title: Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption.
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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authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.
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authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.|Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
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authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.|Department of Genomics of Common Diseases, Imperial College London, London, UK.
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authors.affiliation: Medical Department, University of Leipzig, Germany.|IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
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authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.|William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.|King Abdulaziz University, Jeddah, Saudi Arabia.
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authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA.
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authors.affiliation: Health Disparities Research Section, Clinical Research Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA.
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authors.affiliation: Busselton Population Medical Research Foundation Inc., Busselton, Australia.|PathWest Laboratory Medicine WA, Nedlands, Western Australia.|School of Pathology & Laboratory Medicine, The University of Western Australia, Nedlands, Western Australia.
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authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Mass Eye and Ear Infirmary, Boston, Massachusetts, USA.
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authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA.
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authors.affiliation: Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
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authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum-München, Munich-Neuherberg, Germany.
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authors.affiliation: QIMR Berghofer Medical Research Institute, Queensland, Australia.
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authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum-München, Munich-Neuherberg, Germany.
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authors.initials: M
authors.lastname: Waldenberger
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.|Cardiovascular Health Research Unit, Department of Epidemiology, University of Washington, Seattle, Washington, USA.
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authors.initials: DS
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authors.affiliation: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and Turku University Hospital, Turku, Finland.|Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Raitakari
authors.affiliation: Folkhälsan Research Centre, Helsinki, Finland.|Department of General Practice and Primary health Care, University of Helsinki, Helsinki, Finland.|Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland.
authors.forename: Johan G
authors.initials: JG
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authors.affiliation: Centre for Vision Research, Department of Ophthalmology and the Westmead Millennium Institute, University of Sydney, New South Wales, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Mitchell
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, USA.
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authors.affiliation: Program in Genetic Epidemiology and Statistical Genetics, Harvard School of Public Health, Boston, Massachusetts, USA.
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authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.|Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Rimm
authors.affiliation: Department of Biological Psychology / Netherlands Twin Register, VU University, Amsterdam, The Netherlands.
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.affiliation: Washington University School of Medicine, Department of Genetics, Division of Statistical Genomics, St Louis, Missouri, USA.
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.affiliation: Medical Research Council (MRC) Epidemiology Unit, University of Cambridge, Cambridge, UK.|The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, New York, USA.|The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Ruth Jf
authors.initials: RJ
authors.lastname: Loos
authors.affiliation: Medical Research Council (MRC) Epidemiology Unit, University of Cambridge, Cambridge, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.affiliation: Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Vollenweider
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Caporaso
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medicine Greifswald, HELIOS Hospital Stralsund, Germany.
authors.forename: Hans Jörgen
authors.initials: HJ
authors.lastname: Grabe
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Marian L
authors.initials: ML
authors.lastname: Neuhouser
authors.affiliation: Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Bruce Hr
authors.initials: BH
authors.lastname: Wolffenbuttel
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.|Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Hu
authors.affiliation: 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.|School of Population Health, University of South Australia, Adelaide, Australia.|South Australian Health and Medical Research Institute, Adelaide, Australia.
authors.forename: Elina
authors.initials: E
authors.lastname: Hyppönen
authors.affiliation: Institute of Health Sciences, University of Oulu, Oulu, Finland.|Biocenter Oulu, University of Oulu, Oulu, Finland.|Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPE) Centre for Environment and Health, School of Public Health, Imperial College London, UK.|Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland.|Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Järvelin
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.|The Framingham Heart Study, Framingham, Massachusetts, USA.
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.affiliation: Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.|Department of Clinical Sciences, Lund University, Malmö, Sweden.|Department of Public Health & Clinical Medicine, Section for Medicine, Umeå University, Umeå, Sweden.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Franks
authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.|Netherlands Consortium for Healthy Ageing and National Genomics Initiative, Leiden, The Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Heiss
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.affiliation: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
authors.affiliation: Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Nettleton
authors.affiliation: 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, Singapore.
authors.forename: Rob M
authors.initials: RM
authors.lastname: van Dam
authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D040503:Coffea / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics; D005247:Feeding Behavior; D055106:Genome-Wide Association Study; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D019208:Brain-Derived Neurotrophic Factor; C485100:GCKR protein, human; C116385:MLXIPL protein, human; D019388:Cytochrome P-450 CYP1A2