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The Genetics of Tobacco Use: Methods, Findings and Policy Implications W Hall, P Madden, M Lynskey

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The Genetics of Tobacco Use: Methods, Findings and Policy Implications W Hall, P Madden, M Lynskey 119 Tob Control: first published as 10.1136/tc.11.2.119 on 1 June 2002. Downloaded from REVIEW The genetics of tobacco use: methods, findings and policy implications W Hall, P Madden, M Lynskey ............................................................................................................................. Tobacco Control 2002;11:119–124 Research on the genetics of smoking has increased our Specific study designs—adoption, twin, and link- understanding of nicotine dependence, and it is likely to age designs—are needed to separate the effects of genes from those of the environment. illuminate the mechanisms by which cigarette smoking adversely effects the health of smokers. Given recent Adoption studies advances in molecular biology, including the completion In the adoption design we compare the similarity in smoking between adoptive children and their of the draft sequence of the human genome, interest has biological parents with the similarity between now turned to identifying gene markers that predict a adopted children and their adoptive parents or heightened risk of using tobacco and developing between adoptive sibling pairs and biological sib- ling pairs. If smoking is largely or wholly geneti- nicotine dependence cally determined, then there should be greater .......................................................................... similarity between children and their biological parents and siblings than between adopted hanks to RA Fisher, genetics has been linked children and their adoptive parents or siblings. to scepticism about a causal relation between One early adoption study found an association cigarette smoking and lung cancer.12 Fisher3 between the smoking of foster children and their T biological siblings but not their adoptive argued that the association between smoking and 5 6 lung cancer was explained by shared genes that siblings. A recent adoption study reported mod- predisposed people to initiate smoking as young erate to strong associations between adoptees’ adults and to develop lung cancer in late smoking and that of their biological siblings, and adulthood. Much use was made of his hypothesis between male adoptees’ and their biological http://tobaccocontrol.bmj.com/ by the tobacco industry to manufacture a mothers’ smoking. spurious controversy about the health effects of It has become increasingly difficult to conduct smoking, a fact that may have discouraged public adoption studies because fewer children are health research into the genetic contribution to available for adoption except transnationally and smoking.1 there are ethical concerns about such studies. The Over the past decade, research on the genetics older studies often lacked detailed information on of tobacco use has strongly suggested that genetic biological parents and the placement of adoptees factors do play a role in different stages of tobacco (usually to more advantaged homes) restricted use and dependence. Given the possible misuse variation in the environments to which they were and misunderstanding of this work, it is impor- exposed. Adoption studies also had a limited abil- tant for researchers and policy makers in the ity to assess the role of family environment because in some countries the practice was to tobacco field to be acquainted with the research on September 30, 2021 by guest. Protected copyright. and its policy implications. Our aims are accord- match biological and adoptive parents on key ingly: (1) to summarise the results of recent demographic features (for example, education or research on the genetics of tobacco use from religious affiliation), introducing a correlation adoption, twin, linkage, and association studies; between genes and environment. Finally, adop- and (2) to consider the implications of these tion studies that included subjects who were not findings for public health and tobacco control adopted immediately at birth may have overesti- policies. mated genetic effects by attributing the effects of early environmental exposures to genetic influences.7 GENETIC STUDY DESIGNS AND RESEARCH FINDINGS Twin studies Traditional family studies suggest that genetic The twin study method compares the agreement See end of article for factors influence smoking by reporting elevated in the behaviour of (1) monozygotic or identical authors’ affiliations ....................... rates of tobacco use and dependence in the twins who share the same genetic make-up, and relatives of people who smoke tobacco. For exam- (2) dizygotic or fraternal twins who share on Correspondence to: ple, Niu and colleagues4 reported that individuals average 50% of their genetic make up, the same as Wayne Hall, Office of Public Policy and Ethics, with a nicotine dependent sibling were 2.1–3.5 ordinary siblings. Twins are said to be “concord- Institute for Molecular times more likely to be nicotine dependent ant” if both engage in the same behaviour (for Bioscience, University of (defined by Fagerstrom score and the revised tol- example, both smoke tobacco). If certain assump- Queensland, St Lucia, erance questionnaire) than those who did not. tions are met (see below), a higher rate of agree- Queensland 4072, Such studies, however, confound genetic and ment in monozygotic than dizygotic twins can be Australia; [email protected] environmental influences because siblings share attributed to genetic factors. Statistical models ....................... environmental influences as well as genes. estimate the percentage of variance in the trait www.tobaccocontrol.com 120 Hall, Madden, Lynskey Tob Control: first published as 10.1136/tc.11.2.119 on 1 June 2002. Downloaded from Table 1 Estimates from twin studies of genetic (A), shared environmental (C), and non-shared environmental (E) influences on smoking initiation and persistence in women and men Women Men AC EACE Initiation Sweden9 44 42 14 51 39 10 Denmark10 79 – 21 84 – 16 Finland11 37 50 13 50 33 17 Australia12 77419284329 Australia13 60 26 14 80 – 20 USA second world war veterans14 – – – 59 21 20 USA Virginia12 84 – 16 84 – 16 USA Vietnam veterans15 – – – 39 49 12 Persistence Sweden9 59 – 41 52 – 48 Finland16 71 – 29 68 – 32 Australia17 53 – 47 53 – 47 Australia13 62 – 38 62 – 38 USA8 58 – 42 58 – 42 USA Vietnam veterans15 ––– 69–31 that is explained by genes (heritability) and by shared (expe- Research has generally,23–27 although not always,28 supported riences shared by family members) and non-shared (experi- the validity of the equal environments assumption in studies ences unique to the individual) environment. of substance use. This has included studies of twin pairs who The results of a number of large scale twin studies of ciga- were misinformed about their zygosity23 24 and retrospective rette smoking from around the world are summarised in table reports of childhood and adult social environments in mono- 9–17 1. The data presented in this table are the result of a zygotic and dizygotic twins.25–28 8 re-analysis of data from the original studies. The top half of The traditional twin method also assumes that the environ- the table provides the results of eight studies that have exam- ments of twins and singleton siblings are comparable. This ined genetic and environmental influences on smoking initia- assumption may not hold because twins have higher rates of tion; the bottom half summarises twin studies of smoking obstetric complications and low birth weight than singleton persistence. http://tobaccocontrol.bmj.com/ births and there are different patterns of family and sibling Because the reported prevalence of smoking initiation was 7 not high in these studies (all substantially lower than 90%) we interactions in families with twins than in those without. can assume that “smoking initiation” generally referred to the A final limitation of the twin study is that it has low statis- initiation of “regular”, usually daily cigarette smoking. In fact, tical power to test for gene–environment interactions and most of the Scandinavian studies of smoking initiation gene–environment correlation effects in the aetiology of defined people who smoked less than 100 cigarettes in their smoking and other behaviours. Some of these problems can be lives as non-smokers. Despite the wide range of cultures, ages, addressed using extensions of the twin design, including the and birth cohorts represented in these papers, estimates of the study of the children of twins and other family members.729 heritability of smoking initiation were substantial for both For example, studies of the offspring of monozygotic twins men and women: they ranged between 37%11 and 84%12 in who are discordant for smoking provide a powerful way of women and between 28%12 and 84%12 in men (see original disentangling genetic and environmental effects because the papers for details). By contrast, there was little consistency offspring of the discordant monozygotic twins share the same on September 30, 2021 by guest. Protected copyright. between studies for the importance of family environment. In genetic relationship to both twins but are exposed to different some studies, shared family environment was estimated to family environments. These designs have yet to be applied to account for 50%11 of the variance in smoking initiation among the study of smoking behaviour and nicotine dependence. women and 49%17 of the variance among men. Yet other studies11 12 reported no significant shared environmental influences on smoking initiation. Studies of twins reared apart Findings from some81517 but not all studies of smoking
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