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      Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche

      research-article
      1 , 2 , 3 , 4 , * , 1 , 1 , 5 , 6 , 3 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 5 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ,   22 , 23 , 24 , 23 , 25 , 26 , 27 , 28 , 26 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 11 , 36 , 19 , 37 , 38 , 7 , 8 , 39 , 40 , 41 , 42 , 43 , 44 , 4 , 12 , 13 , 45 , 46 , 47 , 1 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 6 , 60 , 61 , 62 , 63 , 64 , 9 , 10 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 22 , 38 , 75 ,   26 , 27 , 76 , 77 , 78 , 6 , 79 , 63 , 64 , 80 , 31 , 81 , 82 , 83 , 84 , 54 , 85 , 86 , 87 , 44 , 88 , 89 , 90 , 91 , 20 , 43 , 92 , 93 , 94 , 5 , 95 , 31 , 32 , 96 , 97 , 98 , 22 , 99 , 100 , 101 , 102 , 103 , 104 , 94 , 76 , 77 , 105 , 13 , 76 , 77 , 10 , 106 , 106 , 107 , 108 , 109 , 110 , 111 , 17 , 18 , 29 , 112 , 113 , 114 , 11 , 22 , 110 , 111 , 69 , 5 , 47 , 27 ,   20 , 115 , 6 , 11 , 36 , 11 , 93 , 94 , 116 , 117 , 118 , 119 , 39 , 19 , 120 , 121 , 122 , 123 , 22 , 124 , 125 , 80 , 126 , 81 , 127 , 128 , 129 , 26 , 27 , 33 , 34 , 103 , 38 , 75 , 9 , 65 , 81 , 29 , 130 , 131 , 132 , 133 , 134 , 76 , 77 , 105 , 135 , 136 , 123 , 26 , 27 , 80 , 33 , 137 , 138 , 139 , 137 , 140 , 100 , 139 , 6 , 43 , 128 , 141 , 142 , Australian Ovarian Cancer Study 42 , 143 , The GENICA Network 61 , 62 , 99 , 144 , 145 , 146 , 147 , kConFab 143 , The LifeLines Cohort Study, The InterAct Consortium, Early Growth Genetics (EGG) Consortium, 43 , 44 , 123 , 148 , 1 , 149 , 3 , 150 , 151 , 142 , 40 , 47 , 152 , 5 , 95 , 34 , 39 , 153 , 28 , 17 , 18 , 154 , 20 , 29 , 38 , 75 , 15 , 89 , 155 , 133 , 156 , 157 , 158 , 159 , 76 , 160 , 26 , 27 , 11 , 36 , 16 , 9 , 10 , 28 , 161 , 162 , 4 , 163 , 33 , 34 , 103 , 1 , 19 , 164 , 2 , 6 , 5 , 95 , 23 , 165 , * , 1 , 166
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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality 1 . Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation 2, 3 , but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence ( P<5×10 −8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci ( DLK1/WDR25, MKRN3/MAGEL2 and KCNK9) demonstrating parent-of-origin specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signaling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

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          Most cited references81

          • Record: found
          • Abstract: found
          • Article: not found

          GCTA: a tool for genome-wide complex trait analysis.

          For most human complex diseases and traits, SNPs identified by genome-wide association studies (GWAS) explain only a small fraction of the heritability. Here we report a user-friendly software tool called genome-wide complex trait analysis (GCTA), which was developed based on a method we recently developed to address the "missing heritability" problem. GCTA estimates the variance explained by all the SNPs on a chromosome or on the whole genome for a complex trait rather than testing the association of any particular SNP to the trait. We introduce GCTA's five main functions: data management, estimation of the genetic relationships from SNPs, mixed linear model analysis of variance explained by the SNPs, estimation of the linkage disequilibrium structure, and GWAS simulation. We focus on the function of estimating the variance explained by all the SNPs on the X chromosome and testing the hypotheses of dosage compensation. The GCTA software is a versatile tool to estimate and partition complex trait variation with large GWAS data sets.
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            • Article: found
            Is Open Access

            METAL: fast and efficient meta-analysis of genomewide association scans

            Summary: METAL provides a computationally efficient tool for meta-analysis of genome-wide association scans, which is a commonly used approach for improving power complex traits gene mapping studies. METAL provides a rich scripting interface and implements efficient memory management to allow analyses of very large data sets and to support a variety of input file formats. Availability and implementation: METAL, including source code, documentation, examples, and executables, is available at http://www.sph.umich.edu/csg/abecasis/metal/ Contact: goncalo@umich.edu
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              • Article: not found

              Genetics of gene expression and its effect on disease.

              Common human diseases result from the interplay of many genes and environmental factors. Therefore, a more integrative biology approach is needed to unravel the complexity and causes of such diseases. To elucidate the complexity of common human diseases such as obesity, we have analysed the expression of 23,720 transcripts in large population-based blood and adipose tissue cohorts comprehensively assessed for various phenotypes, including traits related to clinical obesity. In contrast to the blood expression profiles, we observed a marked correlation between gene expression in adipose tissue and obesity-related traits. Genome-wide linkage and association mapping revealed a highly significant genetic component to gene expression traits, including a strong genetic effect of proximal (cis) signals, with 50% of the cis signals overlapping between the two tissues profiled. Here we demonstrate an extensive transcriptional network constructed from the human adipose data that exhibits significant overlap with similar network modules constructed from mouse adipose data. A core network module in humans and mice was identified that is enriched for genes involved in the inflammatory and immune response and has been found to be causally associated to obesity-related traits.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                26 June 2014
                23 July 2014
                2 October 2014
                02 April 2015
                : 514
                : 7520
                : 92-97
                Affiliations
                [1 ]MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
                [2 ]University of Exeter Medical School, University of Exeter, Exeter, UK EX1 2LU.
                [3 ]Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
                [4 ]Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK.
                [5 ]deCODE Genetics, Reykjavik, Iceland.
                [6 ]Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, UK.
                [7 ]Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IN 46202, USA.
                [8 ]Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA.
                [9 ]Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA 02215.
                [10 ]Harvard Medical School, Boston, MA 02115.
                [11 ]Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia.
                [12 ]Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA 02115, USA.
                [13 ]Broad Institute of the Massachusetts Institute of Technology and Harvard University, 140 Cambridge 02142, MA, USA.
                [14 ]Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
                [15 ]Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
                [16 ]School of Women’s and Infants’ Health, The University of Western Australia.
                [17 ]Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
                [18 ]Swiss Institute of Bioinformatics, Lausanne, Switzerland.
                [19 ]Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
                [20 ]Department of Epidemiology Research, Statens Serum Institut, DK-2300 Copenhagen, Denmark.
                [21 ]Department of Epidemiology, University of North Carolina, Chapel Hill, NC.
                [22 ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
                [23 ]NHLBI’s and Boston University’s Framingham Heart Study, Framingham, MA.
                [24 ]Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
                [25 ]Boston University School of Public Health, Department of Biostatistics. Boston, MA.
                [26 ]MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
                [27 ]School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.
                [28 ]Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
                [29 ]Institute of Genetics and Biomedical Research, National Research Council, Cagliari, Italy.
                [30 ]University of Sassari, Dept. Of Biomedical Sciences, Sassari, Italy.
                [31 ]Icelandic Heart Association, Kopavogur, Iceland.
                [32 ]University of Iceland, Reykjavik, Iceland.
                [33 ]Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands.
                [34 ]Netherlands Consortium on Health Aging and National Genomics Initiative, Leiden, the Netherlands.
                [35 ]Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, 17475 Greifswald, Germany.
                [36 ]Department of Biotechnology, University of Tartu, Tartu, 51010, Estonia.
                [37 ]Hjelt Institute, University of Helsinki, Finland.
                [38 ]Institute for Maternal and Child Health - IRCCS “Burlo Garofolo” – Trieste, Italy.
                [39 ]Genetic Epidemiology Unit Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.
                [40 ]Dept. of Psychiatry, Washington University, St. Louis, MO 63110.
                [41 ]The University of Queensland, Queensland Brain Institute, St.Lucia, QLD, Australia.
                [42 ]QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
                [43 ]Department of Biological Psychology, VU University Amsterdam, van der Boechorststraat 1, 1081 BT, Amsterdam, The Netherlands.
                [44 ]Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana USA.
                [45 ]Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, US.
                [46 ]Center for Biological Sequence Analysis, Department of Systems Biology, Technical 142 University of Denmark, Lyngby 2800, Denmark.
                [47 ]Program in Personalized and Genomic Medicine, and Department of Medicine, Division of Endocrinology, Diabetes and Nutrition - University of Maryland School of Medicine, USA. Baltimore, MD 21201.
                [48 ]Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
                [49 ]Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
                [50 ]Department of Epidemiology, University of California Irvine, Irvine, California, USA.
                [51 ]Sanquin Research, Nijmegen, The Netherlands.
                [52 ]Tuscany Regional Health Agency, Florence, Italy, I.O.T. and Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy.
                [53 ]Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Italy.
                [54 ]University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
                [55 ]Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
                [56 ]Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
                [57 ]Department of Oncology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
                [58 ]Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
                [59 ]Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.
                [60 ]Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Milan, Italy.
                [61 ]Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart.
                [62 ]University of Tübingen, Germany.
                [63 ]Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
                [64 ]German Cancer Consortium (DKTK), Heidelberg, Germany.
                [65 ]Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
                [66 ]Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
                [67 ]Departments of Anatomy and Neurological Surgery, Indiana University school of Medicine, Indianapolis, IN 46202, USA.
                [68 ]Stark Neuroscience Research Center, Indiana University school of Medicine, Indianapolis, IN 46202, USA.
                [69 ]Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
                [70 ]Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
                [71 ]Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
                [72 ]Department of Biostatistics, University of North Carolina, Chapel Hill, NC.
                [73 ]Boston University School of Medicine, Department of Medicine, Sections of Preventive Medicine and Endocrinology, Boston, MA.
                [74 ]Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield, UK.
                [75 ]Department of Clinical Medical Sciences, Surgical and Health, University of Trieste, Italy.
                [76 ]Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
                [77 ]Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA.
                [78 ]Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minn., USA.
                [79 ]Department of Human Genetics & Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
                [80 ]Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, UK.
                [81 ]National Institute for Health and Welfare, Finland.
                [82 ]Department of General Practice and Primary health Care, University of Helsinki, Finland.
                [83 ]Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland.
                [84 ]Folkhalsan Research Centre, Helsinki, Finland.
                [85 ]Longitudinal Studies Section, Clinical Research Branch, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, United States of America.
                [86 ]Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany.
                [87 ]Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
                [88 ]Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
                [89 ]National Insitute on Aging, National Institutes of Health, Baltimore, MD 20892, USA.
                [90 ]Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK.
                [91 ]Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
                [92 ]EMGO + Institute for Health and Care Research, VU University Medical Centre, Van der Boechorststraat 7, 1081 Bt, Amsterdam, The Netherlands.
                [93 ]Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
                [94 ]Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
                [95 ]Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
                [96 ]Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France.
                [97 ]University Paris-Sud, UMRS 1018, Villejuif, France.
                [98 ]Department of Obstetrics and Gynecology, Southern Medical University, Guangzhou, China.
                [99 ]Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
                [100 ]Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, 17475 Greifswald, Germany.
                [101 ]Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
                [102 ]Washington University, Department of Psychiatry, St.Louis, Missouri, USA.
                [103 ]Department of Epidemiology, Erasmus MC, Rotterdan, the Netherlands.
                [104 ]Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.
                [105 ]Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA.
                [106 ]Hebrew SeniorLife Institute for Aging Research, Boston, MA.
                [107 ]Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115.
                [108 ]Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
                [109 ]Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
                [110 ]School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
                [111 ]Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
                [112 ]Vesalius Research Center (VRC), VIB, Leuven, Belgium.
                [113 ]Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
                [114 ]Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
                [115 ]Department of Medicine, Stanford School of Medicine, Stanford, USA.
                [116 ]Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
                [117 ]KULeuven (University of Leuven), Department of Oncology, Multidisciplinary Breast Center, University Hospitals Leuven, Belgium.
                [118 ]Research Unit of Obstetrics & Gynecology, Institute of Clinical Research, University of Southern denmark, DK.
                [119 ]Interdisciplinary Center Psychopathology and Emotion Regulation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
                [120 ]Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
                [121 ]Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
                [122 ]Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
                [123 ]Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana USA.
                [124 ]IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
                [125 ]Non-communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, UK.
                [126 ]University Groningen, University Medical Center Groningen, Department Pulmonary Medicine and Tuberculosis, GRIAC Research Institute, Groningen, The Netherlands.
                [127 ]Department of Obstetrics and Gynecology, Oulu University Hospital, Finland.
                [128 ]Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu University Hospital/NordLab Oulu, Oulu, Finland.
                [129 ]Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
                [130 ]National Institute on Aging, Intramural Research Program, Baltimore, MD, USA.
                [131 ]Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
                [132 ]Department of Pathology, The University of Melbourne, Melbourne, Australia.
                [133 ]Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, UK.
                [134 ]Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, United Kingdom.
                [135 ]Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
                [136 ]Department of Obstetrics and Gynaecology, Campus Grosshadern, Ludwig-Maximilians- University, Munich, Germany.
                [137 ]Department of Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland.
                [138 ]Institute for Community Medicine, University Medicine Greifswald, 17475 Greifswald, Germany.
                [139 ]DZHK (German Centre for Cardiovascular Research), partner site Greifswald, 17475 Greifswald, Germany.
                [140 ]Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
                [141 ]Department of Endocrinology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
                [142 ]Queensland Insitute of Medical Research, Brisbane, Queensland, Australia.
                [143 ]Peter MacCallum Cancer Centre, Melbourne, Australia.
                [144 ]Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany.
                [145 ]Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany.
                [146 ]Institute of Pathology, Medical Faculty of the University of Bonn, Bonn, Germany.
                [147 ]Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
                [148 ]Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, CB2 0QQ, UK.
                [149 ]Genetics of Obesity and Related Metabolic Traits Program, The Charles Bronfman Institute for Personalized Medicine, The Mindich Child Health and Development Institute, Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1003, New York, NY 10029, USA.
                [150 ]NIHR Oxford Biomedical Research Centre, Churchill Hospital, OX3 7LE Oxford, UK.
                [151 ]Oxford Centre for Diabetes, Endocrinology, & Metabolism, University of Oxford, Churchill Hospital, OX37LJ Oxford, UK.
                [152 ]Geriatric Research and Education Clinical Center (GRECC) - Veterans Administration Medical Center, USA. Baltimore, MD 21201.
                [153 ]Centre of Medical Systems Biology, Leiden, the Netherlands.
                [154 ]Human Genetics Center and Div. of Epidemiology, University of Houston, TX.
                [155 ]Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
                [156 ]Institute of Health Sciences, P.O.Box 5000, FI-90014 University of Oulu, Finland.
                [157 ]Biocenter Oulu, P.O.Box 5000, Aapistie 5A, FI-90014 University of Oulu, Finland.
                [158 ]Department of Children and Young People and Families, National Institute for Health and Welfare, Aapistie 1, Box 310, FI-90101 Oulu, Finland.
                [159 ]Unit of Primary Care, Oulu University Hospital, Kajaanintie 50, P.O.Box 20, FI-90220 Oulu, 90029 OYS, Finland.
                [160 ]Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.
                [161 ]Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
                [162 ]Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, The Capital Region, Copenhagen, Denmark.
                [163 ]Division of Population Health Sciences and Education, St George’s, University of London, Cranmer Terrace, London SW17 0RE, UK.
                [164 ]Department of Obstetrics and Gynecology, University Medicine Greifswald, 17475 Greifswald, Germany.
                [165 ]Boston University School of Medicine, Department of Medicine, Section of General Internal Medicine, Boston, MA.
                [166 ]Department of Paediatrics,University of Cambridge,Cambridge,UK.
                Author notes

                Author Contributions

                Overall project management

                JRBP, FD, CEE, PS, DJT, DFE, KS, JMM, KKO

                Core analyses

                JRBP, FD, CEE, PS, TF, DJT, DIC, TE

                Individual study analysts

                AAR, AD, AG, AJ, AT, AVS, BZA, BF, CEE, DFG, DIC, DJT, DLC, DLK, EA, EKW, EM, EMB, ET, FD, GM, GmM, IMN, JAV, JD, JH, JRBP, JT, JZ, KLL, KM, LLP, LMR, LMY, LS, MM, NF, NTs, PK, PS, RM, SK, SS, SSU, TC, TE, TF, TFo, THP, WQA, ZK

                Individual study data management and generation

                AAR, ACH, AD, ADC, AGU, AJO, AMS, AMu, AP, APo, BAO, CAH, DC, DIC, DJH, DK, DLw, DPK, DPS, DS, EAN, EP, EW, FA, FBH, FG, FR, GD, GE, GGW, HS, HW, ID, JC, JH, JPR, LF, LFr, LM, LMR, MEG, MJS, MJW, MKB, MMb, MP, MW, NA, NJT, NLP, PKM, QW, RH, SB, SC, SG, SL, SR, SSU, TE, US, UT, VS, WLM

                Individual study PIs

                AC, AGU, AH, AJO, AKD, AL, AM, AMD, AMm, AMu, AR, BB, BZA, BHRW, CB, CEP, CG, CH, CMv, DIB, DF, DFE, DJH, DL, DLw, DSP, DPS, DSs, EAS, EB, EEJd, EI, EW, EWD, FBH, FJC, GC, GD, GGG, GW, GW, GWM, HA, HAB, HB, HBe, HF, HN, HS, HV, ID, ILA, JAK, JB, JCC, JGE, JEB, JLH, JMC, JMM, JP, KC, KK, KKO, KP, KS, LC, LF, LJB, MCS, MG, MIM, MJ, MJE, MJH, MJS, MKS, MWB, MZ, NGM, NJW, PAF, PD, PDPP, PFM, PG, PH, PK, PMR, PN, PP, PPG, PR, PV, RJFL, RLM, RW, SB, SBm, SC, SEB, TBH, TDS, TIAS, UH, VG, VK, VS

                [* ] Correspondence to: John R.B. Perry ( john.perry@ 123456mrc-epid.cam.ac.uk ) and Joanne Murabito ( Murabito@ 123456bu.edu )
                Article
                EMS58897
                10.1038/nature13545
                4185210
                25231870
                7e76113a-4320-4eae-95ea-693a40d2ab39
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