australia 6009, Australia. ; Department of Epidemiology and Public Health, University College London, London WC1E 6BT, UK. ; Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA. ; 1] Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, D-68187 Mannheim, Germany. [2] Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8036, Austria. [3] Synlab Academy, Synlab Services GmbH, 68163 Mannheim, Germany. ; 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC University Medical Center, 3015 GE Rotterdam, The Netherlands. [2] Center for Medical Sytems Biology, 2300 RC Leiden, The Netherlands. [3] Department of Clinical Genetics, Erasmus MC University Medical Center, 3000 CA Rotterdam, The Netherlands. ; 1] Estonian Genome Center, University of Tartu, Tartu 51010, Estonia. [2] National Institute for Health and Welfare, FI-00271 Helsinki, Finland. [3] Institute for Molecular Medicine, University of Helsinki, FI-00014 Helsinki, Finland. ; 1] Institute of Nutrition and Functional Foods, Laval University, Quebec QC G1V 0A6, Canada. [2] Department of Kinesiology, Laval University, Quebec, QC G1V 0A6, Canada. ; Population, Policy, and Practice, University College London Institute of Child Health, London WC1N 1EH, UK. ; Department of Medicine, Stanford University School of Medicine, Palo Alto, California 94304, USA. ; 1] Kuopio Research Institute of Exercise Medicine, FI-70100 Kuopio, Finland. [2] Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital and University of Eastern Finland, FI-70210 Kuopio, Finland. ; 1] Finnish Diabetes Association, Kirjoniementie 15, FI-33680 Tampere, Finland. [2] Pirkanmaa Hospital District, FI-33521 Tampere, Finland. ; 1] Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK. [2] Center for Non-Communicable Diseases, Karatchi, Pakistan. [3] Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 USA. ; Helsinki University Central Hospital Heart and Lung Center, Department of Medicine, Helsinki University Central Hospital, FI-00290 Helsinki, Finland. ; 1] deCODE Genetics, Amgen Inc., Reykjavik 101, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland. ; 1] National Institute for Health and Welfare, FI-00271 Helsinki, Finland. [2] Instituto de Investigacion Sanitaria del Hospital Universario LaPaz (IdiPAZ), 28046 Madrid, Spain. [3] Diabetes Research Group, King Abdulaziz University, 21589 Jeddah, Saudi Arabia. [4] Centre for Vascular Prevention, Danube-University Krems, 3500 Krems, Austria. ; 1] Department of Public Health and Clinical Nutrition, University of Eastern Finland, FI-70211 Kuopio, Finland. [2] Research Unit, Kuopio University Hospital, FI-70210 Kuopio, Finland. ; 1] Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands. [2] Department of Cardiology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands. [3] Durrer Center for Cardiogenetic Research, Interuniversity Cardiology Institute Netherlands-Netherlands Heart Institute, 3501 DG Utrecht, The Netherlands. ; EPIMED Research Center, Department of Clinical and Experimental Medicine, University of Insubria, Varese I-21100, Italy. ; Institute of Cellular Medicine, Newcastle University, Newcastle NE1 7RU, UK. ; 1] Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universitat, D-85764 Munich, Germany. [2] Klinikum Grosshadern, D-81377 Munich, Germany. [3] Institute of Epidemiology I, Helmholtz Zentrum Munchen - German Research Center for Environmental Health, Neuherberg, Germany, D-85764 Neuherberg, Germany. ; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; 1] Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. [2] William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK. [3] Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, 21589 Jeddah, Saudi Arabia. ; 1] Institute for Molecular Medicine, University of Helsinki, FI-00014 Helsinki, Finland. [2] Lund University Diabetes Centre and Department of Clinical Science, Diabetes &Endocrinology Unit, Lund University, Malmo 221 00, Sweden. ; 1] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA. [3] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA. ; Albert Einstein College of Medicine, Department of Epidemiology and Population Health, Belfer 1306, New York 10461, USA. ; 1] Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. [2] Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. ; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. ; Division of Population Health Sciences &Education, St George's, University of London, London SW17 0RE, UK. ; 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC University Medical Center, 3015 GE Rotterdam, The Netherlands. [2] Netherlands Consortium for Healthy Aging (NCHA), 3015GE Rotterdam, The Netherlands. [3] Department of Epidemiology, Erasmus MC University Medical Center, 3015GE Rotterdam, The Netherlands. [4] Center for Medical Sytems Biology, 2300 RC Leiden, The Netherlands. ; 1] Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA. [2] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA. [3] Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA. ; 1] Queensland Brain Institute, The University of Queensland, Brisbane 4072, Australia. [2] The University of Queensland Diamantina Institute, The Translation Research Institute, Brisbane 4012, Australia. ; 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK. [3] Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford OX3 7LJ, UK. ; 1] Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. [2] Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. ; National Heart, Lung, and Blood Institute, the Framingham Heart Study, Framingham Massachusetts 01702, USA. ; 1] Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. [2] University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 OQQ, UK. [3] NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 OQQ, UK. ; 1] Department of Public Health and Clinical Medicine, Unit of Medicine, Umea University, 901 87 Umea, Sweden. [2] Department of Clinical Sciences, Genetic &Molecular Epidemiology Unit, Lund University Diabetes Center, Skane University Hosptial, 205 02 Malmo, Sweden. ; 1] Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, D-93053 Regensburg, Germany. [2] Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen - German Research Center for Environmental Health, D-85764 Neuherberg, Germany. ; 1] MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. [2] The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. [3] The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. [4] The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. ; 1] Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA. [2] National Heart, Lung, and Blood Institute, the Framingham Heart Study, Framingham Massachusetts 01702, USA. ; 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Estonian Genome Center, University of Tartu, Tartu 51010, Estonia. [3] Department of Biostatistics, University of Liverpool, Liverpool L69 3GA, UK. ; 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25673412" target="_blank"〉PubMed〈/a〉
    Keywords: Adipocytes/metabolism ; Adipogenesis/genetics ; Adipose Tissue/*metabolism ; Age Factors ; *Body Fat Distribution ; Body Mass Index ; Continental Population Groups/genetics ; Epigenesis, Genetic ; Europe/ethnology ; Female ; Genome, Human/genetics ; *Genome-Wide Association Study ; Humans ; Insulin/*metabolism ; Insulin Resistance/genetics ; Male ; Models, Biological ; Neovascularization, Physiologic/genetics ; Obesity/genetics ; Polymorphism, Single Nucleotide/genetics ; Quantitative Trait Loci/*genetics ; Sex Characteristics ; Transcription, Genetic/genetics ; Waist-Hip Ratio
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Abstract: BACKGROUND: -DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders. METHODS AND RESULTS: -To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15,907 blood derived DNA samples from participants in 16 cohorts (including 2,433 current, 6,518 former, and 6,956 never smokers). Comparing current versus never smokers, 2,623 CpG sites (CpGs), annotated to 1,405 genes, were statistically significantly differentially methylated at Bonferroni threshold of p〈1x10-7 (18,760 CpGs at False Discovery Rate (FDR)〈0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant p〈1x10-7 (2,623 CpGs at FDR〈0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs. CONCLUSIONS: -Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biologic effects of smoking, and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.
    Type of Publication: Journal article published
    PubMed ID: 27651444
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  • 4
    ISSN: 1573-2878
    Keywords: Numerical methods ; computing methods ; optimal control ; optimality properties ; supplementary optimality properties ; gradient methods ; gradient-restoration algorithms ; sequential gradient-restoration algorithms ; general boundary conditions ; nondifferential constraints
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract In this paper, sequential gradient-restoration algorithms for optimal control problems are considered, and attention is focused on the gradient phase. It is shown that the Lagrange multipliers associated with the gradient phase not only solve the auxiliary minimization problem of the gradient phase, but are also endowed with a supplementary optimality property: they minimize the error in the optimality conditions, subject to the multiplier differential equations and boundary conditions, for given state, control, and parameter.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1573-2878
    Keywords: Optimal control ; numerical methods ; computing methods ; transformation techniques ; sequential gradient-restoration algorithm ; nondifferential constraints ; state inequality constraints ; linear state inequality constraints ; partially linear state inequality constraints
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract This paper considers optimal control problems involving the minimization of a functional subject to differential constraints, terminal constraints, and a state inequality constraint. The state inequality constraint is of a special type, namely, it is linear in some or all of the components of the state vector. A transformation technique is introduced, by means of which the inequality-constrained problem is converted into an equality-constrained problem involving differential constraints, terminal constraints, and a control equality constraint. The transformation technique takes advantage of the partial linearity of the state inequality constraint so as to yield a transformed problem characterized by a new state vector of minimal size. This concept is important computationally, in that the computer time per iteration increases with the square of the dimension of the state vector. In order to illustrate the advantages of the new transformation technique, several numerical examples are solved by means of the sequential gradient-restoration algorithm for optimal control problems involving nondifferential constraints. The examples show the substantial savings in computer time for convergence, which are associated with the new transformation technique.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1077-3118
    Source: AIP Digital Archive
    Topics: Physics
    Notes: A steady-state photovoltaic effect of picosecond response speed has been observed in an asymmetrical graded InAlGaAs superlattice structure with a responsivity of ∼0.3 V/W and a saturation photovoltage of ∼0.3 V. For 10 devices of varying sizes ranging from 51 to 502 μm in diameter, the measured full width at half-maximum of the impulse response to a 1.6-ps laser pulse varies only twofold from 29 to 58 ps. The intrinsic rise time of each device is less than 10 ps. Steady-state photovoltage signals were observed in all the devices when excited with 100-ps–2-μs laser pulses. No dc bias voltage is needed.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1077-3118
    Source: AIP Digital Archive
    Topics: Physics
    Notes: We have used molecular beam epitaxy to grow at 500 °C a graded InAlGaAs superlattice structure sandwiched by two heavily doped window layers which are directly connected to the gate and source of a discrete field-effect transistor (FET). Upon band-gap illumination, a steady-state photovoltage controllable by the light intensity is generated by the superlattice structure, which then modulates the drain current of the FET to the same amount as does a dc voltage source. The intrinsic response time of the photovoltaic effect is on the order of picoseconds, thus the modulation speed on the drain current is completely limited by the FET.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1077-3118
    Source: AIP Digital Archive
    Topics: Physics
    Notes: Electron effective mass in the InxGa1−xAs conduction channel of strained AlGaAs/InGaAs/GaAs pseudomorphic structures is measured using far-infrared cyclotron resonance techniques at 4.2 K. The measured cyclotron mass is heavier than the conduction-band-edge mass in bulk InxGa1−xAs. This result is explained by the large two-dimensional electron density realized in the structure, and the lattice strain that exists in the InxGa1−xAs layer.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1077-3118
    Source: AIP Digital Archive
    Topics: Physics
    Notes: Cyclotron resonance of the two-dimensional hole gas (2DHG) in the strained-layer quantum well structure of In0.20Ga0.80As/GaAs is observed in far-infrared transmission measurements made at 4.2 K. The cyclotron mass of the 2DHG in the In0.20Ga0.80As channel is (0.191±0.008)me for a 2D hole density p2D =8.5×1011/cm2.
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  • 10
    ISSN: 1077-3118
    Source: AIP Digital Archive
    Topics: Physics
    Notes: We have studied the low-field magnetoresistance of the two-dimensional electron gas in GaAs/〈m1;&33〉AlxGa1−xAs in the presence of a two-dimensional lateral surface superlattice (2D LSSL) potential, and observed, for the first time, the guiding-center drift resonance, previously reported for one-dimensional LSSL structures. The 2D LSSL potential is created by applying a voltage Vg to a 200 nm period grid-gate structure fabricated on top of the sample and can be tuned continuously from being repulsive to attractive by tuning Vg.
    Type of Medium: Electronic Resource
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