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. 2010 May;42(5):448-53.
doi: 10.1038/ng.573. Epub 2010 Apr 25.

Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior

Thorgeir E Thorgeirsson  1 , Daniel F Gudbjartsson, Ida Surakka, Jacqueline M Vink, Najaf Amin, Frank Geller, Patrick Sulem, Thorunn Rafnar, Tõnu Esko, Stefan Walter, Christian Gieger, Rajesh Rawal, Massimo Mangino, Inga Prokopenko, Reedik Mägi, Kaisu Keskitalo, Iris H Gudjonsdottir, Solveig Gretarsdottir, Hreinn Stefansson, John R Thompson, Yurii S Aulchenko, Mari Nelis, Katja K Aben, Martin den Heijer, Asger Dirksen, Haseem Ashraf, Nicole Soranzo, Ana M Valdes, Claire Steves, André G Uitterlinden, Albert Hofman, Anke Tönjes, Peter Kovacs, Jouke Jan Hottenga, Gonneke Willemsen, Nicole Vogelzangs, Angela Döring, Norbert Dahmen, Barbara Nitz, Michele L Pergadia, Berta Saez, Veronica De Diego, Victoria Lezcano, Maria D Garcia-Prats, Samuli Ripatti, Markus Perola, Johannes Kettunen, Anna-Liisa Hartikainen, Anneli Pouta, Jaana Laitinen, Matti Isohanni, Shen Huei-Yi, Maxine Allen, Maria Krestyaninova, Alistair S Hall, Gregory T Jones, Andre M van Rij, Thomas Mueller, Benjamin Dieplinger, Meinhard Haltmayer, Steinn Jonsson, Stefan E Matthiasson, Hogni Oskarsson, Thorarinn Tyrfingsson, Lambertus A Kiemeney, Jose I Mayordomo, Jes S Lindholt, Jesper Holst Pedersen, Wilbur A Franklin, Holly Wolf, Grant W Montgomery, Andrew C Heath, Nicholas G Martin, Pamela A F Madden, Ina Giegling, Dan Rujescu, Marjo-Riitta Järvelin, Veikko Salomaa, Michael Stumvoll, Tim D Spector, H-Erich Wichmann, Andres Metspalu, Nilesh J Samani, Brenda W Penninx, Ben A Oostra, Dorret I Boomsma, Henning Tiemeier, Cornelia M van Duijn, Jaakko Kaprio, Jeffrey R Gulcher; ENGAGE Consortium; Mark I McCarthy, Leena Peltonen, Unnur Thorsteinsdottir, Kari Stefansson
Collaborators, Affiliations

Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior

Thorgeir E Thorgeirsson et al. Nat Genet. 2010 May.

Abstract

Smoking is a common risk factor for many diseases. We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P < 5 x 10(-8)), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 x 10(-69)), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 x 10(-12)) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 x 10(-8)), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006).

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Figures

Figure 1
Figure 1
The genomic regions of association with CPD on chromosomes 15q25 (A), 19q13 (B), and 8p11 (C) and 7p14 (D). Shown are the −log10 association P values of SNPs in the region with CPD from the ENGAGE meta analysis (black circles), the in silico replication studies (orange crosses), and joint analysis of ENGAGE, TAG, and OX-GSK GWA data (magenta crosses), the SNP build 36 coordinates, the genes in the region and their exons (in blue) and recombination rates in centimorgans (cM) per megabase (Mb) (pink histogram).
Figure 1
Figure 1
The genomic regions of association with CPD on chromosomes 15q25 (A), 19q13 (B), and 8p11 (C) and 7p14 (D). Shown are the −log10 association P values of SNPs in the region with CPD from the ENGAGE meta analysis (black circles), the in silico replication studies (orange crosses), and joint analysis of ENGAGE, TAG, and OX-GSK GWA data (magenta crosses), the SNP build 36 coordinates, the genes in the region and their exons (in blue) and recombination rates in centimorgans (cM) per megabase (Mb) (pink histogram).
Figure 1
Figure 1
The genomic regions of association with CPD on chromosomes 15q25 (A), 19q13 (B), and 8p11 (C) and 7p14 (D). Shown are the −log10 association P values of SNPs in the region with CPD from the ENGAGE meta analysis (black circles), the in silico replication studies (orange crosses), and joint analysis of ENGAGE, TAG, and OX-GSK GWA data (magenta crosses), the SNP build 36 coordinates, the genes in the region and their exons (in blue) and recombination rates in centimorgans (cM) per megabase (Mb) (pink histogram).
Figure 1
Figure 1
The genomic regions of association with CPD on chromosomes 15q25 (A), 19q13 (B), and 8p11 (C) and 7p14 (D). Shown are the −log10 association P values of SNPs in the region with CPD from the ENGAGE meta analysis (black circles), the in silico replication studies (orange crosses), and joint analysis of ENGAGE, TAG, and OX-GSK GWA data (magenta crosses), the SNP build 36 coordinates, the genes in the region and their exons (in blue) and recombination rates in centimorgans (cM) per megabase (Mb) (pink histogram).
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Comment in

References

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