Cohort Effects on Tobacco Consumption and its Genetic and Environmental Variance Among Finnish Adults born between 1880-1957.

INTRODUCTION: Population research indicates that smoking behaviors in Finland have varied over time by sex and birth cohort. Smoking behaviors are influenced by genes and the environment; like the behaviors themselves, these underlying influences are not necessarily stable over time and may be modifiable by national drug policy. METHODS: We utilized longitudinal mixed effects models and causal-common-contingent twin models to evaluate sex and cohort effects on tobacco consumption and the underlying genetic and environmental variance components in a birth cohort sample of same-sex twins born in Finland between 1880-1957, assessed in 1975, 1981, 1990, and 2011. RESULTS: We identified significant main effects of age, sex, and cohort on quantity of cigarette consumption, as well as significant age×cohort and sex×cohort interactions. We also identified sex and cohort effects on the liability to initiate regular smoking and the magnitude of variation underlying quantity of cigarette consumption. That said, heritability and environmental contributions to both traits were not different between the four sex×cohort groups. CONCLUSIONS: Our results indicate sex and cohort effects on the prevalence of smoking and its underlying variation. Our results on changing prevalence mirror existing population-level research in Finnish samples, but we did not identify differences in heritability found in other studies of cohort effects in tobacco use, potentially due to power issues. These results highlight the importance of considering age, cohort, and timing of policy changes when evaluating changes in substance consumption across time. IMPLICATIONS: This study identifies sex and cohort effects influencing tobacco consumption in a sample of Finnish adult twins born between 1880-1957. Our results are in line with other population level research in Finland and research on cohort effects influencing alcohol use in the same sample. Our results highlight the intertwining effects of age, cohort, sex, and substance policies on substance use.

Clinical, environmental, and genetic risk factors for substance use disorders: characterizing combined effects across multiple cohorts.

Substance use disorders (SUDs) incur serious social and personal costs. The risk for SUDs is complex, with risk factors ranging from social conditions to individual genetic variation. We examined whether models that include a clinical/environmental risk index (CERI) and polygenic scores (PGS) are able to identify individuals at increased risk of SUD in young adulthood across four longitudinal cohorts for a combined sample of N = 15,134. Our analyses included participants of European (NEUR = 12,659) and African (NAFR = 2475) ancestries. SUD outcomes included: (1) alcohol dependence, (2) nicotine dependence; (3) drug dependence, and (4) any substance dependence. In the models containing the PGS and CERI, the CERI was associated with all three outcomes (ORs = 01.37-1.67). PGS for problematic alcohol use, externalizing, and smoking quantity were associated with alcohol dependence, drug dependence, and nicotine dependence, respectively (OR = 1.11-1.33). PGS for problematic alcohol use and externalizing were also associated with any substance dependence (ORs = 1.09-1.18). The full model explained 6-13% of the variance in SUDs. Those in the top 10% of CERI and PGS had relative risk ratios of 3.86-8.04 for each SUD relative to the bottom 90%. Overall, the combined measures of clinical, environmental, and genetic risk demonstrated modest ability to distinguish between affected and unaffected individuals in young adulthood. PGS were significant but added little in addition to the clinical/environmental risk index. Results from our analysis demonstrate there is still considerable work to be done before tools such as these are ready for clinical applications.

Alcohol consumption at age 18-25 and number of children at a 33-year follow-up: Individual and within-pair analyses of Finnish twins.

BACKGROUND: Do drinking patterns in late adolescence/early adulthood predict lifetime childlessness and number of children? Research on this question has been only tangentially relevant and the results inconsistent. The designs used to date have been compromised by genetic and environmental confounds that are poorly controlled; covariate effects of smoking and education that are often ignored; males being understudied; population-based sampling rare, and long-term prospective studies with genetically informative designs yet to be reported. METHOD: In a 33-year follow-up, we linked the drinking patterns of >3500 Finnish twin pairs, assessed at ages 18-25, to registry data on their eventual number of children. Analyses distinguished associations of early drinking patterns with lifetime childlessness from those predictive of family size. Within-twin pair analyses used fixed-effects regression models to account for shared familial confounds and genetic liabilities. Childlessness was analyzed with Cox proportional hazards models and family size with Poisson regression. Analyses within-pairs and of twins as individuals were run before and after adjustment for smoking and education, and for oral contraceptive (OC) use in individual-level analyses of female twins. RESULTS: Baseline abstinence and heavier drinking both significantly predicted lifetime childlessness in individual-level analyses. Few abstinent women used OCs, but they were nonetheless more often eventually childless; adjusting for smoking and education did not affect this finding. Excluding childless twins, Poisson models of family size showed heavier drinking at 18-25 to be predictive of fewer children in both men and women. Those associations were replicated in within-pair analyses of dizygotic twins, each level of heavier drinking being associated with smaller families. Among monozygotic twins, associations of drinking with completed family size yielded effects of similar magnitude, reaching significance at the highest levels of consumption, ruling out familial confounds. CONCLUSIONS: Compared to moderate levels of drinking, both abstinence and heavier drinking in late adolescence/early adulthood predicted a greater likelihood of lifetime childlessness and eventual number of children. Familial confounds do not fully explain these associations.

Systemic hormonal contraception and risk of venous thromboembolism.

INTRODUCTION: The increased risk of venous thromboembolism associated with the use of hormonal contraception is well recognized, but evidence regarding hormonal contraception containing natural estradiol is limited. This study aimed to assess the associations between the patterns of use of different systemic hormonal contraceptives and the risk of venous thromboembolism during 2017-2019. MATERIAL AND METHODS: All fertile-aged women (15-49 years) living in Finland in 2017 and using hormonal contraception in 2017 and their 1:1 age- and residence-matched controls not using hormonal contraception in 2017 (altogether 587 559 women) were selected from the Prescription Centre. All incident venous thromboembolism cases during 2018-2019 and their 4:1 age-matched controls were further analyzed in a prospective nested case-control design to assess the associations between the use (starting, stopping, continuous vs no use) of different hormonal contraception types and venous thromboembolism. RESULTS: Altogether, 1334 venous thromboembolism cases occurred during the follow-up period (incidence rate 1.14 per 1000 person-years, 95% confidence interval [CI] 1.08-1.20), with an incidence rate ratio of hormonal contraception vs no hormonal contraception use of 1.42 (95% CI 1.27-1.58). Compared with non-use, starting the use of gestodene and ethinylestradiol (adjusted odds ratio [aOR] 2.85; 95% CI 1.62-5.03), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 0.98-2.44), desogestrel and ethinylestradiol (aOR 1.97; 95% CI 0.99-3.92), and transdermal patch releasing norelgestromin and ethinylestradiol (aOR 5.10; 95% CI 1.12-23.16), as well as continuing the use of gestodene and ethinylestradiol (aOR 2.60; 95% CI 1.61-4.21), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 1.02-2.37), cyproterone-acetate and estrogen/ethinylestradiol (aOR 1.66; 95% CI 1.06-2.61), and vaginal ring releasing etonogestrel and ethinylestradiol (aOR 3.27; 95% CI 1.95-5.48) were associated with venous thromboembolism risk. Regarding the type of estrogen, the highest risk was associated with current use (vs non use in the previous 180 days) of ethinylestradiol-containing preparations (aOR 2.20; 95% CI 1.82-2.65), followed by estradiol-containing preparations (aOR 1.39; 95% CI 1.04-1.87) with no risk for progestin-only hormonal contraception. Current use of estradiol-containing preparations was not associated with venous thromboembolism risk after exclusion of cyproterone-acetate and estrogen/ethinylestradiol (aOR 1.05; 95% CI 0.66-1.66). CONCLUSIONS: An increased risk of venous thromboembolism is associated with ethinylestradiol-containing combined preparations. The use of estradiol-containing combined preparations confers only a slightly increased risk, possibly driven by cyproterone-containing combined oral contraceptives, whereas the use of progestin-only contraception is not associated with venous thromboembolism.

Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects.

Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.

Validity of five foot and ankle specific electronic patient-reported outcome (ePRO) instruments in patients undergoing elective orthopedic foot or ankle surgery.

BACKGROUND: Patient-reported outcomes (PROs) are widely accepted measures for evaluating outcomes of surgical interventions. As patient-reported information is stored in electronic health records, it is essential that there are valid electronic PRO (ePRO) instruments available for clinicians and researchers. The aim of this study was to evaluate the validity of electronic versions of five widely used foot and ankle specific PRO instruments. METHODS: Altogether 111 consecutive elective foot/ankle surgery patients were invited face-to-face to participate in this study. Patients completed electronic versions of the Foot and Ankle Ability Measure (FAAM), the Foot and Ankle Outcome Score (FAOS), the modified Lower Extremity Function Scale (LEFS), the Manchester-Oxford Foot Questionnaire (MOXFQ), and the Visual Analogue Scale Foot and Ankle (VAS-FA) on the day of elective foot and/or ankle surgery. Construct validity, coverage, and targeting of the scales were assessed. RESULTS: Based on general and predefined thresholds, construct validity, coverage, and targeting of the ePRO versions of the FAAM, the FAOS, the MOXFQ, and the VAS-FA were acceptable. Major issues arose with score distribution and convergent validity of the modified LEFS instrument. CONCLUSIONS: The ePRO versions of the FAAM, the FAOS, the MOXFQ, and the VAS-FA provide valid scores for foot and ankle patients. However, our findings do not support the use of the modified LEFS as an electronic outcome measure for patients with orthopedic foot and/or ankle pathologies.

Structural validity of the Finnish Manchester-Oxford Foot Questionnaire (MOXFQ) using the Rasch model.

BACKGROUND: The 16-item patient-reported Manchester-Oxford Foot Questionnaire (MOXFQ) with subscales of pain, social interactions, and walking/standing has been claimed for strongest scientific evidence in measuring foot and ankle complaints. This study tests the validity of the Finnish MOXFQ for orthopaedic foot and ankle population using the Rasch analysis. METHODS: We translated the MOXFQ into Finnish and used that translation in our study. MOXFQ scores were obtained from 183 patients. Response category distribution, item fit, coverage, targeting, item dependency, ability to measure latent trait (unidimensionality), internal consistency (Cronbach's alpha), and person separation index (PSI) were analyzed. RESULTS: Fifteen of the items had ordered response categories and/or sufficient fit statistics. The subscales provided coverage and targeting. Some residual correlation was noted. Removing one item in the pain subscale led to a unidimensional structure. Alphas and PSIs ranged between 0.68-0.90 and 0.67-0.92, respectively. CONCLUSIONS: Despite some infractions of the Rasch model, the instrument functioned well. The subscales of the MOXFQ are meaningful for assessing patient-reported complaints and outcomes in orthopaedic foot and ankle population.

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.

Which adolescent factors predict alcohol misuse in young adulthood? A co-twin comparisons study.

BACKGROUND AND AIMS: Research on adolescent predictors of later alcohol misuse is typically conducted on samples of singletons, and associations may be confounded by between-family differences. To address potential confounding, we applied a co-twin comparison design to evaluate whether differences between co-twins in a wide array of adolescent risk factors predicted differences in young adult alcohol misuse. DESIGN: Longitudinal study in which associations between characteristics of the sample as adolescents were used to predict young adult alcohol misuse in individual-level analyses and co-twin comparisons. SETTING: Finland. PARTICIPANTS: A total of 3402 individuals (1435 complete twin pairs; 36% monozygotic; 57% female) from the FinnTwin12 study. MEASUREMENTS: The young adult alcohol misuse outcome was a composite score of alcohol use and intoxication frequency. Adolescent predictors included factor scores representing academic performance, substance use, externalizing problems, internalizing problems, peer environment, physical health and relationship with parents; and single measures tapping alcohol expectancies, life events and pubertal development. FINDINGS: In individual-level analyses, individuals with higher adolescent substance use, externalizing problems, time with friends, peer deviance, sports involvement, sleeping difficulties, parental discipline, positive alcohol expectancies and difficulty of life events reported higher alcohol misuse in young adulthood (Ps < 0.019, R2  = 0.0003-0.0310%). Conversely, those with higher adolescent internalizing problems, parent-child relationship quality and time with parents reported lower alcohol misuse (Ps < 0021, R2  = 0.0018-0.0093%). The associations with adolescent substance use and alcohol expectancies remained significant in co-twin comparisons (Ps < 0.049, R2  = 0.0019-0.0314%). Further, academic performance emerged as a significant predictor, such that individuals with higher grades compared with their co-twin reported higher young adult alcohol misuse (Ps < 0.029, R2  = 0.0449-0.0533%). CONCLUSIONS: Adolescent substance use, positive alcohol expectancies and higher academic performance appear to be robust predictors of later alcohol misuse.

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.

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.

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.

Association of current and former smoking with body mass index: A study of smoking discordant twin pairs from 21 twin cohorts.

BACKGROUND: Smokers tend to weigh less than never smokers, while successful quitting leads to an increase in body weight. Because smokers and non-smokers may differ in genetic and environmental family background, we analysed data from twin pairs in which the co-twins differed by their smoking behaviour to evaluate if the association between smoking and body mass index (BMI) remains after controlling for family background. METHODS AND FINDINGS: The international CODATwins database includes information on smoking and BMI measured between 1960 and 2012 from 156,593 twin individuals 18-69 years of age. Individual-based data (230,378 measurements) and data of smoking discordant twin pairs (altogether 30,014 pairwise measurements, 36% from monozygotic [MZ] pairs) were analysed with linear fixed-effects regression models by 10-year periods. In MZ pairs, the smoking co-twin had, on average, 0.57 kg/m2 lower BMI in men (95% confidence interval (CI): 0.49, 0.70) and 0.65 kg/m2 lower BMI in women (95% CI: 0.52, 0.79) than the never smoking co-twin. Former smokers had 0.70 kg/m2 higher BMI among men (95% CI: 0.63, 0.78) and 0.62 kg/m2 higher BMI among women (95% CI: 0.51, 0.73) than their currently smoking MZ co-twins. Little difference in BMI was observed when comparing former smoking co-twins with their never smoking MZ co-twins (0.13 kg/m2, 95% CI 0.04, 0.23 among men; -0.04 kg/m2, 95% CI -0.16, 0.09 among women). The associations were similar within dizygotic pairs and when analysing twins as individuals. The observed series of cross-sectional associations were independent of sex, age, and measurement decade. CONCLUSIONS: Smoking is associated with lower BMI and smoking cessation with higher BMI. However, the net effect of smoking and subsequent cessation on weight development appears to be minimal, i.e. never more than an average of 0.7 kg/m2.

Early-onset tobacco use and suicide-related behavior - A prospective study from adolescence to young adulthood.

BACKGROUND: Developmental relationships between tobacco use and suicide-related behaviors (SRB) remain unclear. Our objective was to investigate the longitudinal associations of tobacco use in adolescence and SRB in adulthood. METHODS: Using a prospective design, we examined whether tobacco use in adolescence is associated with SRB (intentional self-injury, suicide ideation) in young adulthood in a population-based sample of 1330 twins (626 males, 704 females). The baseline and follow-up data were collected by professionally administered semi-structured poly-diagnostic interviews at ages 14 and 22, respectively. RESULTS: After adjusting for multiple potential confounders, those who reported early-onset of regular tobacco use had a significantly increased risk for intentional self-injury, such as cutting or burning, at age 22 (adjusted odds ratio [AOR] 4.57, 95% CI 1.93-10.8) in comparison to those who had not at all initiated tobacco use. Also, daily cigarette smoking at baseline was associated with future intentional self-injury (AOR 4.45, 95% CI 2.04-9.70). Early-onset tobacco use was associated with suicidal ideation in females (AOR 3.69, 95% CI 1.56-8.72) but not in males. Considering any SRB, baseline daily smokers (AOR 2.13, 95% CI 1.12-4.07) and females with early onset of regular tobacco use (AOR 3.97, 95% CI 1.73-9.13) had an increased likelihood. Within-family analyses among twin pairs discordant for exposure and outcome controlling for familial confounds showed similar, albeit statistically non-significant, associations. CONCLUSION: Early-onset tobacco use in adolescence is longitudinally associated with SRB (intentional self-injury and/or suicide ideation) in young adulthood, particularly among females. Further investigation may reveal whether this association has implications for prevention of SRB in adolescence and young adulthood.

Role of overlapping genetic and environmental factors in the relationship between early adolescent conduct problems and substance use in young adulthood.

AIMS: To determine (1) the prospective associations of conduct problems during early adolescence with tobacco, alcohol and cannabis use in young adulthood and (2) to what extent these associations are due to overlapping genetic versus environmental influences. DESIGN: A prospective twin study using biometric twin modelling. SETTING: Finland. PARTICIPANTS: A total of 1847 Finnish twins (943 males and 904 females) were interviewed in early adolescence, 73% of whom (n = 1353, 640 males and 713 females) were retained in young adulthood. MEASUREMENTS: Symptom counts of conduct disorder (CD) criteria were obtained from a semi-structured clinical interview in early adolescence [age 14-15 years, mean = 14.2, standard deviation (SD) = 0.15]. Frequency of alcohol, tobacco and cannabis use was obtained from a semi-structured clinical interview in young adulthood (age 19.9-26.6 years, mean = 22.4, SD = 0.7). FINDINGS: We found modest to moderate phenotypical correlations (r = 0.16-0.35) between early adolescent CD symptoms and substance use in young adulthood. In males, the phenotypical correlations of CD symptoms with all three substance use variables are explained largely by overlapping genetic influences. In females, overlapping shared environmental influences predominantly explain the phenotypical correlation between CD symptoms and tobacco and cannabis use. CONCLUSIONS: Conduct disorder symptoms in early adolescence appear to moderately predict substance use in early adulthood. In males, genetic influences seem to be most important in explaining the relationship between conduct disorder symptoms and substance use whereas in females, shared environmental influences seem to be most important.

Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts.

The mu1 opioid receptor gene, OPRM1, has long been a high-priority candidate for human genetic studies of addiction. Because of its potential functional significance, the non-synonymous variant rs1799971 (A118G, Asn40Asp) in OPRM1 has been extensively studied, yet its role in addiction has remained unclear, with conflicting association findings. To resolve the question of what effect, if any, rs1799971 has on substance dependence risk, we conducted collaborative meta-analyses of 25 datasets with over 28,000 European-ancestry subjects. We investigated non-specific risk for "general" substance dependence, comparing cases dependent on any substance to controls who were non-dependent on all assessed substances. We also examined five specific substance dependence diagnoses: DSM-IV alcohol, opioid, cannabis, and cocaine dependence, and nicotine dependence defined by the proxy of heavy/light smoking (cigarettes-per-day >20 vs. ≤ 10). The G allele showed a modest protective effect on general substance dependence (OR = 0.90, 95% C.I. [0.83-0.97], p value = 0.0095, N = 16,908). We observed similar effects for each individual substance, although these were not statistically significant, likely because of reduced sample sizes. We conclude that rs1799971 contributes to mechanisms of addiction liability that are shared across different addictive substances. This project highlights the benefits of examining addictive behaviors collectively and the power of collaborative data sharing and meta-analyses.

Role of nicotine dependence in the association between the dopamine receptor gene DRD3 and major depressive disorder.

BACKGROUND: The aims of this study were to analyze associations of dopamine receptor genes (DRD1-5) with Major Depressive Disorder (MDD) and nicotine dependence (ND), and to investigate whether ND moderates genetic influences on MDD. METHODS: The sample was ascertained from the Finnish Twin Cohort. Twin pairs concordant for smoking history were recruited along with their family members, as part of the multisite Nicotine Addiction Genetics consortium. Genetic association analyses were based on 1428 adults. Total of 70 tagging single nucleotide polymorphisms within the dopamine receptor genes were genotyped and analyzed for association with MDD, ND, and MD-ND co-morbidity. Individual level logistic regression analyses were based on 1296 adults with data on ND and MDD diagnoses, as well as on dopamine receptor genotypes adjusted for sex, age, and alcohol use. Four independent samples, such as population-based and case-control samples, were used for replication. RESULTS: Rs2399496, located 1.5 kb downstream of DRD3, showed suggestive association for MDD (p = 0.00076) and significant association for MDD-ND co-morbidity (p = 0.000079). Suggestive gene-(rs2399496) by-ND-interaction justified analyses by genetic risk variant and ND status. Individuals with ND and two minor alleles (AA) of rs2399496 had almost six-fold risk for MDD (OR 5.74, 95%CI 3.12-10.5, p = 9.010e-09) compared to individuals without ND and with two major alleles (TT). CONCLUSIONS: Significant association between a variant downstream of DRD3 and a co-morbid MDD-ND phenotype was detected. Our results further suggest that nicotine dependence may potentiate the influence of the DRD3 genetic variant on MDD.

Drinking, smoking, and educational achievement: cross-lagged associations from adolescence to adulthood.

BACKGROUND: Adolescent substance use is associated with lower educational achievement but the directionality of the association remains uncertain. We analyzed data on drinking, smoking and educational achievement to study the associations between substance use and education from early adolescence to young adulthood. METHODS: Longitudinal data from four time points (ages 12, 14, 17, and 19-27 years) from a population-based cohort study of Finnish twin individuals were used to estimate bivariate cross-lagged path models for substance use and educational achievement, adjusting for sex, parental covariates, and adolescent externalizing behavior. A total of 4761 individuals (49.4% females) were included in the analyses. Educational achievement was assessed with teacher-reported grade point average at ages 12 and 14, and with self-reported student status and completed education at age 17 and in young adulthood. From self-reported questionnaire items, frequency of any drinking, frequency of drinking to intoxication, any smoking and daily smoking were analyzed. RESULTS: Alcohol use and smoking behaviors at ages 12 and 14 predicted lower educational achievement at later time points even after previous achievement and confounding factors were taken into account. Lower school achievement in adolescence predicted a higher likelihood of engaging in smoking behaviors but did not predict later alcohol use. Higher educational attainment at age 17 predicted more frequent drinking in young adulthood. CONCLUSIONS: Adolescent drinking behaviors are associated with lower future educational achievement independently of prior achievement, whereas smoking both predicts and is predicted by lower achievement. Early substance use indexes elevated risk for poor educational outcomes.

Genetic and environmental influences underlying externalizing behaviors, cigarette smoking and illicit drug use across adolescence.

We investigated genetic and environmental influences common to adolescent externalizing behavior (at age 12), smoking (at age 14) and initiation of drug use (at age 17) using the FinnTwin12 cohort data. Multivariate Cholesky models were fit to data from 737 monozygotic and 722 dizygotic twin pairs. Heritability of externalizing behavior was 56%, that of smoking initiation/amount 20/32%, and initiation of drug use 27%. In the best-fitting model common environmental influences explained most of the covariance between externalizing behavior and smoking initiation (69%) and amount (77%). Covariance between smoking initiation/amount and drug use was due to additive genetic (42/22%) and common environmental (58/78%) influences. Half of the covariance between externalizing behavior and drug use was due to shared genetic and half due to the environments shared by co-twins. Using a longitudinal, prospective design, our results indicate that early observed externalizing behavior provides significant underlying genetic and environmental influences common to later substance use, here manifested as initiation of drug use in late adolescence.