Tellervo Korhonen

Role of individual, peer and family factors in the use of cannabis and other illicit drugs: A longitudinal analysis among Finnish adolescent twins

BACKGROUND Although use of illicit drugs shows varying degree of heritability, the influence of shared and unique environmental factors predominate among adolescents. We explored factors predicting use of cannabis and other illicit drugs among Finnish adolescent twins. METHODS We used longitudinal data from the FinnTwin12-17 study with baseline at age 11-12 and follow-up at ages 14 and 17(1/2), including 4138 individuals. The outcome was self-reported ever use of cannabis or other illicit drugs at age 17(1/2). The potential predictors were measures reported by the twins, their parents or teachers. As individual factors we tested smoking, alcohol use, behavioral and emotional problems; as peer factors: number of smoking friends and acquaintances with drug experience; as family factors: parental substance use, socio-economic status and pre-natal exposure to nicotine. We used logistic regression models, controlling for twinship, age and sex, to compute odds ratios (OR) for each potential predictor. To adjust for within-family confounds, we conducted conditional logistic regressions among 246 twin pairs discordant for drug use. RESULTS 13.5% of subjects had initiated use of cannabis or other illicit drugs by age of 17(1/2). When adjusted for within-family confounds, smoking, drinking, and aggressiveness, as well as smoking and drug use among peers predicted use of illicit drugs. In the final regression model, the significant predictors were female sex, early smoking onset, drinking to intoxication, having smoking peers and acquaintances with drug experience, fathers weekly drinking to intoxication, and aggressive behavior among boys. Smoking initiation by age of 12 was the most powerful predictor among individuals (OR=26, p<0.001) and within discordant pairs (OR=22, p<0.001). CONCLUSIONS Early onset smoking is a powerful predictor for subsequent use of illicit drugs among Finnish adolescents, but the causal nature of this relationship needs to be clarified.

Smoking behaviour as a predictor of depression among Finnish men and women: a prospective cohort study of adult twins

BACKGROUND Depression is associated with smoking, but the causality of the relationship is debated. The authors examine smoking behaviour as a predictor of depression among the Finnish adult twin population. METHOD Based on responses to surveys in 1975 and 1981, the authors characterized the subjects as never smokers, persistent former smokers, quitters, recurrent smokers and persistent smokers. The Beck Depression Inventory (BDI) was applied in 1990 to measure depression (BDI score >9). Although the population consisted of twins, the authors first considered the subjects as individuals. Logistic regression models were computed for 4164 men and 4934 women. In order to control for family and genetic background, conditional logistic regression analyses were conducted among twin pairs discordant for depression. Bivariate genetic modelling was used to examine genetic and environmental components of the correlation between smoking and depression. RESULTS Among the men, persistent smoking (OR 1 x 42, 95% CI 1 x 07-1 x 89) and smoking in 1975 but quitting by 1981 (OR 1 x 68, 95% CI 1 x 17-2 x 42) was associated with a higher risk of depression, while among the women only the quitters had an elevated risk (OR 1 x 38, 96% CI 1 x 01-1 x 87). The gender x smoking interaction showed persistent smoking to be a stronger risk for men. When family and genetic background were controlled, smoking remained a predictor of depression. Genetic modelling among the men suggested a modest correlation (rg=0 x 25) between genetic components of smoking and depression. CONCLUSIONS Smoking behaviour may be a gender-sensitive predictor of depression, the stronger association in men being partly accounted for by having underlying genes in common.

Longitudinal Study on Poor Sleep and Life Dissatisfaction in a Nationwide Cohort of Twins

Life satisfaction and quality of sleep are important, related components of subjective well-being and general health. However, no earlier investigation is known to have tested the direction of the temporal relation between poor sleep and diminished life satisfaction, including simultaneous examination of shared genetic influences. These features were examined in the present study of a nationwide cohort of 18,631 same-sex Finnish twins with repeated measurements of life satisfaction, sleep quality, and several potential confounders within an interval of 6 years (1975 and 1981). Most individuals (59%) with new-onset life dissatisfaction had experienced suboptimal sleep at baseline. Poor sleep predicted a consistent pattern of life dissatisfaction (odds ratio = 2.1, 95% confidence interval: 1.7, 2.7 from logistic regression on individuals; odds ratio = 3.0, 95% confidence interval: 1.7, 5.3 from conditional logistic regression on twin pairs discordant for life dissatisfaction), whereas life dissatisfaction did not consistently predict poor sleep. There was substantial heritability for both traits, but their shared genetic component was relatively weak, as indicated by genetic correlations of 0.21 for men and 0.27 for women in a multivariate genetic model. This finding is consistent with the hypothesis that poor sleep may have direct effects on the brain, emotions, and mood.

Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium

Objectives To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. Design Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress. Participants Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). Primary outcome measures Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis. Results The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers. Conclusions Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.

Genetics of Smoking Behavior

The public health significance of sustained smoking is difficult to overstate. Worldwide, every other current smoker will prematurely die from tobacco-related diseases (Doll, Peto, Wheatley, Gray, & Sutherland, 1994; Neubauer et al., 2006). Should current trends continue, annual deaths attributable to smoking will exceed 10 million by 2025 (Mackay, Eriksen, & Shafey, 2006). Persistent smoking is the most preventable cause of disability and death; it is associated with wide-ranging adverse health effects, including heart disease, pulmonary disease, and lung and other cancers (Doll, Peto, Boreham, & Sutherland, 2005; Risch et al., 1993) in both industrialized and developing countries (Mackay, et al.). Smoking behaviors aggregate in families and in peer networks, due to genetic dispositions and familial and extrafamilial environmental influences. In a recent study of adult twins, achieving a high school education halved the likelihood of persistent smoking, parental smoking almost doubled it and having an MZ co-twin who ever smoked increased the likelihood nearly 10-fold (Hamilton et al., 2006). Smoking, like drinking, may be understood within a developmental framework – behavior for which precursors are found in early childhood with causal modifiers evident throughout lifetime. Risk of nicotine dependence is conditional on initiating smoking; some at high risk never smoke, and the factors underlying individual differences in smoking initiation, like those underlying drinking/abstaining, are multiple in nature and include factors outside, as well as within, family households. A developmental perspective is necessary to appreciate the associations of smoking behaviors with drinking, with other patterns of substance use/abuse, and with behav-

Telomere length in circulating leukocytes is associated with lung function and disease

Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (&bgr;= −0.0452, p=0.024) as well as COPD (&bgr;= −0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07×10−7), FVC (p=2.07×10−5), and FEV1/FVC (p=5.27×10−3). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases. Telomere length is decreased in asthma and COPD patients and positively associated with spirometric indices http://ow.ly/qOLFa

Analysis of Detailed Phenotype Profiles Reveals CHRNA5-CHRNA3-CHRNB4 Gene Cluster Association With Several Nicotine Dependence Traits

INTRODUCTION The role of the nicotinic acetylcholine receptor gene cluster on chromosome 15q24-25 in the etiology of nicotine dependence (ND) is still being defined. In this study, we included all 15 tagging single nucleotide polymorphisms (SNPs) within the CHRNA5-CHRNA3-CHRNB4 cluster and tested associations with 30 smoking-related phenotypes. METHODS The study sample was ascertained from the Finnish Twin Cohort study. Twin pairs born 1938-1957 and concordant for a history of cigarette smoking were recruited along with their family members (mainly siblings), as part of the Nicotine Addiction Genetics consortium. The study sample consisted of 1,428 individuals (59% males) from 735 families, with mean age 55.6 years. RESULTS We detected multiple novel associations for ND. DSM-IV ND symptoms associated significantly with the proxy SNP Locus 1 (rs2036527, p = .000009) and Locus 2 (rs578776, p = .0001) and tolerance factor of the Nicotine Dependence Syndrome Scale (NDSS) showed suggestive association to rs11636753 (p = .0059), rs11634351 (p = .0069), and rs1948 (p = .0071) in CHRNB4. Furthermore, we report significant association with DSM-IV ND diagnosis (rs2036527, p = .0003) for the first time in a Caucasian population. Several SNPs indicated suggestive association for traits related to ages at smoking initiation. Also, rs11636753 in CHRNB4 showed suggestive association with regular drinking (p = .0029) and the comorbidity of depression and ND (p = .0034). CONCLUSIONS We demonstrate novel associations of DSM-IV ND symptoms and the NDSS tolerance subscale. Our results confirm and extend association findings for other ND measures. We show pleiotropic effects of this gene cluster on multiple measures of ND and also regular drinking and the comorbidity of ND and depression.

Physical activity in adolescence as a predictor of alcohol and illicit drug use in early adulthood: a longitudinal population-based twin study.

We investigated prospectively whether physical activity level in adolescence predicts use of alcohol and illicit drugs in early adulthood. We studied 4,240 individual twins (1,870 twin pairs). We classified those who consistently reported frequent leisure physical activity at ages 16, 17 and 181/2 as persistent exercisers, those exercising less than three times monthly as persistently inactive, and all others as occasional exercisers. To control for familial confounds, within-family analyses compared activity-substance use associations in co-twins discordant for baseline physical activity. Individual-based analyses showed no clear association between baseline physical activity and subsequent weekly alcohol consumption. However, weekly alcohol intoxication (OR = 1.9, p = .002) and problems due to alcohol use (OR = 2.0, p < .001) were more common among persistently inactive participants. After excluding those reporting weekly intoxication at baseline, the risk for alcohol intoxication remained elevated among women occasionally (OR = 2.4, p = .017) or persistently (OR = 5.8, p < .001) inactive at baseline, but this association was not replicated within discordant twin pairs. Individual-based analyses showed that drug use in adulthood was more common among those persistently physically inactive in adolescence (OR = 3.7, p < .001) in comparison to those persistently active. This finding was replicated within discordant twin pairs. Among those with no drug experience during adolescence, persistent inactivity (OR = 1.9, p = .007) increased risk for drug use. We conclude that persistent physical inactivity in adolescence may increase the risk of later problems due to excess alcohol use. Sedentary lifestyle predicts illicit drug use even when controlling for familial factors.

Depression and Smoking across 25 Years of the Normative Aging Study

Objective: The majority of past findings indicate that smokers are more likely than non-smokers to report depressive symptoms and that depression may act as an impediment to smoking cessation. The aim of the present study is to examine the stability of the relationship between depressive symptoms and smoking status and to determine whether the presence of depressive symptoms predicts continued smoking. Methods: Subjects were initially healthy men (n=2208) from the Veterans Administration Normative Aging Study, an ongoing cohort of older men who have been re-assessed every 3–5 years for a period of 25 years. Depressive symptoms measures employed were the Cornell Medical Index, the MMPI-2 Content Depression Scale, and the Center for Epidemiological Studies Depression Scale. Results: Depression scores were higher among continuing smokers compared to never and former smokers and those who quit after entering the study. None of the three depressive symptoms measures were associated with decreased likelihood of smoking cessation. The change in MMPI-2 depression scores observed in a 4-year follow-up was the same among those who quit and those who remained smokers. Conclusions: Higher prevalence of depressive symptoms among male smokers is stable across time and is likely to contribute to higher morbidity and mortality among these smokers. However, presence of depressive symptoms did not have a significant impact on smoking cessation.

A Genome-Wide Association Study of a Biomarker of Nicotine Metabolism

Individuals with fast nicotine metabolism typically smoke more and thus have a greater risk for smoking-induced diseases. Further, the efficacy of smoking cessation pharmacotherapy is dependent on the rate of nicotine metabolism. Our objective was to use nicotine metabolite ratio (NMR), an established biomarker of nicotine metabolism rate, in a genome-wide association study (GWAS) to identify novel genetic variants influencing nicotine metabolism. A heritability estimate of 0.81 (95% CI 0.70–0.88) was obtained for NMR using monozygotic and dizygotic twins of the FinnTwin cohort. We performed a GWAS in cotinine-verified current smokers of three Finnish cohorts (FinnTwin, Young Finns Study, FINRISK2007), followed by a meta-analysis of 1518 subjects, and annotated the genome-wide significant SNPs with methylation quantitative loci (meQTL) analyses. We detected association on 19q13 with 719 SNPs exceeding genome-wide significance within a 4.2 Mb region. The strongest evidence for association emerged for CYP2A6 (min p = 5.77E-86, in intron 4), the main metabolic enzyme for nicotine. Other interesting genes with genome-wide significant signals included CYP2B6, CYP2A7, EGLN2, and NUMBL. Conditional analyses revealed three independent signals on 19q13, all located within or in the immediate vicinity of CYP2A6. A genetic risk score constructed using the independent signals showed association with smoking quantity (p = 0.0019) in two independent Finnish samples. Our meQTL results showed that methylation values of 16 CpG sites within the region are affected by genotypes of the genome-wide significant SNPs, and according to causal inference test, for some of the SNPs the effect on NMR is mediated through methylation. To our knowledge, this is the first GWAS on NMR. Our results enclose three independent novel signals on 19q13.2. The detected CYP2A6 variants explain a strikingly large fraction of variance (up to 31%) in NMR in these study samples. Further, we provide evidence for plausible epigenetic mechanisms influencing NMR.