Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM

N. Amin; E. Byrne; J. Johnson; G. Chenevix-Trench; S. Walter; I. M. Nolte; J. M. Vink; R. Rawal; M. Mangino; A. Teumer; J. C. Keers; G. Verwoert; S. Baumeister; R. Biffar; A. Petersmann; N. Dahmen; A. Doering; A. Isaacs; L. Broer; N. R. Wray; G. W. Montgomery; D. Levy; B. M. Psaty; V. Gudnason; A. Chakravarti; P. Sulem; D. F. Gudbjartsson; L. A. Kiemeney; U. Thorsteinsdottir; K. Stefansson; F. J.A. Van Rooij; Y. S. Aulchenko; J. J. Hottenga; F. R. Rivadeneira; A. Hofman; A. G. Uitterlinden; C. J. Hammond; S. Y. Shin; A. Ikram; J. C.M. Witteman; A. C.J.W. Janssens; H. Snieder; H. Tiemeier; B. H.R. Wolfenbuttel; B. A. Oostra; A. C. Heath; E. Wichmann; T. D. Spector; H. J. Grabe; D. I. Boomsma; N. G. Martin; C. M. Van Duijn

doi:10.1038/mp.2011.101

Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM

N. Amin, E. Byrne, J. Johnson, G. Chenevix-Trench, S. Walter, I. M. Nolte, J. M. Vink, R. Rawal, M. Mangino, A. Teumer, J. C. Keers, G. Verwoert, S. Baumeister, R. Biffar, A. Petersmann, N. Dahmen, A. Doering, A. Isaacs, L. Broer, N. R. WrayG. W. Montgomery, D. Levy, B. M. Psaty, V. Gudnason, A. Chakravarti, P. Sulem, D. F. Gudbjartsson, L. A. Kiemeney, U. Thorsteinsdottir, K. Stefansson, F. J.A. Van Rooij, Y. S. Aulchenko, J. J. Hottenga, F. R. Rivadeneira, A. Hofman, A. G. Uitterlinden, C. J. Hammond, S. Y. Shin, A. Ikram, J. C.M. Witteman, A. C.J.W. Janssens, H. Snieder, H. Tiemeier, B. H.R. Wolfenbuttel, B. A. Oostra, A. C. Heath, E. Wichmann, T. D. Spector, H. J. Grabe, D. I. Boomsma, N. G. Martin, C. M. Van Duijn

Research output: Contribution to journal › Review article › peer-review

Abstract

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 (N18 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-values1.6 × 10^-11 and 2.7 × 10^-11), which were also in strong linkage disequilibrium (r² 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-value3.9 × 10 09) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value7.1 × 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-value2.2 × 10 ^-05) and Parkinson's disease pathways (P-value3.6 × 10 ^-05).

Original language	English (US)
Pages (from-to)	1116-1129
Number of pages	14
Journal	Molecular psychiatry
Volume	17
Issue number	11
DOIs	https://doi.org/10.1038/mp.2011.101
State	Published - Nov 2012
Externally published	Yes

Keywords

CAB39L
CYP1A1/CYP1A2
NRCAM
P450
Parkinson's disease
coffee

ASJC Scopus subject areas

Molecular Biology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

Access to Document

10.1038/mp.2011.101

Cite this

Amin, N., Byrne, E., Johnson, J., Chenevix-Trench, G., Walter, S., Nolte, I. M., Vink, J. M., Rawal, R., Mangino, M., Teumer, A., Keers, J. C., Verwoert, G., Baumeister, S., Biffar, R., Petersmann, A., Dahmen, N., Doering, A., Isaacs, A., Broer, L., ... Van Duijn, C. M. (2012). Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM. Molecular psychiatry, 17(11), 1116-1129. https://doi.org/10.1038/mp.2011.101

Amin, N, Byrne, E, Johnson, J, Chenevix-Trench, G, Walter, S, Nolte, IM, Vink, JM, Rawal, R, Mangino, M, Teumer, A, Keers, JC, Verwoert, G, Baumeister, S, Biffar, R, Petersmann, A, Dahmen, N, Doering, A, Isaacs, A, Broer, L, Wray, NR, Montgomery, GW, Levy, D, Psaty, BM, Gudnason, V, Chakravarti, A, Sulem, P, Gudbjartsson, DF, Kiemeney, LA, Thorsteinsdottir, U, Stefansson, K, Van Rooij, FJA, Aulchenko, YS, Hottenga, JJ, Rivadeneira, FR, Hofman, A, Uitterlinden, AG, Hammond, CJ, Shin, SY, Ikram, A, Witteman, JCM, Janssens, ACJW, Snieder, H, Tiemeier, H, Wolfenbuttel, BHR, Oostra, BA, Heath, AC, Wichmann, E, Spector, TD, Grabe, HJ, Boomsma, DI, Martin, NG & Van Duijn, CM 2012, 'Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM', Molecular psychiatry, vol. 17, no. 11, pp. 1116-1129. https://doi.org/10.1038/mp.2011.101

@article{b53e95e7c5464036a1398841b07fd6db,

title = "Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM",

abstract = "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 (N18 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-values1.6 × 10-11 and 2.7 × 10-11), which were also in strong linkage disequilibrium (r2 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-value3.9 × 10 09) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value7.1 × 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-value2.2 × 10 -05) and Parkinson's disease pathways (P-value3.6 × 10 -05).",

keywords = "CAB39L, CYP1A1/CYP1A2, NRCAM, P450, Parkinson's disease, coffee",

author = "N. Amin and E. Byrne and J. Johnson and G. Chenevix-Trench and S. Walter and Nolte, {I. M.} and Vink, {J. M.} and R. Rawal and M. Mangino and A. Teumer and Keers, {J. C.} and G. Verwoert and S. Baumeister and R. Biffar and A. Petersmann and N. Dahmen and A. Doering and A. Isaacs and L. Broer and Wray, {N. R.} and Montgomery, {G. W.} and D. Levy and Psaty, {B. M.} and V. Gudnason and A. Chakravarti and P. Sulem and Gudbjartsson, {D. F.} and Kiemeney, {L. A.} and U. Thorsteinsdottir and K. Stefansson and {Van Rooij}, {F. J.A.} and Aulchenko, {Y. S.} and Hottenga, {J. J.} and Rivadeneira, {F. R.} and A. Hofman and Uitterlinden, {A. G.} and Hammond, {C. J.} and Shin, {S. Y.} and A. Ikram and Witteman, {J. C.M.} and Janssens, {A. C.J.W.} and H. Snieder and H. Tiemeier and Wolfenbuttel, {B. H.R.} and Oostra, {B. A.} and Heath, {A. C.} and E. Wichmann and Spector, {T. D.} and Grabe, {H. J.} and Boomsma, {D. I.} and Martin, {N. G.} and {Van Duijn}, {C. M.}",

note = "Funding Information: genomics studies (480-04-004); Genetic determinants of risk behavior in relation to alcohol use and alcohol use disorder: a developmental perspective (ZonMW Addiction 31160008), Center for Medical Systems Biology (NWO Genomics); Spinozapremie (SPI 56-464-14192); Neuroscience campus Amsterdam (NCA-VU); and Genetics of Mental Illness (ERC 230374). Genotyping was funded in part by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health. JMV is financially supported by NWO (VENI 451-06-004). QIMR: We thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, as well as the Clinical Follow-Up Study (funded 2001–2009 by NHMRC and currently by the National Breast Cancer Foundation and Cancer Australia no. 628333) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. We thank the twins and their families for their participation. We also thank Ann Eldridge, Marlene Grace, Kerrie McAloney (sample collection); Lisa Bowdler, Steven Crooks (DNA processing); Dale Nyholt, Sarah Medland and Scott Gordon (imputation and genotyping QC); Allan McRae and Peter Visscher for helpful advice and input. Funding was provided by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498), the Australian Research Council (A7960034, A79906588, A79801419, DP0770096, DP0212016, DP0343921), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254) and the US National Institutes of Health (NIH grants AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206). A portion of the genotyping on which this study was based (Illumina 370K scans on 4300 individuals) was carried out at the Center for Inherited Disease Research, Baltimore (CIDR), through an access award to our late colleague Dr Richard Todd (Psychiatry, Washington University School of Medicine, St Louis). Statistical analyses were carried out on the Genetic Cluster Computer, which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003). GWM and GCT are supported by the National Health and Medical Research Council (NHMRC) Fellowship Scheme. JJ was financially supported by the Cancer Council Queensland. Rotterdam Study (RS-I and RS-II): The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam, The Netherlands Organization for Scientific Research (NWO), The Netherlands Organization for Health Research and Development (ZonMw), The Research Institute for Diseases in the Elderly (RIDE), The Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. The contribution of inhabitants, general practitioners and pharmacists of the Ommoord district to the Rotterdam Study is gratefully acknowledged. AI was financially supported by the Inter-nationaal Parkinson Fonds. The Study of Health in Pomerania (SHIP): SHIP is part of the Community Medicine Research net of the University of Greifs-wald, Germany, which is funded by the Federal Ministry of Education and Research (grants nos 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg, West Pomerania. The University of Greifswald is a member of the {\textquoteleft}Center of Knowledge Interchange{\textquoteright} program of the Siemens AG. HJG was supported by the German Research Foundation; the Federal Ministry of Education and Research Germany; speakers honoraria from Bristol-Myers Squibb, Eli Lilly, Novartis, Eisai, Wyeth, Pfizer, Boehringer Ingelheim, Servier and travel funds from Janssen-Cilag, Lundbeck, Eli Lilly, Novartis, AstraZeneca and SALUS-Institute for Trend-Research and Therapy Evaluation in Mental Health. Twins UK: The study was funded by the Wellcome Trust; European Community{\textquoteright}s Seventh Framework Programme (FP7/2007– 2013)/grant agreement HEALTH-F2-2008-201865-GE-FOS and (FP7/2007–2013), ENGAGE project grant agreement HEALTH-F4-2007-201413 and the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254). The study also receives support from the Department of Health through the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy{\textquoteright}s & St Thomas{\textquoteright} NHS Foundation Trust in partnership with King{\textquoteright}s College London. TDS is an NIHR senior Investigator. The project also received support from a Biotechnology and Biological Sciences Research Council (BBSRC) project grant. (G20234). We acknowledge the funding and support of the National Eye Institute through an NIH/CIDR genotyping project (PI: Terri Young){\textquoteright}. We thank the staff from the Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation, Quality Control and Genotyping led by Leena Peltonen and Panos Deloukas; Le Centre National de G{\'e}notypage, France, led by Mark Lathrop, for genotyping; Duke University, NC, USA, led by David Goldstein, for genotyping; and the Finnish Institute of Molecular Medicine, Finnish Genome Center, University of Helsinki, led by Aarno Palotie. LifeLines: The LifeLines Cohort Study, and generation and management of GWAS genotype data for the LifeLines Cohort Study is supported by the Netherlands Organization of Scientific Research NWO (grant 175.010.2007.006), the Economic Structure Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation and Dutch Diabetes Research Foundation. We thank Behrooz Alizadeh, Annemieke Boesjes, Marcel Bruinenberg, Noortje Festen, Ilja Nolte, Lude Franke and Mitra Valimohammadi for their help in creating the GWAS database, and Rob Bieringa, Joost Keers, Ren{\'e} Oostergo, Rosalie Visser and Judith Vonk for their work related to data-collection and validation. We are grateful to the study participants, the staff from the LifeLines Cohort Study and Medical Biobank Northern Netherlands, and the participating general practitioners and pharmacists. Funding Information: ERF: The genotyping for the ERF study was supported by EUROSPAN (European Special Populations Research Network) and the European Commission FP6 STRP grant (018947; LSHG-CT-2006-01947). The ERF study was further supported by grants from the Netherlands Organization for Scientific Research, Erasmus MC, the Centre for Medical Systems Biology (CMSB) and the Netherlands Brain Foundation (HersenStichting Nederland). We are grateful to all patients and their relatives, general practitioners and neurologists for their contributions and to P Veraart for her help in genealogy, Jeannette Vergeer for the supervision of the laboratory work and P Snijders for his help in data collection. We acknowledge Internationale Stichting Alzheimer Onderzoek (ISAO) and Hersenstichting Netherlands. KORA: The KORA Augsburg studies were financed by the Helmholtz Zentrum M{\"u}nchen, German Research Center for Environmental Health, Neuherberg, Germany, and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was financed by the German National Genome Research Network (NGFN). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. Netherlands Twin Register(NTR): We acknowledge support from: Genetic basis of anxiety and depression (904-61-090); Twin-family database for behavior",

year = "2012",

month = nov,

doi = "10.1038/mp.2011.101",

language = "English (US)",

volume = "17",

pages = "1116--1129",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "11",

}

TY - JOUR

T1 - Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM

AU - Amin, N.

AU - Byrne, E.

AU - Johnson, J.

AU - Chenevix-Trench, G.

AU - Walter, S.

AU - Nolte, I. M.

AU - Vink, J. M.

AU - Rawal, R.

AU - Mangino, M.

AU - Teumer, A.

AU - Keers, J. C.

AU - Verwoert, G.

AU - Baumeister, S.

AU - Biffar, R.

AU - Petersmann, A.

AU - Dahmen, N.

AU - Doering, A.

AU - Isaacs, A.

AU - Broer, L.

AU - Wray, N. R.

AU - Montgomery, G. W.

AU - Levy, D.

AU - Psaty, B. M.

AU - Gudnason, V.

AU - Chakravarti, A.

AU - Sulem, P.

AU - Gudbjartsson, D. F.

AU - Kiemeney, L. A.

AU - Thorsteinsdottir, U.

AU - Stefansson, K.

AU - Van Rooij, F. J.A.

AU - Aulchenko, Y. S.

AU - Hottenga, J. J.

AU - Rivadeneira, F. R.

AU - Hofman, A.

AU - Uitterlinden, A. G.

AU - Hammond, C. J.

AU - Shin, S. Y.

AU - Ikram, A.

AU - Witteman, J. C.M.

AU - Janssens, A. C.J.W.

AU - Snieder, H.

AU - Tiemeier, H.

AU - Wolfenbuttel, B. H.R.

AU - Oostra, B. A.

AU - Heath, A. C.

AU - Wichmann, E.

AU - Spector, T. D.

AU - Grabe, H. J.

AU - Boomsma, D. I.

AU - Martin, N. G.

AU - Van Duijn, C. M.

N1 - Funding Information: genomics studies (480-04-004); Genetic determinants of risk behavior in relation to alcohol use and alcohol use disorder: a developmental perspective (ZonMW Addiction 31160008), Center for Medical Systems Biology (NWO Genomics); Spinozapremie (SPI 56-464-14192); Neuroscience campus Amsterdam (NCA-VU); and Genetics of Mental Illness (ERC 230374). Genotyping was funded in part by the Genetic Association Information Network (GAIN) of the Foundation for the US National Institutes of Health. JMV is financially supported by NWO (VENI 451-06-004). QIMR: We thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, as well as the Clinical Follow-Up Study (funded 2001–2009 by NHMRC and currently by the National Breast Cancer Foundation and Cancer Australia no. 628333) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. We thank the twins and their families for their participation. We also thank Ann Eldridge, Marlene Grace, Kerrie McAloney (sample collection); Lisa Bowdler, Steven Crooks (DNA processing); Dale Nyholt, Sarah Medland and Scott Gordon (imputation and genotyping QC); Allan McRae and Peter Visscher for helpful advice and input. Funding was provided by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498), the Australian Research Council (A7960034, A79906588, A79801419, DP0770096, DP0212016, DP0343921), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254) and the US National Institutes of Health (NIH grants AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206). A portion of the genotyping on which this study was based (Illumina 370K scans on 4300 individuals) was carried out at the Center for Inherited Disease Research, Baltimore (CIDR), through an access award to our late colleague Dr Richard Todd (Psychiatry, Washington University School of Medicine, St Louis). Statistical analyses were carried out on the Genetic Cluster Computer, which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003). GWM and GCT are supported by the National Health and Medical Research Council (NHMRC) Fellowship Scheme. JJ was financially supported by the Cancer Council Queensland. Rotterdam Study (RS-I and RS-II): The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam, The Netherlands Organization for Scientific Research (NWO), The Netherlands Organization for Health Research and Development (ZonMw), The Research Institute for Diseases in the Elderly (RIDE), The Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. The contribution of inhabitants, general practitioners and pharmacists of the Ommoord district to the Rotterdam Study is gratefully acknowledged. AI was financially supported by the Inter-nationaal Parkinson Fonds. The Study of Health in Pomerania (SHIP): SHIP is part of the Community Medicine Research net of the University of Greifs-wald, Germany, which is funded by the Federal Ministry of Education and Research (grants nos 01ZZ9603, 01ZZ0103 and 01ZZ0403), the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg, West Pomerania. The University of Greifswald is a member of the ‘Center of Knowledge Interchange’ program of the Siemens AG. HJG was supported by the German Research Foundation; the Federal Ministry of Education and Research Germany; speakers honoraria from Bristol-Myers Squibb, Eli Lilly, Novartis, Eisai, Wyeth, Pfizer, Boehringer Ingelheim, Servier and travel funds from Janssen-Cilag, Lundbeck, Eli Lilly, Novartis, AstraZeneca and SALUS-Institute for Trend-Research and Therapy Evaluation in Mental Health. Twins UK: The study was funded by the Wellcome Trust; European Community’s Seventh Framework Programme (FP7/2007– 2013)/grant agreement HEALTH-F2-2008-201865-GE-FOS and (FP7/2007–2013), ENGAGE project grant agreement HEALTH-F4-2007-201413 and the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254). The study also receives support from the Department of Health through the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London. TDS is an NIHR senior Investigator. The project also received support from a Biotechnology and Biological Sciences Research Council (BBSRC) project grant. (G20234). We acknowledge the funding and support of the National Eye Institute through an NIH/CIDR genotyping project (PI: Terri Young)’. We thank the staff from the Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation, Quality Control and Genotyping led by Leena Peltonen and Panos Deloukas; Le Centre National de Génotypage, France, led by Mark Lathrop, for genotyping; Duke University, NC, USA, led by David Goldstein, for genotyping; and the Finnish Institute of Molecular Medicine, Finnish Genome Center, University of Helsinki, led by Aarno Palotie. LifeLines: The LifeLines Cohort Study, and generation and management of GWAS genotype data for the LifeLines Cohort Study is supported by the Netherlands Organization of Scientific Research NWO (grant 175.010.2007.006), the Economic Structure Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation and Dutch Diabetes Research Foundation. We thank Behrooz Alizadeh, Annemieke Boesjes, Marcel Bruinenberg, Noortje Festen, Ilja Nolte, Lude Franke and Mitra Valimohammadi for their help in creating the GWAS database, and Rob Bieringa, Joost Keers, René Oostergo, Rosalie Visser and Judith Vonk for their work related to data-collection and validation. We are grateful to the study participants, the staff from the LifeLines Cohort Study and Medical Biobank Northern Netherlands, and the participating general practitioners and pharmacists. Funding Information: ERF: The genotyping for the ERF study was supported by EUROSPAN (European Special Populations Research Network) and the European Commission FP6 STRP grant (018947; LSHG-CT-2006-01947). The ERF study was further supported by grants from the Netherlands Organization for Scientific Research, Erasmus MC, the Centre for Medical Systems Biology (CMSB) and the Netherlands Brain Foundation (HersenStichting Nederland). We are grateful to all patients and their relatives, general practitioners and neurologists for their contributions and to P Veraart for her help in genealogy, Jeannette Vergeer for the supervision of the laboratory work and P Snijders for his help in data collection. We acknowledge Internationale Stichting Alzheimer Onderzoek (ISAO) and Hersenstichting Netherlands. KORA: The KORA Augsburg studies were financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany, and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was financed by the German National Genome Research Network (NGFN). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. Netherlands Twin Register(NTR): We acknowledge support from: Genetic basis of anxiety and depression (904-61-090); Twin-family database for behavior

PY - 2012/11

Y1 - 2012/11

N2 - 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 (N18 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-values1.6 × 10-11 and 2.7 × 10-11), which were also in strong linkage disequilibrium (r2 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-value3.9 × 10 09) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value7.1 × 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-value2.2 × 10 -05) and Parkinson's disease pathways (P-value3.6 × 10 -05).

AB - 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 (N18 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-values1.6 × 10-11 and 2.7 × 10-11), which were also in strong linkage disequilibrium (r2 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-value3.9 × 10 09) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value7.1 × 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-value2.2 × 10 -05) and Parkinson's disease pathways (P-value3.6 × 10 -05).

KW - CAB39L

KW - CYP1A1/CYP1A2

KW - NRCAM

KW - P450

KW - Parkinson's disease

KW - coffee

UR - http://www.scopus.com/inward/record.url?scp=84861817713&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861817713&partnerID=8YFLogxK

U2 - 10.1038/mp.2011.101

DO - 10.1038/mp.2011.101

M3 - Review article

C2 - 21876539

AN - SCOPUS:84861817713

VL - 17

SP - 1116

EP - 1129

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 11

ER -

Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM

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