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

Cornelia M van Duijn (1) , Najaf Amin (1) , Enda M Byrne (1) , Julie Johnson (1) , Georgia Chenevix-Trench (1) , Stefan Walter (1) , Ilja M Nolte (1) , Kconfab Investigators (1) , Jacqueline Vink (1) , Rajesh Rawal (1) , Massimo Mangino (1) , Alexander Teumer (1) , Joost C Keers (1) , Germaine Verwoert (1) , Sebastian Baumeister (1) , Reiner Biffar (1) , Astrid Petersmann (1) , Norbert Dahmen (1) , Angela Doering (1) , Aaron J Isaacs (1) , Linda Broer (1) , Naomi Wray (1) , Grant Montgomery (1) , Daniel Levy (1) , Bruce M Psaty (1) , Villi Gudnason (1) , Aravinda Chakravarti (1) , Patrick Sulem (1) , Daniel F Gudbjartsson (1) , Lambertus A. Kiemeney (1) , Unnur Thorsteinsdottir (1) , Kari Stefansson (1) , Frank Ja van Rooij (1) , Yurii Aulchenko (1) , Jouke-Jan Hottenga (1) , Fernando Rivadeneira (1) , Albert Hofman (1) , André Uitterlinden (1) , Chris J Hammond (1) , So‐youn Shin (1) , Arfan Ikram (1) , Jacqueline Cm Witteman (1) , Cecile Janssens (1) , Harold Snieder (1) , Henning Tiemeier (1) , Bruce Hr Wolfenbuttel (1) , Ben Oostra (1) , Andrew Heath (1) , Heinz-Erich Wichmann (1) , T Spector (1) , Hans Joergen Grabe (1) , Dorret Boomsma (1) , Nick Martin (1)

1 King‘s College London

Coffee consumption is a model for addictive behaviour. We performed a meta-analysis of genome-wide association studies (GWAS) on coffee intake from eight Caucasian cohorts (N = 18,176) and sought replication of our top findings in a further 7,929 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 & 2.7*10-11), which were also in strong linkage disequilibrium (r2 = 0.7) with each other, lie in the 23-kilobases long commonly shared 5-prime flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be down-regulated in the lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons which are important constituents of coffee, while CYP1A2 is involved in primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (p-value = 3.9*10-09) near the NRCAM -- a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (p-value = 7.1*10-09) - a SNP associated with blood pressure -- in the 15q24 region near gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWAS 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).

Mots clés: Coffee; Caffeine; P450; NRCAM; GWAS; CAB39L; Parkinson's disease; Ubiquitin; CYP1A1/CYP1A2

Domaines: Psychiatrie et santé mentale

Cornelia M van Duijn, Najaf Amin, Enda M Byrne, Julie Johnson, Georgia Chenevix-Trench, et al.. Genome-wide association analysis of coffee drinking suggests association to CYP1A1/CYP1A2 and NRCAM. Molecular Psychiatry, 2011, ⟨10.1038/mp.2011.101⟩. ⟨hal-00675396⟩