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Original Article |

Polygenic Risk and the Developmental Progression to Heavy, Persistent Smoking and Nicotine Dependence:  Evidence From a 4-Decade Longitudinal Study

Daniel W. Belsky, PhD; Terrie E. Moffitt, PhD; Timothy B. Baker, PhD; Andrea K. Biddle, PhD; James P. Evans, MD, PhD; HonaLee Harrington, BA; Renate Houts, PhD; Madeline Meier, PhD; Karen Sugden, PhD; Benjamin Williams, BS; Richie Poulton, PhD; Avshalom Caspi, PhD
JAMA Psychiatry. 2013;70(5):534-542. doi:10.1001/jamapsychiatry.2013.736.
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Importance 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.

Objective 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.

Design A 38-year, prospective, longitudinal study of a representative birth cohort.

Setting The Dunedin Multidisciplinary Health and Development Study of New Zealand.

Participants The study included 1037 male and female participants.

Exposure 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.

Main Outcomes and Measures 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.

Results 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.

Conclusions and Relevance 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.

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Figures

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Figure 1. Genetic risk and the developmental progression of smoking behavior. In the hypothesized model, genetic risk influences the mature phenotypes of heavy smoking persistence, nicotine dependence, and cessation failure through a pathway mediated by 3 developmental phenotypes: smoking initiation, conversion to daily smoking, and progression to heavy smoking.

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Figure 2. Smoking behavior in the Dunedin cohort. A, Developmental progression of smoking behavior in the Dunedin cohort. Study members reported their smoking status during in-person assessments at the ages of 11 (percentage of ever-smokers =  7%), 13 (13%), 15 (62%), 18 (66%), 21 (70%), 26 (70%), 32 (71%), and 38 (71%) years and their daily cigarette consumption at the ages of 13 (percentage of daily smokers = 1%), 15 (14%), 18 (31%), 21 (34%), 26 (35%), 32 (30%), and 38 (20%) years. We assessed nicotine dependence using the Fagerström Test of Nicotine Dependence (FTND),41 completed by study members at the ages of 21, 26, and 38 years. We assessed cessation failure using study members' reports of quit attempts and outcomes at the ages of 18, 21, 26, 32, and 38 years. B, Measurements of developmental and mature smoking phenotypes. Data are number (percentage) of study members unless otherwise indicated.

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Figure 3. Genetic risk score (GRS) derived from genome-wide association study of smoking quantity is associated with the developmental progression of smoking behavior in a birth cohort of European-descent individuals. A, Individuals at higher genetic risk progressed more rapidly from smoking initiation to heavy smoking. This panel graphs hazard functions for onset of heavy smoking among individuals at low genetic risk (GRS = −1), average genetic risk (GRS = 0), and high genetic risk (GRS = 1). The dashed gray line marks the cumulative hazard for individuals at average genetic risk. The hazard function was estimated from a Cox proportional hazard model with time since onset of ever-smoking as the exposure time and the first assessment a study member reported smoking 20 or more cigarettes per day (CPD) as the failure event. The hazard model included all individuals who ever initiated smoking (n = 627). Individuals at higher genetic risk progressed more rapidly from smoking initiation to smoking 20 or more CPD (hazard ratio = 1.35; 95% CI, 1.14-1.58). B, Genetic risk was highest among individuals who progressed to heavy smoking and lowest among individuals who initiated smoking but who did not progress to heavy smoking. This panel shows the GRSs (±1 SE) for each group. A GRS of 0 corresponds to the average genetic risk in the cohort. Error bars reflect SEs of the subgroup means.

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Figure 4. Genetic risk predicts mature phenotypes of smoking behavior. A, Among individuals who initiated smoking, those at higher genetic risk smoked more cigarettes by 38 years of age. Ever-smokers were all individuals who initiated smoking by 38 years of age (n = 627). The bars of the histogram graph the percentages of the sample carrying 1 to 12 risk alleles. The dots and SE bars reflect mean lifetime cigarette consumption (in pack-years) for ever-smokers carrying 1 to 3, 4, 5, 6, 7, 8, 9, 10, and 11 to 12 risk alleles. The regression line shows the association between the genetic risk score (GRS) and pack-years smoked by 38 years of age (Pearson correlation r = 0.12, P = .003). B, Ever-smokers at higher genetic risk were more likely to be nicotine dependent. The bars of the chart graph the proportion of ever-smokers at low (n = 157), average (n = 292), and high (n = 178) genetic risk who became nicotine dependent (≥4 Fagerström symptoms) by 38 years of age and who were nicotine dependent at 2 or more assessments. C, Smokers at higher genetic risk were more likely to experience cessation failure during their 30s. The bars of the chart graph the proportions of daily smokers at low, average, and high genetic risk who experienced relapse after a quit attempt lasting 1 month or longer and who achieved successful cessation (abstinence ≥1 year) through 38 years of age. Percentage with relapse was calculated from cohort members who quit smoking for 1 month or longer during 32 to 38 years of age (n = 36 for the low genetic risk group, n = 61 for the average genetic risk group, and n = 34 for the high genetic risk group). Percentage with successful cessation was calculated for cohort members who smoked daily during their 30s (n = 65 for the low genetic risk group, n = 120 for the average genetic risk group, and n = 77 for the high genetic risk group). B and C, Low genetic risk individuals had GRSs more than 0.5 SD below the cohort mean, average genetic risk individuals had GRSs within 0.5 SD of the cohort mean, and high genetic risk individuals had GRSs more than 0.5 SD above the cohort mean. Error bars reflect SEs.

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