Genome-wide time-to-event analysis on smoking progression stages in a family-based study.
paper
Cited
Public
- Authors
- He, Liang; Pitkäniemi, Janne; Heikkilä, Kauko; Chou, Yi-Ling; Madden, Pamela A F; Korhonen, Tellervo; Sarin, Antti-Pekka; Ripatti, Samuli; Kaprio, Jaakko; Loukola, Anu
- Year
- 2016
- Journal
- Brain and behavior
- PMID
- 27134767
- DOI
- 10.1002/brb3.462
- PMCID
- PMC4842934
BACKGROUND: Various pivotal stages in smoking behavior can be identified, including initiation, conversion from experimenting to established use, development of tolerance, and cessation. Previous studies have shown high heritability for age of smoking initiation and cessation; however, time-to-event genome-wide association studies aiming to identify underpinning genes that accelerate or delay these transitions are missing to date. METHODS: We investigated which single nucleotide polymorphisms (SNPs) across the whole genome contribute to the hazard ratio of transition between different stages of smoking behavior by performing time-to-event analyses within a large Finnish twin family cohort (N = 1962), and further conducted mediation analyses of plausible intermediate traits for significant SNPs. RESULTS: Genome-wide significant signals were detected for three of the four transitions: (1) for smoking cessation on 10p14 (P = 4.47e-08 for rs72779075 flanked by RP11-575N15 and GATA3), (2) for tolerance on 11p13 (P = 1.29e-08 for rs11031684 in RP1-65P5.1), mediated by smoking quantity, and on 9q34.12 (P = 3.81e-08 for rs2304808 in FUBP3), independent of smoking quantity, and (3) for smoking initiation on 19q13.33 (P = 3.37e-08 for rs73050610 flanked by TRPM4 and SLC6A16) in analysis adjusted for first time sensations. Although our top SNPs did not replicate, another SNP in the TRPM4-SLC6A16 gene region showed statistically significant association after region-based multiple testing correction in an independent Australian twin family sample. CONCLUSION: Our results suggest that the functional effect of the TRPM4-SLC6A16 gene region deserves further investigation, and that complex neurotransmitter networks including dopamine and glutamate may play a critical role in smoking initiation. Moreover, comparison of these results implies that genetic contributions to the complex smoking behavioral phenotypes vary among the transitions.
A flowchart of the study design. Circle: smoking stage; orange rectangle: milestone in smoking behavior; green rectangle: considered covariates. Numbers indicate the number of subject included in the analysis with sex as a covariate for each transition (for Smoking initiation also birth year was included).
LLM interpretation
This figure is a flowchart illustrating a study design on smoking behavior transitions, moving from "Birth" to "Successful quit." Yellow circles represent smoking stages, orange rectangles denote behavioral milestones, and green rectangles list the covariates considered for each transition. The flow includes subject counts (N) for each transition, such as N=1615 from Birth to First cigarette and N=686 from Daily smoking to Successful quit.
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| Citation | PMID | DOI | Status |
|---|---|---|---|
| Aceto, M. D. , S. M. Tucker , G. S. Ferguson , and J. R. Hinson . 1986 Rapid and brief tolerance to (+)‐ and (‐)‐nicotine in unanesthetized rats. Eur. J. Pharmacol. 132:213–218.381697610.1016/0014-2999(86)90607-2 | — | — | — |
| Adeyemo, A. , and C. Rotimi . 2010 Genetic variants associated with complex human diseases show wide variation across multiple populations. Public Health Genomics 13:72–79.1943991610.1159/000218711PMC2835382 | — | — | — |
| Argos, M. , L. Tong , B. L. Pierce , M. Rakibuz‐Zaman , A. Ahmed , T. Islam , et al. 2014 Genome‐wide association study of smoking behaviours among Bangladeshi adults. J. Med. Genet. 51:327–333.2466506010.1136/jmedgenet-2013-102151PMC4126189 | — | — | — |
| Arredondo, J. , A. I. Chernyavsky , and S. A. Grando . 2006 Nicotinic receptors mediate tumorigenic action of tobacco‐derived nitrosamines on immortalized oral epithelial cells. Cancer Biol. Ther. 5:511–517.1658259110.4161/cbt.5.5.2601 | — | — | — |
| Association, A. P . 2000 Diagnostic and statistical manual of mental disorders, Fourth Edition: DSM‐IV‐TR® (American Psychiatric Association). | — | — | — |
| Barnes, P. J. 2008 Role of GATA‐3 in allergic diseases. Curr. Mol. Med. 8:330–334.1869105910.2174/156652408785160952 | — | — | — |
| Belsky, D. W. , T. E. Moffitt , T. B. Baker , A. K. Biddle , J. P. Evans , H. Harrington , et al. 2013 Polygenic risk and the developmental progression to heavy, persistent smoking and nicotine dependence: evidence from a 4‐decade longitudinal study. JAMA Psychiatry 70:534–542.2353613410.1001/jamapsychiatry.2013.736PMC3644004 | — | — | — |
| Bevilacqua, L. , S. Doly , J. Kaprio , Q. Yuan , R. Tikkanen , T. Paunio , et al. 2010 A population‐specific HTR2B stop codon predisposes to severe impulsivity. Nature 468:1061–1066.2117916210.1038/nature09629PMC3183507 | — | — | — |
| Breslau, N. , N. Fenn , and E. L. Peterson . 1993 Early smoking initiation and nicotine dependence in a cohort of young adults. Drug Alcohol Depend. 33:129–137.826187710.1016/0376-8716(93)90054-t | — | — | — |
| Broms, U. , K. Silventoinen , P. A. F. Madden , A. C. Heath , and J. Kaprio . 2006 Genetic architecture of smoking behavior: a study of Finnish adult twins. Twin Res. Hum. Genet. Off. J. Int. Soc. Twin Stud. 9:64–72.10.1375/18324270677640304616611469 | — | — | — |
| Broms, U. , P. A. F. Madden , A. C. Heath , M. L. Pergadia , S. Shiffman , and J. Kaprio . 2007 The Nicotine Dependence Syndrome Scale in Finnish smokers. Drug Alcohol Depend. 89:42–51.1717403910.1016/j.drugalcdep.2006.11.017PMC1950147 | — | — | — |
| Broström, G. , and H. Holmberg . 2011 Generalized linear models with clustered data: fixed and random effects models. Comput. Stat. Data Anal. 55:3123–3134. | — | — | — |
| Bruno, P. , G. Gentile , R. Mancini , C. De Vitis , M. C. Esposito , D. Scozzi , et al. 2012 WT1 CpG islands methylation in human lung cancer: a pilot study. Biochem. Biophys. Res. Commun. 426:306–309.2292589610.1016/j.bbrc.2012.08.059 | — | — | — |
| Chen, L.‐S. , T. B. Baker , M. E. Piper , N. Breslau , D. S. Cannon , K. F. Doheny , et al. 2012 Interplay of genetic risk factors (CHRNA5‐CHRNA3‐CHRNB4) and cessation treatments in smoking cessation success. Am. J. Psychiatry 169:735–742.2264837310.1176/appi.ajp.2012.11101545PMC3433845 | — | — | — |
| Comasco, E. , J. Hallman , and Å. Wallén‐Mackenzie . 2014 Haplotype‐tag single nucleotide polymorphism analysis of the Vesicular Glutamate Transporter (VGLUT) genes in severely alcoholic women. Psychiatry Res. 219:403–405.2495342310.1016/j.psychres.2014.05.052 | — | — | — |
| Cox, D. R. 1972 Regression models and life‐tables. J. R. Stat. Soc. Ser. B Methodol. 34:187–220. | — | — | — |
| Delaneau, O. , B. Howie , A. J. Cox , J.‐F. Zagury , and J. Marchini . 2013 Haplotype estimation using sequencing reads. Am. J. Hum. Genet. 93:687–696.2409474510.1016/j.ajhg.2013.09.002PMC3791270 | — | — | — |
| Farmer, M. K. , M. J. Robbins , A. D. Medhurst , D. A. Campbell , K. Ellington , M. Duckworth , et al. 2000 Cloning and characterization of human NTT5 and v7‐3: two orphan transporters of the Na+/Cl–dependent neurotransmitter transporter gene family. Genomics 70:241–252.1111235210.1006/geno.2000.6387 | — | — | — |
| Flatscher‐Bader, T. , N. Zuvela , N. Landis , and P. A. Wilce . 2008 Smoking and alcoholism target genes associated with plasticity and glutamate transmission in the human ventral tegmental area. Hum. Mol. Genet. 17:38–51.1792830410.1093/hmg/ddm283 | — | — | — |
| Gao, X. , J. Starmer , and E. R. Martin . 2008 A multiple testing correction method for genetic association studies using correlated single nucleotide polymorphisms. Genet. Epidemiol. 32:361–369.1827102910.1002/gepi.20310 | — | — | — |
| Genomes Project Consortium . 2012 An integrated map of genetic variation from 1,092 human genomes. Nature 491:56–65.2312822610.1038/nature11632PMC3498066 | — | — | — |
| Guinamard, R. , M. Demion , and P. Launay . 2010 Physiological roles of the TRPM4 channel extracted from background currents. Physiology 25:155–164.2055122910.1152/physiol.00004.2010 | — | — | — |
| Hartz, S. M. , S. E. Short , N. L. Saccone , R. Culverhouse , L. Chen , T.‐H. Schwantes‐An , et al. 2012 Increased genetic vulnerability to smoking at CHRNA5 in early‐onset smokers. Arch. Gen. Psychiatry 69:854–860.2286893910.1001/archgenpsychiatry.2012.124PMC3482121 | — | — | — |
| Heath, A. C. , J. B. Whitfield , N. G. Martin , M. L. Pergadia , A. M. Goate , P. A. Lind , et al. 2011 A quantitative‐trait genome‐wide association study of alcoholism risk in the community: findings and implications. Biol. Psychiatry 70:513–518.2152978310.1016/j.biopsych.2011.02.028PMC3210694 | — | — | — |
| Heatherton, T. F. , L. T. Kozlowski , R. C. Frecker , and K. O. Fagerström . 1991 The Fagerström Test for Nicotine Dependence: a revision of the Fagerström tolerance questionnaire. Br. J. Addict. 86:1119–1127.193288310.1111/j.1360-0443.1991.tb01879.x | — | — | — |
| Hendricks, A. E. , J. Dupuis , M. W. Logue , R. H. Myers , and K. L. Lunetta . 2014 Correction for multiple testing in a gene region. Eur. J. Hum. Genet. 22:414–418.2383859910.1038/ejhg.2013.144PMC3925272 | — | — | — |
| Ho, M. K. , D. Goldman , A. Heinz , J. Kaprio , M. J. Kreek , M. D. Li , et al. 2010 Breaking barriers in the genomics and pharmacogenetics of drug addiction. Clin. Pharmacol. Ther. 88:779–791.2098100210.1038/clpt.2010.175PMC3738009 | — | — | — |
| Horimoto, A. R. V. R. , C. M. Oliveira , S. R. Giolo , J. P. Soler , M. de Andrade , J. E. Krieger , et al. 2012 Genetic analyses of smoking initiation, persistence, quantity, and age‐at‐onset of regular cigarette use in Brazilian families: the Baependi Heart Study. BMC Med. Genet. 13:9.2228994710.1186/1471-2350-13-9PMC3395823 | — | — | — |
| Howie, B. N. , P. Donnelly , and J. Marchini . 2009 A flexible and accurate genotype imputation method for the next generation of genome‐wide association studies. PLoS Genet. 5:e1000529.1954337310.1371/journal.pgen.1000529PMC2689936 | — | — | — |
| Hughes, J. R. , J. P. Keely , R. S. Niaura , D. J. Ossip‐Klein , R. L. Richmond , and G. E. Swan . 2003 Measures of abstinence in clinical trials: issues and recommendations. Nicotine Tob. Res. Off. J. Soc. Res. Nicotine Tob. 5:13–25.12745503 | — | — | — |
| Jiang, G. , A. Chakraborty , Z. Wang , M. Boustani , Y. Liu , T. Skaar , et al. 2013 New aQTL SNPs for the CYP2D6 identified by a novel mediation analysis of genome‐wide SNP arrays, gene expression arrays, and CYP2D6 activity. BioMed Res. Int. 2013:e493019.10.1155/2013/493019PMC381982924232670 | — | — | — |
| Kendler, K. S. , J. Myers , M. I. Damaj , and X. Chen . 2013 Early smoking onset and risk for subsequent nicotine dependence: a monozygotic co‐twin control study. Am. J. Psychiatry 170:408–413.2331837210.1176/appi.ajp.2012.12030321PMC3615117 | — | — | — |
| Kozlowski, L. T. , C. Q. Porter , C. T. Orleans , M. A. Pope , and T. Heatherton . 1994 Predicting smoking cessation with self‐reported measures of nicotine dependence: FTQ, FTND, and HSI. Drug Alcohol Depend. 34:211–216.803375810.1016/0376-8716(94)90158-9 | — | — | — |
| Lange, T. , and J. V. Hansen . 2011 Direct and indirect effects in a survival context. Epidemiol. Camb. Mass. 22:575–581.10.1097/EDE.0b013e31821c680c21552129 | — | — | — |
| Li, X. , S. Semenova , M. S. D'Souza , A. K. Stoker , and A. Markou . 2014 Involvement of glutamatergic and GABAergic systems in nicotine dependence: implications for novel pharmacotherapies for smoking cessation. Neuropharmacology 76 Pt B:554–565.2375209110.1016/j.neuropharm.2013.05.042PMC3830589 | — | — | — |
| Lim, E. T. , P. Würtz , A. S. Havulinna , P. Palta , T. Tukiainen , K. Rehnström , et al. 2014 Distribution and medical impact of loss‐of‐function variants in the Finnish founder population. PLoS Genet. 10:e1004494.2507877810.1371/journal.pgen.1004494PMC4117444 | — | — | — |
| Liu, J. Z. , F. Tozzi , D. M. Waterworth , S. G. Pillai , P. Muglia , L. Middleton , et al. 2010 Meta‐analysis and imputation refines the association of 15q25 with smoking quantity. Nat. Genet. 42:436–440.2041888910.1038/ng.572PMC3612983 | — | — | — |
| Liu, Y. , M. J. Aryee , L. Padyukov , M. D. Fallin , E. Hesselberg , A. Runarsson , et al. 2013 Epigenome‐wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat. Biotechnol. 31:142–147.2333445010.1038/nbt.2487PMC3598632 | — | — | — |
| Loukola, A. , J. Wedenoja , K. Keskitalo‐Vuokko , U. Broms , T. Korhonen , S. Ripatti , et al. 2014 Genome‐wide association study on detailed profiles of smoking behavior and nicotine dependence in a twin sample. Mol. Psychiatry 19:615–624.2375224710.1038/mp.2013.72PMC3883996 | — | — | — |
| Madden, P. A. F. , N. L. Pedersen , J. Kaprio , M. J. Koskenvuo , and N. G. Martin . 2004 The epidemiology and genetics of smoking initiation and persistence: crosscultural comparisons of twin study results. Twin Res. Off. J. Int. Soc. Twin Stud. 7:82–97.10.1375/1369052046074147115053857 | — | — | — |
| Morabia, A. , M. C. Costanza , M. S. Bernstein , and J.‐C. Rielle . 2002 Ages at initiation of cigarette smoking and quit attempts among women: a generation effect. Am. J. Public Health 92:71–74.1177276410.2105/ajph.92.1.71PMC1447391 | — | — | — |
| Mrejeru, A. , A. Wei , and J. M. Ramirez . 2011 Calcium‐activated non‐selective cation currents are involved in generation of tonic and bursting activity in dopamine neurons of the substantia nigra pars compacta. J. Physiol. 589:2497–2514.2148676010.1113/jphysiol.2011.206631PMC3115821 | — | — | — |
| Nemes, S. , T. Z. Parris , A. Danielsson , Z. Einbeigi , G. Steineck , J. M. Jonasson , et al. 2013 Integrative genomics with mediation analysis in a survival context. Comput. Math. Methods Med. 2013:413783.2445453510.1155/2013/413783PMC3878392 | — | — | — |
| Okoli, C. , L. Greaves , and V. Fagyas . 2013 Sex differences in smoking initiation among children and adolescents. Public Health 127:3–10.2314888810.1016/j.puhe.2012.09.015 | — | — | — |
| Peltonen, L. , A. Palotie , and K. Lange . 2000 Use of population isolates for mapping complex traits. Nat. Rev. Genet. 1:182–190.1125274710.1038/35042049 | — | — | — |
| Phillips, P. E. M. , G. D. Stuber , M. L. A. V. Heien , R. M. Wightman , and R. M. Carelli . 2003 Subsecond dopamine release promotes cocaine seeking. Nature 422:614–618.1268700010.1038/nature01476 | — | — | — |
| Price, A. L. , N. J. Patterson , R. M. Plenge , M. E. Weinblatt , N. A. Shadick , and D. Reich . 2006 Principal components analysis corrects for stratification in genome‐wide association studies. Nat. Genet. 38:904–909.1686216110.1038/ng1847 | — | — | — |
| Rios‐Bedoya, C. F. , C. S. Pomerleau , R. J. Neuman , and O. F. Pomerleau . 2009 Using MIMIC models to examine the relationship between current smoking and early smoking experiences. Nicotine Tob. Res. 11:1035–1041.1957815210.1093/ntr/ntp093PMC2725005 | — | — | — |
| Ripatti, S. , and J. Palmgren . 2000 Estimation of multivariate frailty models using penalized partial likelihood. Biometrics 56:1016–1022.1112945610.1111/j.0006-341x.2000.01016.x | — | — | — |
| Ritchie, G. R. S. , I. Dunham , E. Zeggini , and P. Flicek . 2014 Functional annotation of noncoding sequence variants. Nat. Methods 11:294–296.2448758410.1038/nmeth.2832PMC5015703 | — | — | — |
| Rosenberg, N. A. , L. Huang , E. M. Jewett , Z. A. Szpiech , I. Jankovic , and M. Boehnke . 2010 Genome‐wide association studies in diverse populations. Nat. Rev. Genet. 11:356–366.2039596910.1038/nrg2760PMC3079573 | — | — | — |
| Service, S. , J. DeYoung , M. Karayiorgou , J. L. Roos , H. Pretorious , G. Bedoya , et al. 2006 Magnitude and distribution of linkage disequilibrium in population isolates and implications for genome‐wide association studies. Nat. Genet. 38:556–560.1658290910.1038/ng1770 | — | — | — |
| Sham, P. C. , and S. M. Purcell . 2014 Statistical power and significance testing in large‐scale genetic studies. Nat. Rev. Genet. 15:335–346.2473967810.1038/nrg3706 | — | — | — |
| Shigeri, Y. , R. P. Seal , and K. Shimamoto . 2004 Molecular pharmacology of glutamate transporters, EAATs and VGLUTs. Brain Res. Brain Res. Rev. 45:250–265.1521030710.1016/j.brainresrev.2004.04.004 | — | — | — |
| Siedlinski, M. , M. H. Cho , P. Bakke , A. Gulsvik , D. A. Lomas , W. Anderson , et al. 2011 Genome‐wide association study of smoking behaviours in patients with COPD. Thorax 66:894–902.2168518710.1136/thoraxjnl-2011-200154PMC3302576 | — | — | — |
| Swami, M. 2010 Small RNAs: pseudogenes act as microRNA decoys. Nat. Rev. Genet. 11:530–531.10.1038/nrg283520628348 | — | — | — |
| The Tobacco and Genetics Consortium . 2010 Genome‐wide meta‐analyses identify multiple loci associated with smoking behavior. Nat. Genet. 42:441–447.2041889010.1038/ng.571PMC2914600 | — | — | — |
| Therneau, T . 2012 coxme: Mixed effects Cox models. R package version 2. https://cran.r-project.org/web/packages/coxme/coxme.pdf. | — | — | — |
| Thorgeirsson, T. E. , D. F. Gudbjartsson , I. Surakka , J. M. Vink , N. Amin , F. Geller , et al. 2010 Sequence variants at CHRNB3‐CHRNA6 and CYP2A6 affect smoking behavior. Nat. Genet. 42:448–453.2041888810.1038/ng.573PMC3080600 | — | — | — |
| VanderWeele, T. J. 2011 Causal mediation analysis with survival data. Epidemiol. Camb. Mass. 22:582–585.10.1097/EDE.0b013e31821db37ePMC310932121642779 | — | — | — |
| Vink, J. M. , A. B. Smit , E. J. C. de Geus , P. Sullivan , G. Willemsen , J.‐J. Hottenga , et al. 2009 Genome‐wide association study of smoking initiation and current smoking. Am. J. Hum. Genet. 84:367–379.1926827610.1016/j.ajhg.2009.02.001PMC2667987 | — | — | — |
| Yu, B. , and Y. Peng . 2008 Mixture cure models for multivariate survival data. Comput. Stat. Data Anal. 52:1524–1532. | — | — | — |
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External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Genetic Liability to Higher Muscle Strength Associates With a Lower Risk of Cardiovascular Disease Mortality in Men Irrespective of Leisure-Time Physical Activity in Adulthood: A Longitudinal Cohort Study. | Herranen P et al. | — | 2025 | → |
| The SLC6A15-SLC6A20 Neutral Amino Acid Transporter Subfamily: Functions, Diseases, and Their Therapeutic Relevance. | Kukułowicz J et al. | — | 2023 | → |
| DNA Methylation Is Predictive of Mortality in Current and Former Smokers. | Morrow JD et al. | — | 2020 | → |
| Fast Algorithms for Conducting Large-Scale GWAS of Age-at-Onset Traits Using Cox Mixed-Effects Models. | He L et al. | — | 2020 | → |
| Genome-wide association analysis of age-at-onset traits using Cox mixed-effects models | He L et al. | — | 2019 | — |
| Genome-wide association study in Finnish twins highlights the connection between nicotine addiction and neurotrophin signaling pathway. | Hällfors J et al. | — | 2019 | → |
| Neurogenetic determinants and mechanisms of addiction to nicotine and smoked tobacco. | Sharp BM et al. | — | 2019 | → |
| The Older Finnish Twin Cohort - 45 Years of Follow-up. | Kaprio J et al. | — | 2019 | → |
| Association of internal smoking dose with blood DNA methylation in three racial/ethnic populations. | Park SL et al. | — | 2018 | → |
| Neuregulin signaling pathway in smoking behavior. | Gupta R et al. | — | 2017 | → |
| SurvivalGWAS_SV: software for the analysis of genome-wide association studies of imputed genotypes with "time-to-event" outcomes. | Syed H et al. | — | 2017 | → |
| The genetic epidemiology of substance use disorder: A review. | Prom-Wormley EC et al. | — | 2017 | → |
| Genome-wide time-to-event analysis on smoking progression stages in a family-based study. | He L et al. | — | 2016 | → |