Dataset Information

Pathways to smoking behaviours: biological insights from the Tobacco and Genetics Consortium meta-analysis.

ABSTRACT: By running gene and pathway analyses for several smoking behaviours in the Tobacco and Genetics Consortium (TAG) sample of 74?053 individuals, 21 genes and several chains of biological pathways were implicated. Analyses were carried out using the HYbrid Set-based Test (HYST) as implemented in the Knowledge-based mining system for Genome-wide Genetic studies software. Fifteen genes are novel and were not detected with the single nucleotide polymorphism-based approach in the original TAG analysis. For quantity smoked, 14 genes passed the false discovery rate of 0.05 (corrected for multiple testing), with the top association signal located at the IREB2 gene (P=1.57E-37). Three genomic loci were significantly associated with ever smoked. The top signal is located at the noncoding antisense RNA transcript BDNF-AS (P=6.25E-07) on 11p14. The SLC25A21 gene (P=2.09E-08) yielded the top association signal in the analysis of smoking cessation. The 19q13 noncoding RNA locus exceeded the genome-wide significance in the analysis of age at initiation (P=1.33E-06). Pathways belonging to the Neuronal system pathways, harbouring the nicotinic acetylcholine receptor genes expressing the ? (CHRNA 1-9), ? (CHRNB 1-4), ?, ? and ? subunits, yielded the smallest P-values in the pathway analysis of the quantity smoked (lowest P=4.90E-42). Additionally, pathways belonging to 'a subway map of cancer pathways' regulating the cell cycle, mitotic DNA replication, axon growth and synaptic plasticity were found significantly enriched for genetic variants in ever smokers relative to never smokers (lowest P=1.61E-07). In addition, these pathways were also significantly associated with the quantity smoked (lowest P=4.28E-17). Our results shed light on one of the world's leading causes of preventable death and open a path to potential therapeutic targets. These results are informative in decoding the biological bases of other disease traits, such as depression and cancers, with which smoking shares genetic vulnerabilities.

SUBMITTER: Minica CC

PROVIDER: S-EPMC5777181 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Pathways to smoking behaviours: biological insights from the Tobacco and Genetics Consortium meta-analysis.

Minicã C C CC Mbarek H H Pool R R Dolan C V CV Boomsma D I DI Vink J M JM

Molecular psychiatry 20160329 1

By running gene and pathway analyses for several smoking behaviours in the Tobacco and Genetics Consortium (TAG) sample of 74 053 individuals, 21 genes and several chains of biological pathways were implicated. Analyses were carried out using the HYbrid Set-based Test (HYST) as implemented in the Knowledge-based mining system for Genome-wide Genetic studies software. Fifteen genes are novel and were not detected with the single nucleotide polymorphism-based approach in the original TAG analysis. ...[more]

PMID: 27021816

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Project description:ImportanceUnderstanding birth cohort-specific tobacco smoking patterns and their association with total and cause-specific mortality is important for projecting future deaths due to tobacco smoking across Asian populations.ObjectivesTo assess secular trends of tobacco smoking by countries or regions and birth cohorts and evaluate the consequent mortality in Asian populations.Design, setting, and participantsThis pooled meta-analysis was based on individual participant data from 20 prospective cohort studies participating in the Asia Cohort Consortium. Between September 1, 2017, and March 31, 2018, a total of 1 002 258 Asian individuals 35 years or older were analyzed using Cox proportional hazards regression analysis and random-effects meta-analysis. The pooled results were presented for mainland China; Japan; Korea, Singapore, and Taiwan; and India.ExposuresTobacco use status, age at starting smoking, number of cigarettes smoked per day, and age at quitting smoking.Main outcomes and measuresCountry or region and birth cohort-specific mortality and the population attributable risk for deaths from all causes and from lung cancer.ResultsOf 1 002 258 participants (51.1% women and 48.9% men; mean [SD] age at baseline, 54.6 [10.4] years), 144 366 deaths (9158 deaths from lung cancer) were ascertained during a mean (SD) follow-up of 11.7 (5.3) years. Smoking prevalence for men steadily increased in China and India, whereas it plateaued in Japan and Korea, Singapore, and Taiwan. Among Asian male smokers, the mean age at starting smoking decreased in successive birth cohorts, while the mean number of cigarettes smoked per day increased. These changes were associated with an increasing relative risk of death in association with current smoking in successive birth cohorts of pre-1920, 1920s, and 1930 or later, with hazard ratios for all-cause mortality of 1.26 (95% CI, 1.17-1.37) for the pre-1920 birth cohort, 1.47 (95% CI, 1.35-1.61) for the 1920s birth cohort, and 1.70 (95% CI, 1.57-1.84) for the cohort born in 1930 or later. The hazard ratios for lung cancer mortality were 3.38 (95% CI, 2.25-5.07) for the pre-1920 birth cohort, 4.74 (95% CI, 3.56-6.32) for the 1920s birth cohort, and 4.80 (95% CI, 3.71-6.19) for the cohort born in 1930 or later. Tobacco smoking accounted for 12.5% (95% CI, 8.4%-16.3%) of all-cause mortality in the pre-1920 birth cohort, 21.1% (95% CI, 17.3%-24.9%) of all-cause mortality in the 1920s birth cohort, and 29.3% (95% CI, 26.0%-32.3%) of all-cause mortality for the cohort born in 1930 or later. Tobacco smoking among men accounted for 56.6% (95% CI, 44.7%-66.3%) of lung cancer mortality in the pre-1920 birth cohort, 66.6% (95% CI, 58.3%-73.5%) of lung cancer mortality in the 1920s birth cohort, and 68.4% (95% CI, 61.3%-74.4%) of lung cancer mortality for the cohort born in 1930 or later. For women, tobacco smoking patterns and lung cancer mortality varied substantially by countries and regions.Conclusions and relevanceIn this study, mortality associated with tobacco smoking continued to increase among Asian men in recent birth cohorts, indicating that tobacco smoking will remain a major public health problem in most Asian countries in the coming decades. Implementing comprehensive tobacco-control programs is warranted to end the tobacco epidemic.

Project description:RationaleAbout 1.1 billion people smoke tobacco globally and tobacco-related health care costs 1.8% of GDP in many countries. The majority of people are unable to quit smoking despite pharmacological intervention, highlighting the need to understand the pathophysiology associated with tobacco smoking to aid the development of new therapeutics. The reinforcing effects of tobacco smoking are thought to be mediated by the dopamine system. However, the nature of dopamine dysfunction seen in smokers is unclear.ObjectiveTo determine the nature and robustness of the evidence for dopaminergic alterations in smokers.MethodsThe entire MEDLINE, EMBASE, and PsycINFO databases were searched for studies from inception date to November 18, 2018. In vivo human molecular imaging studies of dopamine measures (dopamine synthesis or release capacity, transporter levels, receptor levels) in tobacco smokers were selected. Demographic, clinical, and imaging measures were extracted from each study and meta-analyses, and sensitivity analyses were conducted.ResultsFourteen studies met inclusion criteria comprising a total sample of 219 tobacco smokers and 297 controls. The meta-analysis showed a significant reduction in dopamine transporter availability in the smokers relative to controls with an effect size of - 0.72 ([95% CI, - 1.38 to - 0.05], p = 0.03). However, there was no difference in D2/3 receptor availability in smokers relative to controls (d = -0.16 ([95% CI, - 0.42 to 0.1], p = 0.23). There were insufficient studies for meta-analysis of other measures. However, findings from the published studies indicated blunted dopamine release and lower D1 receptor availability, while findings for dopamine synthesis capacity were inconsistent.ConclusionOur data indicate that striatal dopamine transporter availability is lower but D2/3 receptors are unaltered in smokers relative to controls. We discuss the putative mechanisms underlying this and their implications.

Dataset Information

Pathways to smoking behaviours: biological insights from the Tobacco and Genetics Consortium meta-analysis.

Publications

Pathways to smoking behaviours: biological insights from the Tobacco and Genetics Consortium meta-analysis.

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