Life-Course Associations Between Smoking and Depressive Symptoms. A 30-Year Finnish Follow-up Study.

INTRODUCTION: Relatively little is known about whether the association between smoking and depressive symptoms changes with age and how the trajectories of smoking and depressive symptoms are intertwined during the life course. In this population-based study, these associations were examined from young adulthood to middle age. METHODS: Participants of a Finnish cohort study (N = 1955) were assessed at the ages of 22, 32, 42, and 52 using questionnaires covering daily smoking (yes/no) and the short 13-item Beck Depression Inventory. Longitudinal latent class and longitudinal latent profile analyses were used to identify life course trajectories of smoking and depressive symptoms. RESULTS: The proportions of daily smokers decreased, while levels of depressive symptoms increased among both females and males from age 22 to 52 years. Smoking was associated with higher levels of depressive symptoms from age 22 to 42 years, while not at 52. Associations among males prevailed when adjusting for education, marital status, and alcohol use. Four life course classes of daily smoking (nonsmokers, decreasing prevalence of smoking, persistent smokers, and increasing prevalence of smoking) and four trajectories of depressive symptoms (low, increasing/moderate, decreasing/moderate, and high) were identified. In males, persistent daily smokers (relative risk ratio (RRR) = 4.5, 95% confidence interval (CI): 2.2 to 9.2) and those in the class with increasing smoking prevalence (RRR = 3.2, 95% CI: 1.1 to 9.1) had an increased risk of belonging to the high depressive symptoms profile. In females these associations were nonsignificant. CONCLUSIONS: Compared to females, the relationship between smoking and depressive symptoms seems more robust among males during adulthood. Specifically, males smoking persistently from young adulthood to middle age have an increased risk of high depressive symptoms trajectory. IMPLICATIONS: This population-based cohort with 30 years of follow-up showed that the life course trajectories of daily smoking and depressive symptoms are associated. Persistent daily smokers and those starting late had an increased risk of belonging to the profile with constantly high levels of depressive symptoms during the life course. However, these associations were statistically significant only in males. Actions should be strengthened, especially in males, to prevent smoking initiation, to help smoking cessation, and to identify and treat depression in smokers with significant depressive symptoms.

A Nationally Representative Study of the Hardening Hypothesis Among Educational Groups Over Four Decades.

INTRODUCTION: As smoking prevalence has decreased, there has been debate about "hardening" (smokers are more resistant to established tobacco control measures) or "softening" (smokers are more responsive to interventions) of the remaining smoking population. Despite growing evidence to reject the "hardening" hypothesis, there is lack of long-term population-based studies to test this hypothesis by educational level. AIMS AND METHODS: Repeated cross-sectional population-based surveys during 1978-2014 and in 2018 were utilized. The target population consisted of ~5000 25-64-year-old Finns annually. The data included 109 257 respondents of which 53 351 ever-smoking individuals were included in the analyses. Response rates varied between 84% and 43%. Five hardening indicators considering smoking frequency, intensity and smoking cessation were used as the dependent variables. The main independent variable was study year (time). Statistical analyses were based on regression models using restricted cubic splines by educational level. RESULTS: Contrary to the hardening hypothesis, hardening indicators showed softening over time among all educational groups. However, educational groups differed from each other. Compared with the highly educated, the quit ratio was lower, number of cigarettes per day (CPD) was higher, the proportions of daily smokers among current smokers and heavy smokers among daily smokers were higher among the less educated. CONCLUSIONS: In accordance with growing evidence, also the Finnish smoking population has "softened" over time. Although the change has been predominantly in the same direction for all educational groups, the rate of change has been stronger among the highly educated, highlighting the continued burden of smoking among the less educated. IMPLICATIONS: Even though "softening" of smoking has occurred, lighter smoking also poses health risks. Therefore, tobacco control policies and cessation services should be developed and targeted to a greater extent also for people who smoke less than daily and for those who smoke fewer CPD. Furthermore, interventions should focus on special requirements of the lower educational groups to promote health equity.

Smoking cessation intervention prior to orthopedic surgery: A study protocol to determine patient outcomes and feasibility.

The aim of the study is to analyze the effect of smoking and smoking cessation on the incidence of complications among orthopedic and hand surgery patients, and to determine the feasibility of smoking cessation intervention, as well as factors predicting success in smoking cessation. Orthopedic and hand surgery patients will be invited to participate in the study, which will recruit 550 participants (at least 20% daily smokers). A participant will be defined as a daily smoker if he/she reports daily smoking and/or laboratory tests show active smoking. Data will be collected using a self-reported questionnaire and from medical records. Smokers will receive information about the benefits of smoking cessation and will be encouraged to quit. Medication or nicotine replacement therapy will be prescribed. Laboratory tests will be taken two weeks before and two weeks after surgery. Follow-up phone calls will be made at 3, 6, and 12 months after surgery. The primary outcome is any complication, defined as a prolonged stay in hospital or any additional visit to or measure taken by a health service during the 12 months after surgery. Data on complications are mainly obtained from personal health records and from the information received at the follow-up; the rest of the data will be collected from the register of healthcare-associated infections. Secondary outcomes are the number and types of complications. The sample (n=550) was calculated to observe a 10% difference in complications between smokers and non-smokers (5% alpha level and 80% power), considering a 10% drop-out rate. Logistic regression and log-linear models will be used for data analyses.

A genome-wide association study of total child psychiatric problems scores.

Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2, a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG > 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG < 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG > 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits.

Smoking remains associated with education after controlling for social background and genetic factors in a study of 18 twin cohorts.

We tested the causality between education and smoking using the natural experiment of discordant twin pairs allowing to optimally control for background genetic and childhood social factors. Data from 18 cohorts including 10,527 monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs discordant for education and smoking were analyzed by linear fixed effects regression models. Within twin pairs, education levels were lower among the currently smoking than among the never smoking co-twins and this education difference was larger within DZ than MZ pairs. Similarly, education levels were higher among former smoking than among currently smoking co-twins, and this difference was larger within DZ pairs. Our results support the hypothesis of a causal effect of education on both current smoking status and smoking cessation. However, the even greater intra-pair differences within DZ pairs, who share only 50% of their segregating genes, provide evidence that shared genetic factors also contribute to these associations.

Life course associations between smoking and depressive symptoms. A 30-year Finnish follow-up study.

BACKGROUND: While the association between smoking and depressive symptoms has been studied quite extensively, only little is known whether the association changes and how the trajectories of smoking and depressive symptoms are intertwined during the life course. In this population-based study, we examined these associations from young adulthood to middle age. METHODS: Participants of a Finnish cohort study (N = 1955) were addressed at ages 22, 32, 42 and 52 using postal questionnaires including questions of daily smoking and depressive symptoms (the short 13-item Beck Depression Inventory). Linear and logistic regression analyses and longitudinal latent class and profile analyses were used. RESULTS: The percentages of daily smokers decreased, while levels of depressive symptoms increased among both women and men from age 22 to 52 years. Daily smoking was associated with higher levels of depressive symptoms between ages 22 and 42, while not at age 52. Associations among men prevailed also in the adjusted models. Four life course trajectories of daily smoking (non-smokers, quitters, persistent smokers, and late starters) and four depressive symptoms (low, increasing/moderate, decreasing/moderate, and high) were identified. In the adjusted models, persistent daily smokers and late starters had significantly higher risk of belonging to the high depressive symptoms profile in men, but not in women. CONCLUSIONS: Compared to women the associations between daily smoking and depressive symptoms seem more robust among men during adulthood. Especially those men smoking persistently from young adulthood to middle age have an increased risk of high depressive symptoms trajectory during the life course.

Cancer in twin pairs discordant for smoking: The Nordic Twin Study of Cancer.

The discordant twin pair study design is powerful to control for familial confounding. We employed this approach to investigate the associations of smoking with several cancers. The NorTwinCan study combines data from the Danish, Finnish, Norwegian and Swedish twin and cancer registries. Follow-up started when smoking status was determined and ended at cancer diagnosis confirmed by information in the cancer registry, death or end of follow-up. We classified the participants as never (n = 59 093), former (n = 21 168) or current (n = 47 314) smokers. We pooled data from twin pairs where one co-twin was diagnosed with any of the following tobacco-related cancers: esophagus, kidney, larynx, liver, oral cavity, pancreas, pharynx or urinary bladder, while their co-twin had none of those. Lung cancer was included in further analysis. We used Cox regression allowing for pair-specific baseline functions to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). For tobacco-related cancer sites, we recorded 7379 cases during median 27 years of follow-up. The analyses based on individual twins showed that former (HR 1.31, 95% CI: 1.17-1.48) and current (HR 2.14 [1.95-2.34]) smokers are at increased risk to develop one of cancers listed above, compared to never smokers. Among 109 monozygotic twin pairs discordant for cancer and smoking, the HR was 1.85 (95% CI: 1.15-2.98) among current smokers and 1.69 (1.00-2.87) among former smokers when compared to their never smoking co-twin. Thus, associations of smoking with several cancers were replicated for discordant identical twin pairs. Analyses based on genetically informative data provide evidence consistent with smoking causing multiple cancers.

The associations of smoking dependence motives with depression among daily smokers.

AIMS: To investigate how strongly smoking dependence and smoking dependence motives are associated with depressive symptoms among daily smokers and if these associations are independent of measured confounders and shared familial factors. DESIGN: Cross-sectional individual-based and within-pair analyses. SETTING: Fourth wave of the population-based Finnish Twin Cohort conducted in 2011. PARTICIPANTS: 918 daily smokers born 1945-1957 (48% men), mean age 59.5 years including 38 twin pairs discordant for depression. MEASUREMENTS: Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression scale with a cut off value ≥20 for depression. Smoking dependence was assessed using the Fagerström Test for Cigarette Dependence (FTCD) and smoking dependence motives with three subscales from the multi-dimensional Brief Wisconsin Inventory of Smoking Dependence Motives (WISDM): primary dependence motives (PDM), affective enhancement (AE), and Taste. Logistic regressions, using standardized scores of independent variables and adjusted for multiple confounders with correction for sampling as twin pairs, were used in the individual-based analyses. Conditional logistic regression was used to control for shared familial factors in discordant twin pairs. FINDINGS: Prevalence of depression was 18% (n = 163: 61 [14%] in men, n = 102 [22%] in women). Higher smoking dependence measured by the FTCD (OR 1.45; 95% CI 1.20, 1.75), and dependence motives measured by the PDM (1.56; 1.30, 1.87) and the AE (1.54; 1.28, 1.85) were associated with higher odds of depression. The associations remained after adjusting for individual confounders, except for neuroticism, which attenuated all associations. FTCD, PDM, and AE showed associations with depression within depression-discordant monozygotic pairs, suggesting an association independent of familial factors. CONCLUSIONS: Depression appears to be associated with smoking dependence and smoking dependence motives related to heavy, automatic use and use to regulate affective states. The associations appear to be confounded or mediated by neuroticism but are independent of shared familial influences.

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan.

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10-7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

Genome-wide association meta-analysis of nicotine metabolism and cigarette consumption measures in smokers of European descent.

Smoking behaviors, including amount smoked, smoking cessation, and tobacco-related diseases, are altered by the rate of nicotine clearance. Nicotine clearance can be estimated using the nicotine metabolite ratio (NMR) (ratio of 3'hydroxycotinine/cotinine), but only in current smokers. Advancing the genomics of this highly heritable biomarker of CYP2A6, the main metabolic enzyme for nicotine, will also enable investigation of never and former smokers. We performed the largest genome-wide association study (GWAS) to date of the NMR in European ancestry current smokers (n = 5185), found 1255 genome-wide significant variants, and replicated the chromosome 19 locus. Fine-mapping of chromosome 19 revealed 13 putatively causal variants, with nine of these being highly putatively causal and mapping to CYP2A6, MAP3K10, ADCK4, and CYP2B6. We also identified a putatively causal variant on chromosome 4 mapping to TMPRSS11E and demonstrated an association between TMPRSS11E variation and a UGT2B17 activity phenotype. Together the 14 putatively causal SNPs explained ~38% of NMR variation, a substantial increase from the ~20 to 30% previously explained. Our additional GWASs of nicotine intake biomarkers showed that cotinine and smoking intensity (cotinine/cigarettes per day (CPD)) shared chromosome 19 and chromosome 4 loci with the NMR, and that cotinine and a more accurate biomarker, cotinine + 3'hydroxycotinine, shared a chromosome 15 locus near CHRNA5 with CPD and Pack-Years (i.e., cumulative exposure). Understanding the genetic factors influencing smoking-related traits facilitates epidemiological studies of smoking and disease, as well as assists in optimizing smoking cessation support, which in turn will reduce the enormous personal and societal costs associated with smoking.

Cervical Cancer Screening Participation among Women of Russian, Somali, and Kurdish Origin Compared with the General Finnish Population: A Register-Based Study.

Migrant-origin women are less prone to cervical screening uptake compared with host populations. This study examined cervical cancer screening participation and factors associated with it in the Finnish mass screening program during 2008-2012 in women of Russian, Somali and Kurdish origin compared with the general Finnish population (Finns) in Finland. The study population consists of samples from the Finnish Migrant Health and Well-being Study 2010-2012 and Health 2011 Survey; aged 30-64 (n = 2579). Data from the Finnish screening register linked with other population-based registry data were utilized. For statistical analysis we employed logistic regression. Age-adjusted screening participation rates were Russians 63% (95% CI: 59.9-66.6), Somalis 19% (16.4-21.6), Kurds 69% (66.6-71.1), and Finns 67% (63.3-69.8). In the multiple-adjusted model with Finns as the reference; odds ratios for screening were among Russians 0.92 (0.74-1.16), Somalis 0.16 (0.11-0.22), and Kurds 1.37 (1.02-1.83). Among all women, the substantial factor for increased screening likelihood was hospital care related to pregnancy/birth 1.73 (1.27-2.35), gynecological 2.47 (1.65-3.68), or other reasons 1.53 (1.12-2.08). Screening participation was lower among students and retirees. In conclusion, screening among the migrant-origin women varies, being significantly lowest among Somalis compared with Finns. Efforts using culturally tailored/population-specific approaches may be beneficial in increasing screening participation among women of migrant-origin.

Depressive symptoms predict smoking cessation in a 20-year longitudinal study of adult twins.

Depression has been suggested to hinder smoking cessation, especially when co-occurring with nicotine dependence. The study aimed to examine the longitudinal association of depressive symptoms with smoking cessation among daily smokers. The study utilized adult Finnish twin cohort where 1438 daily smokers (mean age: 38.3, range: 33-45) in 1990 were re-examined for their smoking status in 2011. We assessed baseline depressive symptoms with the Beck Depression Inventory, and the self-reported smoking status at follow-up. The methods included multinomial logistic regression and time to event analyses, adjusted for multiple covariates (age, sex, marital status, social class, heavy drinking occasions, and health status) and smoking heaviness at baseline assessed by cigarettes per day (CPD). Additionally, within-twin-pair analyses were conducted. Results indicated that moderate/severe depressive symptoms at baseline were associated with a lower likelihood of smoking cessation two decades later. Adjusting for covariates, those with moderate/severe depressive symptoms (vs. no/minimal depressive symptoms) had 46% lower likelihood of quitting (relative risk ratio, RRR = 0.54, 95% CI: 0.30-0.96). After including CPD, the association of depressive symptoms with smoking cessation attenuated modestly (RRR = 0.62, 95% CI: 0.34-1.12). Further, time to event analysis for quitting year since baseline yielded similar findings. In the within-pair analysis, depressive symptoms were not associated with quitting smoking. The results suggest that reporting more depressive symptoms is associated with a lower likelihood of smoking cessation during a 20-year period. The baseline amount of smoking and familial factors partly explain the observed association. Smoking cessation programs should monitor depressive symptoms.

Is Brain-Derived Neurotrophic Factor Associated With Smoking Initiation? Replication Using a Large Finnish Population Sample.

INTRODUCTION: Brain-derived neurotrophic factor (BDNF) is a growth factor in the central nervous system. There is evidence for the involvement of BDNF in addictions and mental disorders. We aimed to replicate the earlier reported association of a functional genetic variant of BDNF with smoking initiation (SI) using a large population-based sample and to test whether the association is independent of depression. METHODS: Our sample was drawn from the Finnish population-based FINRISK surveys conducted in 1992, 1997, 2002, and 2007. We had nonmissing data on the genotype BDNF  Val66Met (G/A) variant (rs6265) and self-reported never (n = 10 619) versus ever (n = 16 028) smoking among 26 647 adults aged 25-74 years. The association between BDNF  Val66Met and SI was modeled using logistic regression adjusted for age and sex, and in secondary analyses also for depression. Depression was defined as self-reported depression diagnosed or treated by physician during the past year. RESULTS: The sex- and age-adjusted analysis confirmed that the major (Val) allele increased the risk of being a lifetime ever smoker (per allele odds ratio [OR] = 1.07; 95% CI = 1.01 to 1.12; p = .01). When depression, which itself was significantly associated with SI (OR = 1.58; 95% CI = 1.37 to 1.82; p < .001), was added to the model, the association of the gene with SI remained significant (per allele OR = 1.06; 95% CI = 1.01 to 1.12; p = .01). Exclusion of depressed individuals did not change the results (OR = 1.06; 95% CI = 1.01 to 1.12; p = .02). CONCLUSIONS: In a Finnish population sample, we replicated the earlier reported association of BDNF Val66Met with SI. Our data further suggest that this association is independent of depression. IMPLICATIONS: Earlier finding about the association between the BDNF gene and smoking initiation is replicated and shown to be independent of depression within Finnish adult population.

Genome-Wide Meta-Analyses of FTND and TTFC Phenotypes.

INTRODUCTION: FTND (FagerstrÓ§m test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. METHODS: Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. RESULTS: We found that SORBS2 on 4q35 (p = 4.05 × 10-8), BG182718 on 11q22 (p = 1.02 × 10-8), and AA333164 on 14q21 (p = 4.11 × 10-9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND. CONCLUSIONS: Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND. IMPLICATIONS: Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.

Association of snus experimentation in late adolescence with daily cigarette smoking in early adulthood: A longitudinal study among Finnish men.

Aims: Swedish smokeless tobacco (snus) is a lower-risk tobacco product than cigarette smoking for individuals. However, the public health impact of snus use is less well studied. Critically, it is uncertain whether use of snus leads to the onset of smoking. This study aimed to investigate prospectively the association between snus experimentation in late adolescence and daily cigarette smoking in early adulthood among Finnish young men. Methods: Data were obtained from 1090 young men within the population-based FinnTwin12 cohort. At baseline (mean age 17 years), we assessed lifetime use of cigarettes and snus, plus other potential predictors of cigarette smoking. At follow-up (mean age 24 years), participants were categorized according to their current smoking status. The final analyses were conducted among 375 young men who were never smokers at baseline with adequate data on follow-up smoking status and other potential predictors of cigarette smoking. Results: Age-adjusted logistic regressions showed an increased risk of becoming a daily smoker at follow-up among those participants who had at least tried snus but had never smoked cigarettes at baseline (odds ratio (OR) 6.48, 95% confidence interval (CI) 2.02-20.7), compared with those who had never used snus. When additionally adjusted for monthly alcohol intoxication, maternal smoking, and peer drug use, the association between snus experimentation and later daily cigarette smoking was attenuated, but remained significant (OR 3.94, 95% CI 1.22-12.7). Conclusions: Our data support the proposition that snus experimentation during late adolescence is longitudinally associated with daily cigarette smoking in early adulthood. Although a causal association cannot be inferred with certainty, snus experimentation might constitute an indicator of the propensity to proceed to regular snus use and initiation of use of other tobacco or nicotine products.

FinnTwin12 Cohort: An Updated Review.

This review offers an update on research conducted with FinnTwin12 (FT12), the youngest of the three Finnish Twin Cohorts. FT12 was designed as a two-stage study. In the first stage, we conducted multiwave questionnaire research enrolling all eligible twins born in Finland during 1983-1987 along with their biological parents. In stage 2, we intensively studied a subset of these twins with in-school assessments at age 12 and semistructured poly-diagnostic interviews at age 14. At baseline, parents of intensively studied twins were administered the adult version of the interview. Laboratory studies with repeat interviews, neuropsychological tests, and collection of DNA were made of intensively studied twins during follow-up in early adulthood. The basic aim of the FT12 study design was to obtain information on individual, familial and school/neighborhood risks for substance use/abuse prior to the onset of regular tobacco and alcohol use and then track trajectories of use and abuse and their consequences into adulthood. But the longitudinal assessments were not narrowly limited to this basic aim, and with multiwave, multirater assessments from ages 11 to 12, the study has created a richly informative data set for analyses of gene-environment interactions of both candidate genes and genomewide measures with measured risk-relevant environments. Because 25 years have elapsed since the start of the study, we are planning a fifth-wave follow-up assessment.

The Older Finnish Twin Cohort - 45 Years of Follow-up.

The older Finnish Twin Cohort (FTC) was established in 1974. The baseline survey was in 1975, with two follow-up health surveys in 1981 and 1990. The fourth wave of assessments was done in three parts, with a questionnaire study of twins born during 1945-1957 in 2011-2012, while older twins were interviewed and screened for dementia in two time periods, between 1999 and 2007 for twins born before 1938 and between 2013 and 2017 for twins born in 1938-1944. The content of these wave 4 assessments is described and some initial results are described. In addition, we have invited twin-pairs, based on response to the cohortwide surveys, to participate in detailed in-person studies; these are described briefly together with key results. We also review other projects based on the older FTC and provide information on the biobanking of biosamples and related phenotypes.

EpiSmokEr: a robust classifier to determine smoking status from DNA methylation data.

Aim: Smoking strongly influences DNA methylation, with current and never smokers exhibiting different methylation profiles. Methods: To advance the practical applicability of the smoking-associated methylation signals, we used machine learning methodology to train a classifier for smoking status prediction. Results: We show the prediction performance of our classifier on three independent whole-blood datasets demonstrating its robustness and global applicability. Furthermore, we examine the reasons for biologically meaningful misclassifications through comprehensive phenotypic evaluation. Conclusion: The major contribution of our classifier is its global applicability without a need for users to determine a threshold value for each dataset to predict the smoking status. We provide an R package, EpiSmokEr (Epigenetic Smoking status Estimator), facilitating the use of our classifier to predict smoking status in future studies.

Testing the reciprocal association between smoking and depressive symptoms from adolescence to adulthood: A longitudinal twin study.

BACKGROUND: Longitudinal studies enhance understanding of the complex reciprocal relationship between smoking and depression from adolescence to young adulthood. Examining bi-directional associations between cigarette smoking and depressive symptoms in a genetically informative twin design can help to understand whether the associations are independent of shared genetic and environmental factors. METHODS: We analyzed longitudinal data on smoking and depressive symptoms in twins participating in the adolescent (mean age 17.5) and young adult (mean age 21.9) surveys of the FinnTwin12 study (maximum N = 2,954 individuals; 1,154 twin pairs). At both waves, self-reported depressive symptoms, assessed with the 10-item version of the General Behavior Inventory (GBI), and smoking status were analyzed. The bi-directional associations were first studied among individuals and then within monozygotic and dizygotic twin pairs. RESULTS: When adjusted for multiple covariates and baseline depressive symptoms, daily smokers at age 17 had higher depressive symptom scores at age 22 than never smokers (Incidence Rate Ratio = 1.17, 95% CI: 1.03-1.33). Similarly, when adjusted for covariates and baseline smoking, higher score in GBI at age 17 was associated with an increased likelihood of being a non-daily (Relative Risk Ratio (RRR) = 1.06, 95% CI: 1.01-1.11) or daily (RRR = 1.05, 95% CI: 1.00-1.10) smoker at age 22. No associations were found in within-pair analyses, suggesting that the individual-level association is explained by shared familial liabilities. CONCLUSION: During the developmental period from adolescence to adulthood, cigarette smoking and depressive symptoms are reciprocally associated. However, these associations are confounded by shared genetic and other familial liabilities.

Predictive Association of Smoking with Depressive Symptoms: a Longitudinal Study of Adolescent Twins.

Longitudinal, genetically informative studies of the association between cigarette smoking and depressive symptoms among adolescents are limited. We examined the longitudinal association of cigarette smoking with subsequent depressive symptoms during adolescence in a Finnish twin cohort. We used prospective data from the population-based FinnTwin12 study (maximum N = 4152 individuals, 1910 twin pairs). Current smoking status and a number of lifetime cigarettes smoked were assessed at the age of 14 and depressive symptoms at the age of 17. Negative binomial regression was conducted to model the association between smoking behavior and subsequent depressive symptoms among individuals, and within-pair analyses were conducted to control for unmeasured familial confounding. Analyses were adjusted for age, sex, school grades, drinking alcohol to intoxication, health status, family structure, parental education, and smoking, as well as for pre-existing depressiveness. The results of the individual-level analyses showed that cigarette smoking at the age of 14 predicted depressive symptoms at the age of 17. Compared to never smokers, those who had smoked over 50 cigarettes (incidence rate ratio, IRR = 1.43, 95% CI 1.28-1.60) and regular smokers (IRR = 1.46, 95% CI 1.32-1.62) had higher depression scores. The associations were attenuated when adjusted for measured covariates and further reduced in within-pair analyses. In the within-pair results, the estimates were lower within monozygotic (MZ) pairs compared to dizygotic (DZ) pairs, suggesting that shared genetic factors contribute to the associations observed in individual-based analyses. Thus, we conclude that cigarette smoking is associated with subsequent depressive symptoms during adolescence, but the association is not independent of measured confounding factors and shared genetic influences.