Journal
MOLECULAR PSYCHIATRY
Volume 17, Issue 11, Pages 1116-1129Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/mp.2011.101
Keywords
coffee; P450; NRCAM; CAB39L; Parkinson's disease; CYP1A1/CYP1A2
Funding
- EUROSPAN (European Special Populations Research Network)
- European Commission [018947, LSHG-CT-2006-01947]
- Netherlands Organization for Scientific Research
- Erasmus MC
- Centre for Medical Systems Biology (CMSB)
- Netherlands Brain Foundation (HersenStichting Nederland)
- Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany
- German Federal Ministry of Education and Research (BMBF)
- German National Genome Research Network (NGFN)
- Munich Center of Health Sciences (MC Health) as part of LMUinnovativ
- Genetic basis of anxiety and depression [904-61-090]
- Twin-family database for behavior genomics studies [480-04-004]
- ZonMW [31160008]
- Center for Medical Systems Biology (NWO Genomics)
- Spinozapremie [SPI 56-464-14192]
- Neuroscience campus Amsterdam (NCA-VU)
- Genetics of Mental Illness [ERC 230374]
- Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health
- NWO [VENI 451-06-004]
- National Breast Cancer Foundation and Cancer Australia [628333]
- National Breast Cancer Foundation
- National Health and Medical Research Council (NHMRC)
- Queensland Cancer Fund
- Cancer Councils of New South Wales, Victoria, Tasmania and South Australia
- Cancer Foundation of Western Australia
- Australian National Health and Medical Research Council [241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498]
- Australian Research Council [A7960034, A79906588, A79801419, DP0770096, DP0212016, DP0343921]
- FP-5 GenomEUtwin Project [QLG2-CT-2002-01254]
- US National Institutes of Health (NIH) [AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206]
- Netherlands Scientific Organization [NWO 480-05-003]
- Cancer Council Queensland
- Erasmus Medical Center and Erasmus University Rotterdam
- Netherlands Organization for Scientific Research (NWO)
- Netherlands Organization for Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- Netherlands Genomics Initiative
- Ministry of Education, Culture and Science
- Ministry of Health, Welfare and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
- Internationaal Parkinson Fonds
- Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]
- Ministry of Cultural Affairs
- Social Ministry of the Federal State of Mecklenburg-West Pomerania
- Siemens Healthcare, Erlangen, Germany
- Federal State of Mecklenburg, West Pomerania
- German Research Foundation
- Federal Ministry of Education and Research Germany
- JanssenCilag
- Lundbeck
- Eli Lilly
- Novartis
- AstraZeneca
- SALUS-Institute for Trend-Research and Therapy Evaluation in Mental Health
- Wellcome Trust
- European Community [HEALTH-F2-2008-201865-GEFOS, HEALTH-F4-2007-201413]
- Department of Health through the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre
- Biotechnology and Biological Sciences Research Council (BBSRC) [G20234]
- National Eye Institute through an NIH/CIDR
- Netherlands Organization of Scientific Research NWO [175.010.2007.006]
- Economic Structure Enhancing Fund (FES) of the Dutch government
- Ministry of Economic Affairs
- Ministry for Health, Welfare and Sports
- Northern Netherlands Collaboration of Provinces (SNN)
- Province of Groningen
- University Medical Center Groningen
- University of Groningen
- Dutch Kidney Foundation
- Dutch Diabetes Research Foundation
- National Institute for Health Research [SRF/01/010] Funding Source: researchfish
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Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N = 18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values = 1.6 x 10(-11) and 2.7 x 10(-11)), which were also in strong linkage disequilibrium (r(2) = 0.7) with each other, lie in the 23-kb long commonly shared 5' flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value = 3.9 x 10(-09)) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value = 7.1 x 10(-09))-an SNP associated with blood pressure-in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value = 2.2 x 10(-05)) and Parkinson's disease pathways (P-value = 3.6 x 10(-05)). Molecular Psychiatry (2012) 17, 1116-1129; doi: 10.1038/mp.2011.101; published online 30 August 2011
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