title: Genome-wide association study of caffeine metabolites provides new insights to caffeine metabolism and dietary caffeine-consumption behavior.
abstract: Caffeine is the most widely consumed psychoactive substance in the world and presents with wide interindividual variation in metabolism. This variation may modify potential adverse or beneficial effects of caffeine on health. We conducted a genome-wide association study (GWAS) of plasma caffeine, paraxanthine, theophylline, theobromine and paraxanthine/caffeine ratio among up to 9,876 individuals of European ancestry from six population-based studies. A single SNP at 6p23 (near CD83) and several SNPs at 7p21 (near AHR), 15q24 (near CYP1A2) and 19q13.2 (near CYP2A6) met GW-significance (P < 5 × 10-8) and were associated with one or more metabolites. Variants at 7p21 and 15q24 associated with higher plasma caffeine and lower plasma paraxanthine/caffeine (slow caffeine metabolism) were previously associated with lower coffee and caffeine consumption behavior in GWAS. Variants at 19q13.2 associated with higher plasma paraxanthine/caffeine (slow paraxanthine metabolism) were also associated with lower coffee consumption in the UK Biobank (n = 94 343, P < 1.0 × 10-6). Variants at 2p24 (in GCKR), 4q22 (in ABCG2) and 7q11.23 (near POR) that were previously associated with coffee consumption in GWAS were nominally associated with plasma caffeine or its metabolites. Taken together, we have identified genetic factors contributing to variation in caffeine metabolism and confirm an important modulating role of systemic caffeine levels in dietary caffeine consumption behavior. Moreover, candidate genes identified encode proteins with important clinical functions that extend beyond caffeine metabolism.
authors.affiliation: Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, USA.
authors.forename: Marilyn C
authors.initials: MC
authors.lastname: Cornelis
authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.|DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Kacprowski
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas Hospital, London, UK.
authors.forename: Cristina
authors.initials: C
authors.lastname: Menni
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gustafsson
authors.affiliation: Division of Chronic Diseases, University Institute of Social and Preventive Medicine (IUMSP), University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
authors.forename: Edward
authors.initials: E
authors.lastname: Pivin
authors.affiliation: Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Lehrstuhl für Experimentelle Genetik, Technische Universität München, Freising-Weihenstephan, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.affiliation: Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Artati
authors.affiliation: Department of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Lausanne, Switzerland.|School of Pharmaceutical Sciences, University of Geneve, University of Lausanne, Geneva, Switzerland.
authors.forename: Chin B
authors.initials: CB
authors.lastname: Eap
authors.affiliation: Cardiology, Department of Specialties of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland.|Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, USA.
authors.forename: Georg
authors.initials: G
authors.lastname: Ehret
authors.affiliation: DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.|Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Germany.
authors.forename: Nele
authors.initials: N
authors.lastname: Friedrich
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ganna
authors.affiliation: Division of Chronic Diseases, University Institute of Social and Preventive Medicine (IUMSP), University Hospital of Lausanne (CHUV), Lausanne, Switzerland.|Department of Community Medicine and Primary Care and Emergency Medicine, Unit of Population Epidemiology, Geneva University Hospitals, Geneva, Switzerland.|Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, USA.
authors.forename: Idris
authors.initials: I
authors.lastname: Guessous
authors.affiliation: Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Homuth
authors.affiliation: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.affiliation: Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden.
authors.forename: Patrik K
authors.initials: PK
authors.lastname: Magnusson
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas Hospital, London, UK.
authors.forename: Massimo
authors.initials: M
authors.lastname: Mangino
authors.affiliation: Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Pedersen
authors.affiliation: DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.|Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Germany.
authors.forename: Maik
authors.initials: M
authors.lastname: Pietzner
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Doha, Qatar.
authors.forename: Karsten
authors.initials: K
authors.lastname: Suhre
authors.affiliation: Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.affiliation: Division of Chronic Diseases, University Institute of Social and Preventive Medicine (IUMSP), University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
authors.forename: Murielle
authors.initials: M
authors.lastname: Bochud
authors.affiliation: Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas Hospital, London, UK.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Grabe
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.|Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
mesh_terms: D015703:Antigens, CD / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002110:Caffeine / Q000097:blood / Q000235:genetics*; D003069:Coffee / Q000235:genetics / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics* / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D013805:Theobromine / Q000097:blood; D013806:Theophylline / Q000097:blood; D044465:White People; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D051792:Basic Helix-Loop-Helix Proteins; D002110:Caffeine; D003069:Coffee; D019388:Cytochrome P-450 CYP1A2; D065637:Cytochrome P-450 CYP2A6; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D018336:Receptors, Aryl Hydrocarbon; D013805:Theobromine; D013806:Theophylline; D000097802:CD83 Antigen; C111235:AHR protein, human; C504573:CYP1A2 protein, human; C585710:CYP2A6 protein, human; C021183:1,7-dimethylxanthine