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 (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)).
authors.affiliation: Unit of Genetic Epidemiology, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Amin
authors.forename: E
authors.initials: E
authors.lastname: Byrne
authors.forename: J
authors.initials: J
authors.lastname: Johnson
authors.forename: G
authors.initials: G
authors.lastname: Chenevix-Trench
authors.forename: S
authors.initials: S
authors.lastname: Walter
authors.forename: I M
authors.initials: IM
authors.lastname: Nolte
authors.forename: J M
authors.initials: JM
authors.lastname: Vink
authors.forename: R
authors.initials: R
authors.lastname: Rawal
authors.forename: M
authors.initials: M
authors.lastname: Mangino
authors.forename: A
authors.initials: A
authors.lastname: Teumer
authors.forename: J C
authors.initials: JC
authors.lastname: Keers
authors.forename: G
authors.initials: G
authors.lastname: Verwoert
authors.forename: S
authors.initials: S
authors.lastname: Baumeister
authors.forename: R
authors.initials: R
authors.lastname: Biffar
authors.forename: A
authors.initials: A
authors.lastname: Petersmann
authors.forename: N
authors.initials: N
authors.lastname: Dahmen
authors.forename: A
authors.initials: A
authors.lastname: Doering
authors.forename: A
authors.initials: A
authors.lastname: Isaacs
authors.forename: L
authors.initials: L
authors.lastname: Broer
authors.forename: N R
authors.initials: NR
authors.lastname: Wray
authors.forename: G W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: D
authors.initials: D
authors.lastname: Levy
authors.forename: B M
authors.initials: BM
authors.lastname: Psaty
authors.forename: V
authors.initials: V
authors.lastname: Gudnason
authors.forename: A
authors.initials: A
authors.lastname: Chakravarti
authors.forename: P
authors.initials: P
authors.lastname: Sulem
authors.forename: D F
authors.initials: DF
authors.lastname: Gudbjartsson
authors.forename: L A
authors.initials: LA
authors.lastname: Kiemeney
authors.forename: U
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: K
authors.initials: K
authors.lastname: Stefansson
authors.forename: F J A
authors.initials: FJ
authors.lastname: van Rooij
authors.forename: Y S
authors.initials: YS
authors.lastname: Aulchenko
authors.forename: J J
authors.initials: JJ
authors.lastname: Hottenga
authors.forename: F R
authors.initials: FR
authors.lastname: Rivadeneira
authors.forename: A
authors.initials: A
authors.lastname: Hofman
authors.forename: A G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: C J
authors.initials: CJ
authors.lastname: Hammond
authors.forename: S-Y
authors.initials: SY
authors.lastname: Shin
authors.forename: A
authors.initials: A
authors.lastname: Ikram
authors.forename: J C M
authors.initials: JC
authors.lastname: Witteman
authors.forename: A C J W
authors.initials: AC
authors.lastname: Janssens
authors.forename: H
authors.initials: H
authors.lastname: Snieder
authors.forename: H
authors.initials: H
authors.lastname: Tiemeier
authors.forename: B H R
authors.initials: BH
authors.lastname: Wolfenbuttel
authors.forename: B A
authors.initials: BA
authors.lastname: Oostra
authors.forename: A C
authors.initials: AC
authors.lastname: Heath
authors.forename: E
authors.initials: E
authors.lastname: Wichmann
authors.forename: T D
authors.initials: TD
authors.lastname: Spector
authors.forename: H J
authors.initials: HJ
authors.lastname: Grabe
authors.forename: D I
authors.initials: DI
authors.lastname: Boomsma
authors.forename: N G
authors.initials: NG
authors.lastname: Martin
authors.forename: C M
authors.initials: CM
authors.lastname: van Duijn
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D002110:Caffeine / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002460:Cell Line; D003069:Coffee / Q000235:genetics*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D004326:Drinking / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D010300:Parkinson Disease / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D051017:Apoptosis Regulatory Proteins; C534238:CAB39L protein, human; D015815:Cell Adhesion Molecules; D003069:Coffee; C491152:NRCAM protein, human; D002110:Caffeine; C569463:CYP1A1 protein, human; C504573:CYP1A2 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D017346:Protein Serine-Threonine Kinases; C547386:ULK3 protein, human