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Polygenic risk and the developmental progression to heavy, persistent smoking and nicotine dependence: evidence from a 4-decade longitudinal study.

ABSTRACT: Genome-wide hypothesis-free discovery methods have identified loci that are associated with heavy smoking in adulthood. Research is needed to understand developmental processes that link newly discovered genetic risks with adult heavy smoking.To test how genetic risks discovered in genome-wide association studies of adult smoking influence the developmental progression of smoking behavior from initiation through conversion to daily smoking, progression to heavy smoking, nicotine dependence, and struggles with cessation.A 38-year, prospective, longitudinal study of a representative birth cohort.The Dunedin Multidisciplinary Health and Development Study of New Zealand.The study included 1037 male and female participants.We assessed genetic risk with a multilocus genetic risk score. The genetic risk score was composed of single-nucleotide polymorphisms identified in 3 meta-analyses of genome-wide association studies of smoking quantity phenotypes.Smoking initiation, conversion to daily smoking, progression to heavy smoking, nicotine dependence (Fagerström Test of Nicotine Dependence), and cessation difficulties were evaluated at 8 assessments spanning the ages of 11 to 38 years.Genetic risk score was unrelated to smoking initiation. However, individuals at higher genetic risk were more likely to convert to daily smoking as teenagers, progressed more rapidly from smoking initiation to heavy smoking, persisted longer in smoking heavily, developed nicotine dependence more frequently, were more reliant on smoking to cope with stress, and were more likely to fail in their cessation attempts. Further analysis revealed that 2 adolescent developmental phenotypes-early conversion to daily smoking and rapid progression to heavy smoking-mediated associations between the genetic risk score and mature phenotypes of persistent heavy smoking, nicotine dependence, and cessation failure. The genetic risk score predicted smoking risk over and above family history.Initiatives that disrupt the developmental progression of smoking behavior among adolescents may mitigate genetic risks for developing adult smoking problems. Future genetic research may maximize discovery potential by focusing on smoking behavior soon after smoking initiation and by studying young smokers.

SUBMITTER: Belsky DW

PROVIDER: S-EPMC3644004 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Polygenic risk and the developmental progression to heavy, persistent smoking and nicotine dependence: evidence from a 4-decade longitudinal study.

Belsky Daniel W DW Moffitt Terrie E TE Baker Timothy B TB Biddle Andrea K AK Evans James P JP Harrington HonaLee H Houts Renate R Meier Madeline M Sugden Karen K Williams Benjamin B Poulton Richie R Caspi Avshalom A

JAMA psychiatry 20130501 5

<h4>Importance</h4>Genome-wide hypothesis-free discovery methods have identified loci that are associated with heavy smoking in adulthood. Research is needed to understand developmental processes that link newly discovered genetic risks with adult heavy smoking.<h4>Objective</h4>To test how genetic risks discovered in genome-wide association studies of adult smoking influence the developmental progression of smoking behavior from initiation through conversion to daily smoking, progression to hea ...[more]

PMID: 23536134

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Project description:IntroductionHeritability estimates of nicotine dependence (ND) range from 40% to 70%, but discovery GWAS of ND are underpowered and have limited predictive utility. In this work, we leverage genetically correlated traits and diseases to increase the accuracy of polygenic risk prediction.MethodsWe employed a multi-trait model using summary statistic-based best linear unbiased predictors (SBLUP) of genetic correlates of DSM-IV diagnosis of ND in 6394 individuals of European Ancestry (prevalence = 45.3%, %female = 46.8%, µ age = 40.08 [s.d. = 10.43]) and 3061 individuals from a nationally-representative sample with Fagerström Test for Nicotine Dependence symptom count (FTND; 51.32% female, mean age = 28.9 [s.d. = 1.70]). Polygenic predictors were derived from GWASs known to be phenotypically and genetically correlated with ND (i.e., Cigarettes per Day [CPD], the Alcohol Use Disorders Identification Test [AUDIT-Consumption and AUDIT-Problems], Neuroticism, Depression, Schizophrenia, Educational Attainment, Body Mass Index [BMI], and Self-Perceived Risk-Taking); including Height as a negative control. Analyses controlled for age, gender, study site, and the first 10 ancestral principal components.ResultsThe multi-trait model accounted for 3.6% of the total trait variance in DSM-IV ND. Educational Attainment (β = -0.125; 95% CI: [-0.149,-0.101]), CPD (0.071 [0.047,0.095]), and Self-Perceived Risk-Taking (0.051 [0.026,0.075]) were the most robust predictors. PGS effects on FTND were limited.ConclusionsRisk for ND is not only polygenic, but also pleiotropic. Polygenic effects on ND that are accessible by these traits are limited in size and act additively to explain risk.ImplicationsThese findings enhance our understanding of inherited genetic factors for nicotine dependence. The data show that genome-wide association study (GWAS) findings across pre- and comorbid conditions of smoking are differentially associated with nicotine dependence and that when combined explain significantly more trait variance. These findings underscore the utility of multivariate approaches to understand the validity of polygenic scores for nicotine dependence, especially as the power of GWAS of broadly-defined smoking behaviors increases. Realizing the potential of GWAS to inform complex smoking behaviors will require similar theory-driven models that reflect the myriad of mechanisms that drive individual differences.

Project description:BackgroundNicotine dependence is a significant public health issue, and understanding the factors associated with nicotine dependence in this population is crucial for developing effective interventions. This study examined the association between family functioning and nicotine dependence levels of smoking fathers based on the McMaster model of family functioning (MMFF), providing evidence for future interventions.MethodsIn this study, we selected fathers of first- to fifth-grade students from 10 pilot elementary schools in Qingdao whose families smoked. We used the Fagerstrom test to assess nicotine dependence and the Family Assessment Device to evaluate family functioning. We performed univariate analysis to compare differences among those with different levels of nicotine dependence, and we used an ordinal logistic regression analysis to investigate the influences related to nicotine dependence.ResultsThis study included 874 smokers, with 78.5% having mild nicotine dependence, 11.7% having moderate dependence, and 9.84% having severe dependence. Univariate analysis showed that smokers with severe dependence had lower education levels, higher prevalence of chronic diseases, more frequent alcohol consumption, and poorer family functioning compared to those with mild to moderate dependence. Ordinal logistic regression analysis showed that poorer general functioning scores (OR = 1.087, 95% CI: 1.008-1.173, P = 0.030), poorer behavioral control (OR = 1.124, 95% CI: 1.026-1.232, P = 0.012), more quit attempts, frequent alcohol consumption, and longer smoking duration may be associated with a higher likelihood of developing severe nicotine dependence. The older age of starting smoking and higher education level may be associated with a lower likelihood of developing severe nicotine dependence. However, it is important to note that the cross-sectional nature of this study precludes the determination of causal relationships.ConclusionsThis study finds that heavy nicotine dependence in smoking fathers is associated with risky behaviors and demographics such as longer smoking duration and frequent alcohol consumption. Targeted smoking cessation interventions are crucial for this group, taking these specific factors into consideration. Family functioning, particularly general functioning and behavioral control, may also be linked to nicotine dependence, indicating the need for further research in this area.

Project description:BackgroundWhile the heritability of cigarette smoking and nicotine dependence (ND) is well-documented, the contribution of specific genetic variants to specific phenotypes has not been closely examined. The objectives of this study were to test the associations between 321 tagging single-nucleotide polymorphisms (SNPs) that capture common genetic variation in 24 genes, and early smoking and ND phenotypes in novice adolescent smokers, and to assess if genetic predictors differ across these phenotypes.MethodsIn a prospective study of 1294 adolescents aged 12-13 years recruited from ten Montreal-area secondary schools, 544 participants who had smoked at least once during the 7-8 year follow-up provided DNA. 321 single-nucleotide polymorphisms (SNPs) in 24 candidate genes were tested for an association with number of cigarettes smoked in the past 3 months, and with five ND phenotypes (a modified version of the Fagerstrom Tolerance Questionnaire, the ICD-10 and three clusters of ND symptoms representing withdrawal symptoms, use of nicotine for self-medication, and a general ND/craving symptom indicator).ResultsThe pattern of SNP-gene associations differed across phenotypes. Sixteen SNPs in seven genes (ANKK1, CHRNA7, DDC, DRD2, COMT, OPRM1, SLC6A3 (also known as DAT1)) were associated with at least one phenotype with a p-value <0.01 using linear mixed models. After permutation and FDR adjustment, none of the associations remained statistically significant, although the p-values for the association between rs557748 in OPRM1 and the ND/craving and self-medication phenotypes were both 0.076.ConclusionsBecause the genetic predictors differ, specific cigarette smoking and ND phenotypes should be distinguished in genetic studies in adolescents. Fifteen of the 16 top-ranked SNPs identified in this study were from loci involved in dopaminergic pathways (ANKK1/DRD2, DDC, COMT, OPRM1, and SLC6A3).ImpactDopaminergic pathways may be salient during early smoking and the development of ND.

Project description:ImportanceMenthol may make cigarette smoke less aversive and could lead youth to smoke more frequently and become more dependent on nicotine.ObjectiveTo assess the association of menthol use with cigarette smoking frequency and nicotine dependence (ND) among youth cigarettes users.Design, setting, and participantsThis cohort study used a pooled sample of cohorts of US youth (aged 12-17 years at their baseline and follow-up interviews) in the Population Assessment of Tobacco and Health Study (September 2013 to November 2019). Household interviews were conducted using audio computer-assisted self-interviews. US youth who were past-30-day cigarette smokers at any of wave 2 through wave 5, completed the preceding survey (eg, wave 2 past-30-day cigarette smokers completed wave 1), and indicated whether they used menthol cigarettes were eligible. The association of menthol use with smoking frequency and ND was estimated using inverse probability of treatment weighting adjusted mean differences (aMDs), adjusted risk ratios (aRRs), and corresponding 95% CIs. Data were analyzed from December 2021 to March 2022.ExposuresMenthol use and transitions in use (switching to or from menthol cigarettes).Main outcomes and measuresMain outcomes were the number of days smoked in the past 30 days, the risk of frequent smoking (smoking ≥20 days in the past 30 days), and symptoms of ND.ResultsThere were a total of 1492 observations among 1096 US youth cigarette smokers, of whom 49.4% were female, 67.2% were non-Hispanic White, and 28.7% were aged 12 to 14 years at their baseline survey (all percentages are weighted). Among those who switched from not smoking to smoking (61% of the sample), menthol use was associated with smoking on 3.1 additional days (aMD; 95% CI, 1.9 to 4.2 days), 59% higher risk of being a frequent smoker (aRR, 1.59; 95% CI, 1.23 to 2.06), and 10% higher ND scores (aMD, 1.09; 95% CI, 1.02 to 1.17). Switching from smoking menthol to smoking nonmenthol (vs maintaining menthol use) was associated with smoking on 3.6 fewer days (aMD; 95% CI, -6.3 to -0.9 days) and 47% lower risk of being a frequent smoker (aRR, 0.68; 95% CI, 0.50 to 0.92).Conclusions and relevanceThese findings suggest that the addition of menthol to cigarettes is associated with increased smoking frequency and ND among US youth.

Project description:BackgroundAttention-deficit/hyperactivity disorder (ADHD) is associated with substance use disorders (SUD; alcohol and/or drug dependence) and nicotine dependence. This study aims to advance our knowledge about the association between SUD, nicotine dependence, and the course of ADHD (persistent versus remittent ADHD and late-onset ADHD).MethodsADHD, SUD, and nicotine dependence were longitudinally assessed (mean age at study entry 11.3?years, mean age at follow-up 21.1?years) using structured psychiatric interviews and multi-informant questionnaires in a subsample of the Dutch part of the International Multicenter ADHD Genetics study. Individuals with persistent ADHD (n?=?62), remittent ADHD (n?=?12), late-onset ADHD (n?=?18; age of onset after 12?years), unaffected siblings (n?=?50), and healthy controls (n?=?47) were assessed. Hazard ratios (HR) with 95% confidence intervals (CIs) were estimated by Cox regression and adjusted for clustered family data, gender, follow-up length, and current age.ResultsIndividuals with persistent ADHD were at significantly higher risk of development of SUD relative to healthy controls (HR?=?4.56, CI 1.17-17.81). In contrast, levels of SUD in those with remittent ADHD were not different from healthy controls (HR?=?1.00, CI .07-13.02). ADHD persisters had also higher prevalence rates of nicotine dependence (24.2%) than ADHD remitters (16.7%) and healthy controls (4.3%). A similar pattern was found in initially unaffected siblings who met ADHD criteria at follow-up ("late-onset" ADHD); they had also a higher prevalence of SUD (33%) compared to stable unaffected siblings (20%) and were at significantly increased risk of development of nicotine dependence compared to healthy controls (HR?=?13.04, CI 2.08-81.83).ConclusionsSUD and nicotine dependence are associated with a negative ADHD outcome. Results further emphasize the need for clinicians to comprehensively assess substance use when diagnosing ADHD in adolescents and adults.

Dataset Information

Polygenic risk and the developmental progression to heavy, persistent smoking and nicotine dependence: evidence from a 4-decade longitudinal study.

Publications

Polygenic risk and the developmental progression to heavy, persistent smoking and nicotine dependence: evidence from a 4-decade longitudinal study.

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