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Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption.

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Molecular psychiatry

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      Abstract

      Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.

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      Most cited references 36

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      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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        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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          Systematic analysis of chromatin state dynamics in nine human cell types

          Chromatin profiling has emerged as a powerful means for genome annotation and detection of regulatory activity. Here we map nine chromatin marks across nine cell types to systematically characterize regulatory elements, their cell type-specificities, and their functional interactions. Focusing on cell type-specific patterns of promoters and enhancers, we define multi-cell activity profiles for chromatin state, gene expression, regulatory motif enrichment, and regulator expression. We use correlations between these profiles to link enhancers to putative target genes, and predict the cell type-specific activators and repressors that modulate them. The resulting annotations and regulatory predictions have implications for interpreting genome-wide association studies. Top-scoring disease SNPs are frequently positioned within enhancer elements specifically active in relevant cell types, and in some cases affect a motif instance for a predicted regulator, thus proposing a mechanism for the association. Our study presents a general framework for deciphering cis-regulatory connections and their roles in disease.
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            Author and article information

            Affiliations
            [1 ] 1] Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
            [2 ] Queensland Brain Institute, The University of Queensland, Queensland, Australia.
            [3 ] 1] Estonian Genome Center, University of Tartu, Tartu, Estonia [2] Division of Endocrinology, Children's Hospital Boston, Boston, MA, USA [3] Department of Genetics, Harvard Medical School, Boston, MA, USA [4] Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
            [4 ] Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health (NIH), Bethesda, MD, USA.
            [5 ] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Karolinska, Sweden.
            [6 ] Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
            [7 ] Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
            [8 ] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
            [9 ] Estonian Genome Center, University of Tartu, Tartu, Estonia.
            [10 ] Department of Clinical Sciences, Lund University, Malmö, Sweden.
            [11 ] Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
            [12 ] Institute of Health Sciences, University of Oulu, Oulu, Finland.
            [13 ] Centre for Paediatric Epidemiology and Biostatistics, Medical Research Council (MRC) Centre of Epidemiology for Child Health, University College London Institute of Child Health, London, UK.
            [14 ] Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands.
            [15 ] Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Germany.
            [16 ] Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
            [17 ] Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland.
            [18 ] Institute of Genetic Epidemiology, Helmholtz Zentrum-München, Munich-Neuherberg, Germany.
            [19 ] Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
            [20 ] Washington University School of Medicine, Department of Genetics, Division of Statistical Genomics, St Louis, MO, USA.
            [21 ] Department of Biological Psychology/Netherlands Twin Register, VU University, Amsterdam, The Netherlands.
            [22 ] Medical Research Council (MRC) Epidemiology Unit, University of Cambridge, Cambridge, UK.
            [23 ] Centre for Vision Research, Department of Ophthalmology and the Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
            [24 ] 1] Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland [2] Folkhälsan Research Centre, Helsinki, Finland.
            [25 ] 1] Department of Food and Environmental Sciences, University of Helsinki, Helsinki, Finland [2] Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and Turku University Hospital, Turku, Finland.
            [26 ] Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
            [27 ] Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
            [28 ] University of Mississippi Medical Center, Jackson, MI, USA.
            [29 ] Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD, USA.
            [30 ] Statens Serum Institut, Department of Epidemiology Research, Copenhagen, Denmark.
            [31 ] 1] Busselton Population Medical Research Foundation Inc., Busselton, Western Australia, Australia [2] PathWest Laboratory Medicine WA, Nedlands, Western Australia, Australia [3] School of Pathology and Laboratory Medicine, The University of Western Australia, Nedlands, Western Australia, Australia [4] School of Population Health, The University of Western Australia, Nedlands, Western Australia, Australia.
            [32 ] Harokopio University, Athens, Greece.
            [33 ] Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Bethesda, MD, USA.
            [34 ] Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK.
            [35 ] QIMR Berghofer Medical Research Institute, Queensland, Australia.
            [36 ] Department of Biostatistics, University of NC at Chapel Hill, Chapel Hill, NC, USA.
            [37 ] Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
            [38 ] 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands [2] Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands [3] Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.
            [39 ] 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands [2] Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.
            [40 ] 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands [2] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
            [41 ] 1] Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK [2] University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
            [42 ] Department of Odontology, Umeå University, Umeå, Sweden.
            [43 ] 1] Institute of Health Sciences, University of Oulu, Oulu, Finland [2] Biocenter Oulu, University of Oulu, Oulu, Finland [3] Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, UK.
            [44 ] Institute for Community Medicine, University Medicine Greifswald, Germany.
            [45 ] Department of Prosthodontics, Gerodontology and Biomaterials, Center of Oral Health, University Medicine Greifswald, Germany.
            [46 ] Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
            [47 ] 1] Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland [2] Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland [3] Swiss Institute of Bioinformatics, Lausanne, Switzerland.
            [48 ] Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
            [49 ] Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
            [50 ] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
            [51 ] Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
            [52 ] Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
            [53 ] Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
            [54 ] Department of Clinical Physiology, Tampere University Hospital and School of Medicine University of Tampere, Tampere, Finland.
            [55 ] Department of Clinical Chemistry, Fimlab Laboratories, and School of Medicine, University of Tampere, Tampere, Finland.
            [56 ] Department of Medicine, University of Turku and Turku University Hospital, Turku, Finland.
            [57 ] 1] Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Department of Nutrition, Harvard School of Public Health, Boston, MA, USA [3] Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA [4] Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA.
            [58 ] Beth Israel Deaconess Medical Center, Boston, MA, USA.
            [59 ] 1] Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA [2] Cardiovascular Health Research Unit, Department of Epidemiology, University of Washington, Seattle, WA, USA [3] Department of Health Services, University of Washington, Seattle, WA, USA [4] Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
            [60 ] Institute of Epidemiology, Helmholtz Zentrum-München, Munich-Neuherberg, Germany.
            [61 ] Department of Psychiatry, Washington University, St Louis, MO, USA.
            [62 ] Department for Psychiatry, Johannes-Gutenberg-University, Mainz, Germany.
            [63 ] School of Applied Sciences, University of Mississippi, Oxford, Mississippi, USA.
            [64 ] Clinical Laboratory and Nutritional Sciences, University of MA Lowell, Lowell, MA, USA.
            [65 ] 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK [2] Department of Genomics of Common Diseases, Imperial College London, London, UK.
            [66 ] 1] Medical Department, University of Leipzig, Leipzig, Germany [2] IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
            [67 ] 1] Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK [2] William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK [3] King Abdulaziz University, Jeddah, Saudi Arabia.
            [68 ] William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
            [69 ] Wake Forest School of Medicine, Winston-Salem, NC, USA.
            [70 ] Wake Forest University Health Sciences, Winston-Salem, NC, USA.
            [71 ] Center for Non-Communicable Diseases, Pakistan.
            [72 ] Health Disparities Research Section, Clinical Research Branch, National Institute on Aging, NIH, Baltimore, MD, USA.
            [73 ] Laboratory of Personality and Cognition, National Institute on Aging, NIH, Baltimore, MD, USA.
            [74 ] Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
            [75 ] 1] Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA [2] Department of Surgery, Harvard Medical School, Boston, MA, USA.
            [76 ] Monell Chemical Senses Center, Philadelphia, Pennsylvania, USA.
            [77 ] 1] Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK [2] Center for Non-Communicable Diseases, Pakistan.
            [78 ] Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
            [79 ] 1] Busselton Population Medical Research Foundation Inc., Busselton, Western Australia, Australia [2] PathWest Laboratory Medicine WA, Nedlands, Western Australia, Australia [3] School of Pathology and Laboratory Medicine, The University of Western Australia, Nedlands, Western Australia, Australia.
            [80 ] 1] Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Mass Eye and Ear Infirmary, Boston, MA, USA.
            [81 ] Geriatric Unit, Azienda Sanitaria Firenze, Florence, Italy.
            [82 ] Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA.
            [83 ] 1] Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Division of Gastroenterology, MA General Hospital, Boston, MA, USA.
            [84 ] Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
            [85 ] Research Unit of Molecular Epidemiology, Helmholtz Zentrum-München, Munich-Neuherberg, Germany.
            [86 ] 1] Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA [2] Cardiovascular Health Research Unit, Department of Epidemiology, University of Washington, Seattle, WA, USA.
            [87 ] 1] Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and Turku University Hospital, Turku, Finland [2] Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
            [88 ] 1] Folkhälsan Research Centre, Helsinki, Finland [2] Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland [3] Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland.
            [89 ] 1] Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA, USA.
            [90 ] Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, MA, USA.
            [91 ] 1] Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Department of Nutrition, Harvard School of Public Health, Boston, MA, USA [3] Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
            [92 ] 1] Medical Research Council (MRC) Epidemiology Unit, University of Cambridge, Cambridge, UK [2] The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, NY, USA [3] The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY, USA.
            [93 ] Department of Psychiatry and Psychotherapy, University Medicine Greifswald, HELIOS Hospital Stralsund, Germany.
            [94 ] Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
            [95 ] 1] Centre for Paediatric Epidemiology and Biostatistics, Medical Research Council (MRC) Centre of Epidemiology for Child Health, University College London Institute of Child Health, London, UK [2] School of Population Health, University of South Australia, Adelaide, South Australia, Australia [3] South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
            [96 ] 1] Institute of Health Sciences, University of Oulu, Oulu, Finland [2] Biocenter Oulu, University of Oulu, Oulu, Finland [3] Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, UK [4] Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland [5] Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
            [97 ] 1] Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA [2] The Framingham Heart Study, Framingham, MA, USA.
            [98 ] 1] Department of Nutrition, Harvard School of Public Health, Boston, MA, USA [2] Department of Clinical Sciences, Lund University, Malmö, Sweden [3] Department of Public Health and Clinical Medicine, Section for Medicine, Umeå University, Umeå, Sweden.
            [99 ] 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands [2] Netherlands Consortium for Healthy Ageing and National Genomics Initiative, Leiden, The Netherlands.
            [100 ] 1] Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
            [101 ] Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA.
            [102 ] Saw Swee Hock School of Public Health and Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore.
            Journal
            Mol. Psychiatry
            Molecular psychiatry
            1476-5578
            1359-4184
            May 2015
            : 20
            : 5
            mp2014107 10.1038/mp.2014.107 25288136 4388784 NIHMS648794
            , , ,

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