FEB/MAR 2008
Volume 14 - No. 1
Book Review: The Cigarette Century
Book Review: The Science of Real-Time Data Capture
Book Review: Public Health Advocacy and Tobacco Control: Making Smoking History
Research Activities at a Featured Program: Twin and Family Research
SRNT Newsletter
February/March 2008, Volume 14, Number 1
Research Activities at a Featured Program:
Twin and Family Research on Smoking Behavior and Nicotine Dependence: The Finnish Chapter
Finland - Northern Natural Genetic Laboratory: Finland - member of the European Union - is located in Northern Europe between Russia and Sweden. It has a population of 5.3 million inhabitants living in an area total of 338 000 km2 with some 190 000 lakes. Because Finland used to be a relatively isolated area for long time, the genetic architecture of the population is quite homogenous. Thus, Finland has become a 'promised land' of genetic research - one might call it a 'northern natural genetic laboratory'.
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In addition to the researchers, there are many
professionals making valuable contributions in our
twin and family projects, such as project coordinators,
interviewers, statisticians and research secretaries.
(Professor Jaakko Kaprio standing left front in the picture.)
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The Department of Public Health at the University of Helsinki is harboring one of the most extensive genetically informative population based data sets, called the Finnish Twin Cohorts. Our goal is to examine genetic and environmental determinants of common, complex diseases, and their behavioral risk factors in Finland. In terms of genetic influences smoking behavior and nicotine dependence are typically complex phenotypes. This means that variation in smoking or nicotine dependence in a specific population cannot be explained by single genes but liability to certain outcome is based on multiple genes and their interactions with environmental factors. Here, we provide a review on the Finnish twin-family study projects and main publications related to smoking and nicotine dependence.
Finnish Adult Twin Cohort: Twin research in Finland was initiated in 1974-75 when the Principal Investigators (PI) Jaakko Kaprio and Markku Koskenvuo collected the baseline data including total of 13,888 twin pairs. This population based adult twin cohort was studied again in 1981 and 1990 with high response rates. The data have been also utilized to recruit families and to follow up for morbidity and mortality using national medical registers (Kaprio 2006). Smoking was among the first phenotypes studied within the Finnish Adult Twin Cohort. From 1975 to 1985 the aim was to study health consequences of cigarette smoking in twin design where twin pairs discordant for smoking were compared in terms of health consequences. Currently the twin studies form one research group in the Academy of Finland Centre of Excellence in Complex Disease Genetics headed by Professor Leena Peltonen.
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Family Study on Nicotine Dependence: The Finnish Family Study of Nicotine Dependence is part of an international consortium led by Dr Pam Madden from Washington University School of Medicine, and primarily funded by the National Institutes of Health (NIH) to address the genetics of nicotine dependence. The PI of the Finnish consortium is Jaakko Kaprio, while Professor Nicholas Martin is the corresponding PI for the Australian site at the Queensland Institute for Medical Research. The Finnish sample consists of families ascertained for heavy smoking in at least two siblings, sampled from amongst the older twin cohort assessed in 1975 (Saccone 2007, Loukola 2007). Data on lifetime tobacco use, nicotine dependence, and associated factors were obtained by a diagnostic telephone interview and questionnaire, including diagnoses of the DSM-IV nicotine dependence, the Fagerström Test for Nicotine Dependence, and the Nicotine Dependence Syndrome Scale. Also other measures of smoking history including initiation, cessation and withdrawal symptoms were assessed. A total of 2265 individuals from 762 families participated and provided DNA samples. Ulla Broms, PhD-student in Public Health has had an overall responsibility for day-to-day data collection. At present she is finalizing her thesis on Genetic Epidemiology of Nicotine Dependence and Smoking Behavior.
Finnish Adolescent Twin Cohorts: Two longitudinal cohorts of adolescent twins and their families, known as the FinnTwin12 and FinnTwin16 studies have focused on determinants of health-related behaviors and disease in adolescents and young adults. The goal is to investigate genetic and environmental contributions to consistency and change in health-related behaviors during late adolescence and early adulthood and to evaluate gene-environment interactions in behavioral development.
FinnTwin16, initiated in 1991, is a longitudinal study of five consecutive birth cohorts (1975-1979) of Finnish twins, their siblings and parents, funded by NIH and headed by Professor Richard J. Rose of Indiana University. Questionnaire assessments including detailed smoking data were conducted on twins as they reached age 16 (baseline), 17, 18 ½ and young adulthood (ages 22-25). Response rates have exceeded 88%. Parents and older sibs have returned questionnaires at similar response rates yielding data on over 2500 extended twin families.
FinnTwin12, initiated in 1994, is another cohort study to examine genetic and environmental determinants of precursors of health-related behaviors in initially 11- to 12-year-old twins. Major funding was obtained again from NIH as well as the Academy of Finland. This research is cast within the perspective of developmental genetic epidemiology, asking whether precursors of risk behaviors are evident to parents, teachers, and classroom peers as early as age 12. The study has a two-stage sampling design. The larger, first-stage study is an epidemiological investigation of five consecutive and complete birth cohorts of Finnish twin children, including questionnaire assessments of both twins and parents at baseline, just before the twins reach age 12 (87% participation rate), with follow-up of all twins at age 14 (88% participation rate), and again at age 17.5 years (92% participation rate). The epidemiological stage includes some 5600 twins and some 5000 parents. The second stage nested within this epidemiological study is an intensive assessment of a sub-sample with 1035 families (Kaprio et al. 2002). Twins selected for intensive study were administered a psychiatric interview at age 14 and are interviewed again, in early adulthood, in research now ongoing.
Twin Data used in Epidemiological Design: We have used twin data in epidemiological designs to investigate predictor and outcome associations. Twins can be analyzed also as individuals and for nearly all traits twins are representative of the population. Further, twin pairs discordant for outcome can be investigated as matched cases and controls.
Within the FinnTwin12, Satu Barman and co-authors (2004) examined how parental smoking (maternal and paternal smoking behavior and history, maternal smoking during pregnancy) together with adolescents' inattentive behavior (assessed by teacher of the twin with the Multidimensional Peer Nomination Inventory), predicted smoking initiation by age 14. Total of 4552 twins were investigated at baseline (aged 11-12) and follow-up (aged 14). At age 14, when smoking was assessed, 57% had never smoked, 34% had experimented, whereas 9% were current smokers. All parental smoking variables and inattentiveness additively predicted both experimental and current smoking. Parental smoking seems to be related to smoking initiation in offspring, although it is not clear whether this is through genetic or environmental transmission.
Within the Adult Twin Cohort, Broms and co-authors (2004) examined, how smoking cessation factors are related to smoking behavior, socio- economic status and transition of marital status. The data collected by postal surveys in 1981 and 1990 comprised 3069 current smokers, of whom 20% had quit smoking by 1990. Indicators of socioeconomic status were important predictors of smoking cessation even when previous smoking behavior was adjusted for. Getting married was associated with the increased probability of cessation in men. This result was confirmed in twin-pair discordant analysis showing that living alone was directly associated to smoking cessation. Further, we examined whether smoking reduction over a six-year period predicted smoking cessation nine years later. Probability of quitting by 1990 increased with increasing levels of reduction in amount smoked between 1975 and 1981. The model among twin pairs discordant for cessation indicated that the association of smoking reduction with increased likelihood of cessation was independent of genetic or early shared family influences on smoking behavior (Broms et al., in press). Within the same cohort Tellervo Korhonen and co-authors (2007) investigated smoking as a predictor of depressive symptoms. Based on responses in 1975 and 1981, the subjects were characterized as never smokers, persistent former smokers, quitters, recurrent smokers and persistent smokers. The Beck Depression Inventory was applied in 1990 to measure depressive symptoms among 4164 men and 4934 women. When family and genetic background were controlled, smoking remained a significant predictor of depression, the association being more consistent in men.
Genetic Architecture of Smoking Behavior and Nicotine Dependence: Our group has studied genetic architecture of smoking and nicotine dependence both in adolescent and adult cohorts. Using data from 1262 same-sex twins in the intensively-studied FinnTwin12 sample, Rose and co-authors (2003) examined factors impacting smoking initiation at age 12. They documented extra familial environmental effects by fitting maximum likelihood models to questionnaire data collected from double dyads consisting of twins and their classmate controls. Most of the variance (73%) in smoking initiation at age 12 was accounted for by common environmental effects. Of that substantial shared environment component, familial effects accounted for 49% of the variation in early onset smoking whereas extra-familial effects for 24% of the variance. Within the same cohort our international collaborator Danielle Dick, Virginia Commonwealth University and colleagues (2007a) studied the role of parental monitoring in adolescent smoking at age 14. Although monitoring had only small main effects, moderation effects associated with parental monitoring were dramatic: At high levels of monitoring, environmental influences were predominant, whereas at low levels of monitoring, genetic influences assumed greater importance in the etiology of smoking. Further, Dick and co-authors (2007b) reported moderating effects associated with parenting and peer characteristics on adolescent smoking measured at ages 14 and 17. They found significant moderating effects associated with dimensions of parenting on adolescent smoking, measured at two time points across development. Genetic influences on smoking increased, and common environmental effects decreased, as adolescents reported less parental monitoring and spending more time with their parents.
Within the Adult Twin Cohort Broms and co-authors (2006) analyzed genetic architecture of smoking behavior. Two-stage bivariate genetic modeling of age at initiation with amount smoked and with smoking cessation was conducted among 9880 twin pairs. For men the heritability estimate for age at initiation was .59, for amount smoked .54 and for smoking cessation .58. For women those estimates were .36, .61, and .50, respectively. The genetic correlations indicated that genetic influences on age at initiation accounted for at most 4% of the genetic factors in amount smoked or in cessation. Within the Family Study of Nicotine Dependence Broms and her colleagues (2007) examined heritability of nicotine dependence measured by the Nicotine Dependence Syndrome Scale (NDSS) and the Fagerström Test for Nicotine Dependence (FTND). Based on genetic modeling heritability estimates were 0.30 for NDSS and 0.40 for FTND suggesting that 30-40 % of phenotypic variation is explained by genetic differences in this specific family population.
Specific Genetic Influences on Smoking and Nicotine Dependence: Within the Family Study of Nicotine Dependence Anu Loukola and co-authors (2007) performed a genomewide scan to identify loci behind the smoking status, nicotine dependence and the comorbid phenotype of nicotine dependence and alcohol use in 505 individuals from 153 families. Previous linkage findings on 10q for a smoker phenotype, and on 7q and 11p for the nicotine dependence phenotype were replicated confirming that these genome regions are involved in the genetic etiology of smoking behavior and nicotine dependence. Further, this study associated for the first time drinking and smoking to a shared locus on 10q. Data of this family study was also included in a genomewide linkage screen of a simple heavy-smoking quantitative trait, the maximum number of cigarettes smoked in a 24-h period. Here, Saccone and co-authors (2007) used two independent samples: 289 Australian and 155 Finnish nuclear multiplex families. The trait was analyzed using a regression of identity-by-descent allele sharing on the sum and difference of the trait values for relative pairs. Suggestive linkage was detected on chromosome 22 at 27-29 cM in each sample, with a LOD score of 5.98 at 26.96 cM in the combined sample.
Ongoing Research and Future Challenges: One example of ongoing research is based on the FinnTwin12 data where we are investigating smoking and subsequent cannabis use. This work is done in collaboration with Dr Anja Huizink from the Erasmus Medical Center, Netherlands. We have observed that early onset smoking is a powerful predictor for subsequent cannabis use. However, the causal nature of this relationship needs to be further clarified. We are currently testing whether the gateway model explains this phenomenon. With data from FinnTwin16 subjects, assessed by questionnaire from mid adolescence and administered neuropsychological tests in early adulthood, we are relating differences in latency and amplitude of visual and auditory ERP to different trajectories of adolescent smoking, using smoking-discordant co-twins in a case-control design. Another line of ongoing studies is related to harm reduction approach based on the adult twin data, where we analyze health consequences of reduced, light and intermittent smoking. For example, we will examine whether smoking reduction serves as an effective harm reduction approach for smokers who are not able to quit, as we have access to extensive register-based health information on the older twin cohort to analyze mortality and morbidity from 1970s to the present.
About the Authors: Jaakko Kaprio, M.D., PhD is a Professor of Genetic Epidemiology at the University of Helsinki and Research Professor at the National Public Health Institute. Richard J. Rose, PhD, is Professor Emeritus of Psychological and Brain Sciences and Medical/Molecular Genetics at Indiana University, Bloomington, USA. Tellervo Korhonen, Ph.D. in Public Health is a Senior Scientist at the University of Helsinki and at the National Public Health Institute, Helsinki, Finland. Ulla Broms, MSc, is a doctoral candidate in Public Health.
References:
Barman,S.K., Pulkkinen,L., Kaprio,J., Rose,R.J (2004). Inattentiveness, parental smoking and adolescent smoking initiation. Addiction, 99 (8), 1049-1061.
Broms, U., Korhonen, T., Kaprio, J. (In press). Smoking reduction predicts cessation: longitudinal evidence from the Finnish adult twin cohort. Nicotine & Tobacco Research.
Broms U, Madden PAF, Heath AC, Pergadia ML, Shiffman S, Kaprio J. (2007). The Nicotine Dependence Syndrome Scale in Finnish Smokers. Drug and Alcohol Dependence, 89, 42-51.
Broms, U., Silventoinen, K., Lahelma, E., Koskenvuo, M., & Kaprio, J. (2004). Smoking cessation by socioeconomic status and marital status: the contribution of smoking behavior and family background. Nicotine & Tobacco Research, 6, 447-455.
Broms, U., Silventoinen, K., Madden, P.A.F., Heath, A.C. & Kaprio, J. (2006). Genetic architecture of smoking behaviour: a study of Finnish twins. Twin Research and Human Genetics, 9, 64-72.
Dick, D.M., Pagan,J.L., Viken,R., Purcell,S., Kaprio,J., Pulkkinen,L., Rose,R.J. (2007b). Changing environmental influences on substance use across development. Twin Research and Human Genetics, 10(2), 315-26.
Dick, D.M.,Viken,R., Purcell,S., Kaprio,J., Pulkkinen,L., Rose, R.J. (2007a). Parental monitoring moderates the importance of genetic and environmental influences on adolescent smoking. Journal of AbnormalPpsychology, 116(1), 213-8.
Kaprio, J. (2006). Twin studies in Finland 2006. Twin Research and Human Genetetics, 9, 772-777.
Kaprio, J., Pulkkinen, L., Rose, R.J. (2002). Genetic and environmental factors in health-related behaviors: studies on Finnish twins and twin families. Twin Research 5, 366-371.
Korhonen, T., Broms, U., Varjonen, J., Romanov, K., Koskenvuo, M., Kinnunen, T., & Kaprio, J. (2007). Smoking behaviour as a predictor of depression among Finnish men and women - a prospective cohort study of adult twins. Psychological Medicine, 37 (5), 705-715.
Loukola, A., Broms, U., Maunu,H., Wide´n, E., Heikkila, K., Siivola, M., Salo, A., Pergadia, M.L., Nyman, E., Sammalisto, S., Perola, M., Agrawal, A., Heath, A., Martin, N.G., Madden, P.A.F., Peltonen, L., & Kaprio, J. Linkage of nicotine dependence and smoking behaviour on 10q, 7q, and 11p in twins with homogeneous genetic background. The Pharmacogenomics Journal 2007 (ePUB June 5).
Rose, R.J., Viken, R.J., Dick, D.M., Bates, J.E., Pulkkinen, L. & Kaprio, J. (2003). It does take a village: nonfamilial environments and children's behaviour. Psycholical Science, 14 (3), 273-7.
Saccone,S.F., Pergadia,M.L., Loukola,A., Broms,U., Montgomery,G.W., Wang,J.C., Agrawal,A., Dick,D.M., Heath,A.C., Todorov,A.A., Maunu,H., Heikkila,K., Morley,K.I., Rice,J.P., Todd,R.D., Kaprio,J., Peltonen,L., Martin,N.G., Goate,A.M., & Madden,P.A. (2007). Genetic linkage to chromosome 22q12 for a heavy-smoking quantitative trait in two independent samples. American Journal of Human Genetics, 80(5), 856-66.