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Incorporating age at onset of smoking into genetic models for nicotine dependence: evidence for interaction with multiple genes.

ABSTRACT: Nicotine dependence is moderately heritable, but identified genetic associations explain only modest portions of this heritability. We analyzed 3369 SNPs from 349 candidate genes and investigated whether incorporation of SNP-by-environment interaction into association analyses might bolster gene discovery efforts and prediction of nicotine dependence. Specifically, we incorporated the interaction between allele count and age at onset of regular smoking (AOS) into association analyses of nicotine dependence. Subjects were from the Collaborative Genetic Study of Nicotine Dependence and included 797 cases ascertained for Fagerström nicotine dependence and 811 non-nicotine-dependent smokers as controls, all of European descent. Compared with main effect models, SNP x AOS interaction models resulted in higher numbers of nominally significant tests, increased predictive utility at individual SNPs and higher predictive utility in a multi-locus model. Some SNPs previously documented in main effect analyses exhibited improved fits in the joint analysis, including rs16969968 from CHRNA5 and rs2314379 from MAP3K4. CHRNA5 exhibited larger effects in later-onset smokers, in contrast with a previous report that suggested the opposite interaction (Weiss et al. 2008). However, a number of SNPs that did not emerge in main effect analyses were among the strongest findings in the interaction analyses. These include SNPs located in GRIN2B (P = 1.5 x 10(-5)), which encodes a subunit of the N-methyl-D-aspartate receptor channel, a key molecule in mediating age-dependent synaptic plasticity. Incorporation of logically chosen interaction parameters, such as AOS, into genetic models of substance use disorders may increase the degree of explained phenotypic variation and constitutes a promising avenue for gene discovery.

SUBMITTER: Grucza RA

PROVIDER: S-EPMC3085318 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Incorporating age at onset of smoking into genetic models for nicotine dependence: evidence for interaction with multiple genes.

Grucza Richard A RA Johnson Eric O EO Krueger Robert F RF Breslau Naomi N Saccone Nancy L NL Chen Li-Shiun LS Derringer Jaime J Agrawal Arpana A Lynskey Michael M Bierut Laura J LJ

Addiction biology 20100701 3

Nicotine dependence is moderately heritable, but identified genetic associations explain only modest portions of this heritability. We analyzed 3369 SNPs from 349 candidate genes and investigated whether incorporation of SNP-by-environment interaction into association analyses might bolster gene discovery efforts and prediction of nicotine dependence. Specifically, we incorporated the interaction between allele count and age at onset of regular smoking (AOS) into association analyses of nicotine ...[more]

PMID: 20624154

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Project description:INTRODUCTION:Although some smokers switch to exclusive use of electronic cigarettes (e-cigarettes), others become dual users of combustible cigarettes and e-cigarettes. Little is known about how the onset of vaping affects the use of and dependence on combustible cigarettes or total nicotine use and dependence, which may influence health-related and cessation outcomes. Using self-report data of current combustible and e-cigarette use and retrospective recall of pre-vaping smoking in a sample of dual users, the aims of this study were (1) to compare pre- and post-vaping number of cigarettes per day and combustible cigarette dependence; (2) to compare pre- and post-vaping total nicotine use frequency (number of vaping sessions and cigarettes smoked per day), and total nicotine dependence; and (3) to examine predictors of nicotine dependence. METHODS:We used baseline data from a smoking cessation trial with 2896 dual users. Nicotine use frequency and the Heaviness of Smoking Index were used as measures of nicotine use and dependence, respectively. RESULTS:Participants decreased cigarettes/day from pre- (M = 19.24, SD = 9.01) to post-vaping (M = 11.15, SD = 8.02, p < .0001) and combustible cigarette dependence declined from pre- (M = 3.55, SD = 1.51) to post-vaping (M = 2.11, SD = 1.60, p < .0001). Total daily nicotine use frequency increased after initiating vaping (M = 19.25, SD = 9.01 vs. M = 29.46, SD = 8.61; p < .0001), as did total nicotine dependence (M = 3.55, SD = 1.51 vs. M = 4.68, SD = 1.38; p < .0001). Hierarchical regression analyses indicated that variables associated with greater overall nicotine dependence included: younger age, lower education, more years smoking, higher pre-vaping nicotine dependence, using e-cigarettes more days per month, more puffs per vaping session, higher e-liquid nicotine concentration, and longer vaping history. CONCLUSIONS:Dual use leads to a reduction in the number of combustible cigarettes, but total nicotine use and dependence increases. IMPLICATIONS:In dual users, a reduction in smoking following onset of vaping may offer some harm reduction via reduction in cigarette intake. However, the increase in total nicotine use and dependence could affect the ability to quit either or both products.

Project description:IntroductionTobacco smoking is the leading cause of preventable death globally. Smoking quantity, measured in cigarettes per day, is influenced both by the age of onset of regular smoking (AOS) and by genetic factors, including a strong effect of the nonsynonymous single-nucleotide polymorphism rs16969968. A previous study by Hartz et al. reported an interaction between these two factors, whereby rs16969968 risk allele carriers who started smoking earlier showed increased risk for heavy smoking compared with those who started later. This finding has yet to be replicated in a large, independent sample.MethodsWe performed a preregistered, direct replication attempt of the rs16969968 × AOS interaction on smoking quantity in 128 383 unrelated individuals from the UK Biobank, meta-analyzed across ancestry groups. We fit statistical association models mirroring the original publication as well as formal interaction tests on multiple phenotypic and analytical scales.ResultsWe replicated the main effects of rs16969968 and AOS on cigarettes per day but failed to replicate the interaction using previous methods. Nominal significance of the rs16969968 × AOS interaction term depended strongly on the scale of analysis and the particular phenotype, as did associations stratified by early/late AOS. No interaction tests passed genome-wide correction (α = 5e-8), and all estimated interaction effect sizes were much smaller in magnitude than previous estimates.ConclusionsWe failed to replicate the strong rs16969968 × AOS interaction effect previously reported. If such gene-moderator interactions influence complex traits, they likely depend on scale of measurement, and current biobanks lack the power to detect significant genome-wide associations given the minute effect sizes expected.ImplicationsWe failed to replicate the strong rs16969968 × AOS interaction effect on smoking quantity previously reported. If such gene-moderator interactions influence complex traits, current biobanks lack the power to detect significant genome-wide associations given the minute effect sizes expected. Furthermore, many potential interaction effects are likely to depend on the scale of measurement employed.

Dataset Information

Incorporating age at onset of smoking into genetic models for nicotine dependence: evidence for interaction with multiple genes.

Publications

Incorporating age at onset of smoking into genetic models for nicotine dependence: evidence for interaction with multiple genes.

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