Nat Genet. 2010 May;42(5):441-7. doi: 10.1038/ng.571. Epub 2010 Apr 25.
Genome-wide meta-analyses identify multiple loci associated with smoking behavior.
Furberg H, Kim Y, Dackor J, Boerwinkle E, Franceschini N, Ardissino D, Bernardinelli L, Mannucci PL, Mauri F, Merlini PA, Absher D, Assimes TL, Fortmann SP, Iribarren C, Knowles JW, Quertermous T, Ferrucci L, Tanaka T, Bis JC, Furberg CD, Haritunians T, McKnight B, Psaty BM, Taylor KD, Thacker EL, Almgren P, Groop L, Ladenvall C, Boehnke M, Jackson AU, Mohlke KL, Stringham HM, Tuomilehto J, Benjamin EJ, Hwang SJ, Levy D, Preis SR, Vasan RS, Duan J, Gejman PV, Levinson DF, Sanders AR, Shi J, Lips EH, McKay JD, Agudo A, Barzan L, Bencko V, Benhamou S, Castellsague X, Canova C, Conway DI, Fabianova E, Foretova L, Janout V, Healy CM, Holcátová I, Kjaerheim K, Lagiou P, Lissowska J, Lowry R, Macfarlane TV, Mates D, Richiardi L, Rudnai P, Szeszenia-Dabrowska N, Zaridze D, Znaor A, Lathrop M, Brennan P, Bandinelli S, Frayling TM, Guralnik JM, Milaneschi Y, Perry JR, Altshuler D, Elosua R, Kathiresan S, Lucas G, Melander O, O'Donnell CJ, Salomaa V, Schwartz SM, Voight BF, Penninx BW, Smit JH, Vogelzangs N, Boomsma DI, de Geus EJ, Vink JM, Willemsen G, Chanock SJ, Gu F, Hankinson SE, Hunter DJ, Hofman A, Tiemeier H, Uitterlinden AG, van Duijn CM, Walter S, Chasman DI, Everett BM, Paré G, Ridker PM, Li MD, Maes HH, Audrain-McGovern J, Posthuma D, Thornton LM, Lerman C, Kaprio J, Rose JE, Ioannidis JP, Kraft P, Lin DY, Sullivan PF.
Source
Department of Genetics, University of North Carolina, Chapel Hill, NC 27710, USA.
Abstract
Consistent but indirect evidence has implicated genetic factors in smoking behavior. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], beta = 1.03, standard error (s.e.) = 0.053, P = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], beta = 0.367, s.e. = 0.059, P = 5.7 x 10(-10); and rs1028936[A], beta = 0.446, s.e. = 0.074, P = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], beta = 0.333, s.e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.
- PMID:
- 20418890
- [PubMed - indexed for MEDLINE]
- PMCID:
- PMC2914600
Free PMC ArticleFigure 1
Genome-wide association results for the TAG Consortium. Manhattan plots showing significance of association of all SNPs in the TAG Consortium meta-analyses for four smoking phenotypes. (a–d) Manhattan plots show SNPs plotted on the x axis according to their position on each chromosome against, on the y axis (shown as −log10 P value), the association with CPD (a), former versus current smoking (b), ever versus never smoking (c) and age of smoking initiation (d).
Nat Genet. 2010 May;42(5):441-447.
Figure 3
Forest and regional plots of significant associations for smoking behavior. (a–d) Shown are plots for smoking initiation (a,b) and smoking cessation (c,d) from meta-analyses of the TAG, Ox-GSK and ENGAGE consortia. Regional association plots show SNPs plotted by position on the chromosome against −log10 P value with each smoking phenotype. Estimated recombination rates (from HapMap-CEU) are plotted in light blue to reflect the local LD structure on a secondary y axis. The SNPs surrounding the most significant SNP (red diamond) are color coded to reflect their LD with this SNP (using pairwise r2 values from HapMap CEU): blue, r2 ≥ 0.8–1.0; green, 0.5–0.8; orange, 0.2–0.5; gray, <0.2. The gray bars at the bottom of the plot represent the relative size and location of genes in the region.
Nat Genet. 2010 May;42(5):441-447.
Figure 2
Forest and regional plots of significant associations for CPD from meta-analyses of the TAG, Ox-GSK and ENGAGE consortia. (a–f) Regional association plots show SNPs plotted by position on chromosome against −log10 P value with each smoking phenotype. Estimated recombination rates (from HapMap-CEU) are plotted in light blue to reflect the local LD structure on a secondary y axis. The SNPs surrounding the most significant SNP (red diamond) are color coded to reflect their LD with this SNP (using pairwise r 2 values from HapMap-CEU): blue, r 2 ≥ 0.8–1.0; green, 0.5–0.8, orange, 0.2–0.5; gray, <0.2. The gray bars at the bottom of the plot represent the relative size and location of genes in the region.
Nat Genet. 2010 May;42(5):441-447.
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