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

• Published in: Molecular psychiatry Vol. 17; no. 11; pp. 1116 - 1129
• Main Authors: 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, Wray, N R, Montgomery, G W, Levy, D, Psaty, B M, Gudnason, V, Chakravarti, A, Sulem, P, Gudbjartsson, D F, Kiemeney, L A, Thorsteinsdottir, U, Stefansson, K, van Rooij, F J A, Aulchenko, Y S, Hottenga, J J, Rivadeneira, F R, Hofman, A, Uitterlinden, A G, Hammond, C J, Shin, S-Y, Ikram, A, Witteman, J C M, Janssens, A C J W, Snieder, H, Tiemeier, H, Wolfenbuttel, B H R, Oostra, B A, Heath, A C, Wichmann, E, Spector, T D, Grabe, H J, Boomsma, D I, Martin, N G, van Duijn, C M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2012; Nature Publishing Group
• Subjects: 631/208/205/2138; 631/378/1689/5; 692/699/375/365/1718; Adult and adolescent clinical studies; Antigens, Neoplasm - genetics; Apoptosis Regulatory Proteins - genetics; Association analysis; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Blood; Caffeine; Caffeine - pharmacology; Cell Adhesion Molecules - genetics; Cell Line; Coffee; Coffee - genetics; Cohort analysis; CYP1A2 protein; Cytochrome P-450 CYP1A1 - genetics; Cytochrome P-450 CYP1A2 - genetics; Cytochrome P450; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Drinking - genetics; Drinking behavior; Female; Gene expression; Gene Expression - drug effects; Gene Expression Profiling - methods; Genetic Predisposition to Disease - genetics; Genome-Wide Association Study - methods; Genotype; Health aspects; Humans; Identification and classification; Linkage disequilibrium; Lymphoblastoid cell lines; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolism; Methods; Movement disorders; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurodegenerative diseases; Neurology; Neurosciences; Organic mental disorders. Neuropsychology; Original; original-article; Parkinson Disease - genetics; Parkinson's disease; Pharmacotherapy; Polycyclic aromatic hydrocarbons; Polymorphism, Single Nucleotide; proteasomes; Protein Serine-Threonine Kinases - genetics; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Replication; Reviews; Single-nucleotide polymorphism; Systematic review; Ubiquitin; White People - genetics; Netherlands; CYP1A1/CYP1A2; P450; NRCAM; Parkinson's disease; CAB39L; coffee; Consumption; Nervous system diseases; Parkinson disease; Drinking; Cerebral disorder; Central nervous system disease; Degenerative disease; Extrapyramidal syndrome
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/mp.2011.101

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 × 10 −11 and 2.7 × 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 × 10 −09 ) near NRCAM —a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 ( P -value=7.1 × 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 -value=2.2 × 10 −05 ) and Parkinson's disease pathways ( P -value=3.6 × 10 −05 ).