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HORIZONS REVIEW doi:10.1111/j.1360-0443.2008.02213.

Are there genetic influences on addiction:


evidence from family, adoption and twin studies

Arpana Agrawal & Michael T. Lynskey


Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA

ABSTRACT

Aims In this exciting era of gene discovery, we review evidence from family, adoption and twin studies that examine
the genetic basis for addiction. With a focus on the classical twin design that utilizes data on monozygotic and dizygotic
twins, we discuss support in favor of heritable influences on alcohol, nicotine, cannabis and other illicit drug
dependence. Methods We review whether these genetic factors also influence earlier stages (e.g. experimentation)
of the addictive process and whether there are genetic influences specific to each psychoactive substance.
Results Converging evidence from these studies supports the role of moderate to high genetic influences on addiction
with estimates ranging from 0.30 to 0.70. The changing role of these heritable factors as a function of gender, age and
cultural characteristics is also discussed. We highlight the importance of the interplay between genes and the envi-
ronment as it relates to risk for addiction and the utility of the children-of-twins design for emerging studies of
gene–environment interaction is presented. Conclusions Despite the advances being made by low-cost high-
throughput whole genome association assays, we posit that information garnered from twin studies, especially
extended twin designs with power to examine gene–environment interactions, will continue to form the foundation for
genomic research.

Keywords Addiction, environment, genetic, heritability, twins.

Correspondence to: Arpana Agrawal, Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid, Box 8134, St Louis, MO 63110,
USA. E-mail: arpana@wustl.edu
Submitted 24 September 2007; initial review completed 24 January 2008; final version accepted 11 February 2008

INTRODUCTION to question the value of genetic research on addictive


disorders [8].
In 2000, the completion of the draft sequence of the In considering the relative merit of attempts to iden-
human genome was announced, with much fanfare, at a tify genes conferring susceptibility to addictive diseases, a
joint press conference held by US President Clinton and necessary first step is to evaluate evidence concerning the
UK Prime Minister Blair [1–3]. Proponents highlighted extent to which alcohol and other drug use disorders
the potential of this work for revolutionizing the diagno- (or ‘addiction’, for the scope of this review) may be influ-
sis and treatment of many illnesses [4,5], while others enced by heritable factors. Such evidence can be derived
urged caution, both questioning the potential of genomic from a range of family-based genetically informative
medicine [6] and highlighting potential ethical and social research designs including adoption, twin and family
challenges of this discovery [7]. This controversy has designs. The aim of the current paper is to review evi-
been perhaps most acute in complex disorders, such as dence from such studies to address the central question of
alcohol and other drug dependence. Complex disorders whether there are heritable influences on liability to drug
are both multi-factorial (where known environmental abuse/dependence. A particular focus of this review is to
and genetic influences are at play) and polygenic (i.e. any evaluate the contributions of the more commonly used
genetic influences are likely to be spread over multiple twin design. Particularly for the study of addiction, twin
genes, each of which may make only minor contributions studies have several advantages over both family and
to variance in disease risk) in nature. These aspects of adoption designs and, as such, are the foundation for
complex or non-Mendelian disorders have led some future extended sampling designs.

© 2008 The Authors. Journal compilation © 2008 Society for the Study of Addiction Addiction, 103, 1069–1081
1070 Arpana Agrawal & Michael T. Lynskey

FAMILIAL TRANSMISSION OF ADOPTION STUDIES


SUBSTANCE USE DISORDERS
Adoption studies are based on a comparison of the con-
Some early family-based studies provided initial clues cordance or correlation between offspring behavior
to potential heritable influences on addictive disorders (e.g. alcohol dependence) and the characteristics of both
by examining the risk of substance use disorders in the biological and adoptive parents: similarity between
the first-degree relatives of individuals either with or offspring and biological parents is suggestive of genetic
without a substance use disorder. For example, in a influences on that behavior, while similarity between off-
study of a large sample of individuals meeting criteria spring and adoptive parents is suggestive of environmen-
for alcohol dependence and their siblings, Bierut et al. tal influences. Some highly influential adoption studies
[9] reported that, relative to a control individual, the sib- have been conducted highlighting the importance of
lings of alcohol-dependent probands had elevated rates genetic influences on substance dependence. In one of
of alcohol dependence (49.3–50.1% for men and 22.4– the earliest of these studies, Goodwin et al. [13] compared
25% for women, depending on the presence of comorbid rates of alcohol problems and psychiatric treatment in 55
drug dependence). While additional substance use disor- male children of biological parents with alcohol depen-
ders in the proband did not appear to increase risks of dence and 78 control children, all of whom were adopted
alcohol dependence in siblings, there was some evidence out within the first 6 weeks after being born and who had
for substance-specific influences on drug dependence: no known contact with their biological parents. Rates of
siblings of cannabis-dependent probands had an elev- psychiatric treatment (40% versus 24%), psychiatric hos-
ated risk of developing cannabis dependence [relative pitalization (15% versus 3%), treatment for alcohol prob-
risk (RR), 1.78], siblings of cocaine-dependent pro- lems (9% versus 1%) and meeting criteria for alcoholism
bands had an elevated risk of developing cocaine depen- (18% versus 5%) were all significantly higher in the
dence (RR, 1.71) and siblings of habitual-smoking adopted-away children of parents with alcohol problems/
probands had an elevated risk for habitual smoking dependence, thus providing strong support for a genetic
(RR, 1.77). component to alcohol dependence. Similarly, Cadoret
Similarly, in a study of the 1267 adult first-degree et al. [14–16] studied the etiological importance of bio-
relatives of 231 probands with dependence on opioids, logical parents’ alcohol problems and antisocial person-
cocaine, cannabis and/or alcohol and 61 control ality (as indexed by hospital and prison records) on the
probands, Merikangas et al. [10] reported an eightfold development of these behaviors in their adopted-away
increased risk of drug disorders among the relatives of offspring. Their analyses of data from 242 male and 201
probands with drug disorders across the range of sub- female offspring provided an early demonstration of the
stances studied, which was largely independent from the importance of genetic factors in the development of drug
familial aggregation of both alcoholism and antisocial abuse/ dependence and also identified two distinct path-
personality disorder. There was also evidence of specific- ways for the transmission of risk. The first mechanism
ity of familial aggregation of the predominant drug of was where parental antisocial behavior increased risk for
abuse, suggesting that there may be risk factors that are offspring antisocial behavior, which in turn increased risk
specific to particular classes of drugs as well as risk for drug abuse. The second was characterized by parental
factors that underlie substance disorders in general. alcohol problems directly influencing risks of drug abuse
Similarly, studies have reported both that alcoholism is in their biological offspring, even in the absence of off-
familial [11] and that having an alcoholic parent is spring antisocial behavior [16]. Two other features of this
associated with a fivefold increase in the risk of alcohol- study are noteworthy. First, comparison of results for
ism [12]. males and females suggested that genetic and environ-
Family studies conclude that both alcoholism and sub- mental risk mechanisms operate similarly across gen-
stance use disorders cluster in families, due presumably to ders. Secondly, their results also highlighted the etiologi-
heritable factors. The family design cannot distinguish cal importance of some environmental influences—
whether the causes of familial similarity are genetic or particularly parental divorce and parental psychiatric
environmental in nature. Further, for substance depen- disorder in the adoptive families—in the development of
dence, there appear to be familial influences that confer a drug abuse. While the importance of these environmen-
non-specific risk for drug dependence. The scope of family tal influences had been recognized previously, this was
studies, while discussed briefly here, is influenced by strat- one of the first studies to be able to isolate the influence of
egy for sample selection (e.g. via a proband from clinics, environmental exposures from potential genetic con-
community samples), for inclusion of relatives (e.g. must founds, thus highlighting the utility of adoption and
have one or more affected siblings) and for exclusion of other family designs for elucidating components of envi-
relatives (e.g. age, non-participation, geography). ronmental risk.

© 2008 The Authors. Journal compilation © 2008 Society for the Study of Addiction Addiction, 103, 1069–1081
Genetic studies of addiction 1071

The adoption study literature must be interpreted ment). Shared environmental factors overlap 100%
with recognition of certain important limitations. First, between members of MZ and DZ twin pairs, under the
due to the challenges involved with accessing adoption important assumption of equal environments (which is
records, these studies are not common. Secondly, because discussed in some detail later). The measure of non-
of the much higher prevalence of alcoholism in males shared environment includes the effects of measurement
than females, particularly for earlier birth cohorts on error and is, by definition, uncorrelated between
which the older adoption studies were based, the studies members of a twin pair.
have mainly been informative about outcomes associated One way to conceptualize the information captured by
with paternal alcoholism, although the Swedish Adop- the twin model is by considering the path diagram (or
tion study [17] provides some data on maternal alcohol- structural equation model) of MZ and DZ twins presented
ism. Similarly, neither biological nor adoptive parents or in Fig. 1. In path analyses, latent measures are repre-
adopted children may be representative of the popula- sented by circles and measured variables in rectangles—
tion: biological parents are likely to have higher rates of hence, additive genetic (A), shared environment (C) and
drug dependence and psychiatric disorders while, con- non-shared environment (E) appear in circles with a
versely, adoptive parents are less likely to be disordered as direct path (denoted by the single-headed directional
well as being, on average, older and relatively socially arrow) on addiction, which is measured/observed and,
advantaged. For example, in the Swedish adoption therefore, denoted by a rectangle. The double-headed
samples, rates of temperance board registrations were arrows represent the extent to which A and C are corre-
32% in biological fathers but only 4% in adoptive fathers, lated between MZ and DZ twins.
relative to a population prevalence of 12% [17]. The use Prior to reviewing twin findings in addiction, it is
of control adoptees from unaffected biological families important to consider the construct of heritability. Heri-
may have ameliorated some of these biases. Selective tability, in statistical terms, is that proportion of the total
placement, whereby adoptive families are selected on the phenotypic variance that can be attributed to genetic
basis of sharing characteristics of the biological parents, factors (or A/A + C + E). The context for measurement of
may be an overstated problem of the evaluations con- heritability is the population and not the individual—
ducted in the adoption process [18]. None the less, hence, the heritability in an individual is undefined. In
environmental exposures occurring before adoptive addition, there are some caveats to estimates from twin
placement, including in utero environment, may inflate studies that should be considered:
estimates of heritable influences, while some have argued 1 The premise that members of MZ and DZ twin pairs are
[19] that the adoption process itself may be pathogenic exposed to, and respond to, ‘shared environment’ to
and account for at least some of the elevated rates of the same extent constitutes the equal environments
psychopathology seen in adopted offspring [20]. assumption (EEA). If the EEA is violated (i.e. members
Overall, adoption studies demonstrate a strong link
between the biological parent’s substance use and off-
spring risk for addiction, thus establishing that genetic
influences are important etiological factors for addiction.

TWIN STUDIES

The classical twin study utilizes data from identical/


monozygotic (MZ) and fraternal/dizygotic (DZ) twin
pairs, reared together, to disentangle the role of genetic
and environmental influences on a given behavior or
other measured outcome. The genetic and environmental
factors are latent (or unmeasured) influences that explain
population variation in a measured phenotype, such as
addiction. Additive genetic influences are shared 100%,
on average, between members of MZ twin pairs while DZ
twin pairs share 50% their additive genetic influences.
There are two sources of environmental variation—those
latent environmental factors that make members of a
twin pair similar to each other (shared environment) and
those environmental factors that make members of a Figure 1 The classical twin model: path diagrams for monozygotic
twin pair different from each other (non-shared environ- (MZ) and dizygotic (DZ) twins

© 2008 The Authors. Journal compilation © 2008 Society for the Study of Addiction Addiction, 103, 1069–1081
1072 Arpana Agrawal & Michael T. Lynskey

of MZ twin pairs receive/perceive their shared environ- of MZ and DZ pairs for alcoholism is R1 and R2, respec-
ment more similarly than DZ twins, and that this tively. We also know that twin similarity is a consequence
change influences concordance for addiction), then of A, D and C (but not E, which contributes to variance
this would inflate the heritability estimate (as any only)
increased similarity in MZ versus DZ twins is captured
R1 = A + D + C
by the genetic parameter). The EEA has been criticized
by some as an unrealistic notion [21–24]. However, R2 = 0.5A + 0.25D + C
studies that examined twin physical similarity or
These equations, when D and C are estimated jointly,
parental behavior towards twins as well as the effects of
cannot be solved as a set of simultaneous equations.]
perceived zygosity (where DZ twins were identified
Keeping these limitations in mind, the following sec-
incorrectly as MZ) and its association with personality
tions highlight the major findings from twin studies esti-
[25,26], eating attitudes [27], behavioral problems
mating the extent to which genetic factors contribute to
[28] and psychiatric disorders [29–31] have concluded
the etiology of alcoholism (abuse/dependence), nicotine
largely that previous assertions of violations of EEA
dependence, cannabis abuse/dependence and abuse of, or
may have been overstated. If the reason that MZ twins
dependence on, other illicit drugs. Due to the incredible
are perceived more similarly then DZ twins is because
wealth of information in this area our description, while
MZ twins are genetically more similar than DZ twins,
aiming to be comprehensive, cannot be as detailed as may
then this is not a violation of EEA.
be desired. We urge readers to refer to the exciting empiri-
2 Heritability encompasses only those genetic mecha-
cal research papers cited in these sections for a detailed
nisms that make MZ twins systematically genetically
discussion of findings.
identical to each other (and DZ twins half as similar).
Therefore, epigenetic modifications (when not inher-
ited) or sporadic structural change in DNA, which can ALCOHOLISM
occur in one member of an MZ pair but not the other,
are not captured by A. Therefore, in the context of the There have now been numerous large twin studies
simple twin design, epigenetic change, albeit biologi- [36–39] of alcohol abuse, dependence and related drink-
cal, is estimated as individual-specific environment (E) ing behaviors conducted across several countries and
[32,33]. also several comprehensive reviews of these studies
3 Twin studies also assume random mating—if, [38,40,41]. As shown in Fig. 2, estimates of the herita-
however, parents of the twins under investigation bility of alcohol abuse/dependence have ranged from
selected each other based on genetic predisposition for, 50% to 70%. Additional studies have demonstrated a
for instance, alcohol consumption, as documented by similarly high level of heritability across a spectrum of
twin studies [34,35], then the genetic correlation alcohol-related behaviors, including heavy consumption
between DZ twins is no longer simply 0.5A and [42] and problem drinking [42–44], with some sugges-
increases by m (a measure of assortative mating). If tion that the heritability may be higher for more severe
there is non-random mating and it is ignored, this forms of alcohol problems [45]. Despite earlier sugges-
excess similarity in DZ twins will inflate estimates of tions that alcohol dependence may be more heritable in
shared environment, and possibly bias heritability men than in women, more recent evidence has estab-
downwardly. lished that a similar proportion of variation in liability to
4 Genetic and environmental factors have direct (‘main’) alcohol dependence in men and women can be explained
effects, and under the simple twin model do not inter- by additive genetic factors. None the less, uncertainty
act. In reality, this is rarely the case. Depending on the remains concerning the extent to which genetic sources
effect of the interaction, ignoring gene–environment of variability in risk of alcohol dependence overlap fully
interactions (and correlations) will bias heritability as [46] or only partially [47] across men and women.
well as other estimates. Later in this review, we provide
a more detailed consideration of the importance of
NICOTINE DEPENDENCE
gene–environment interplay.
In addition to additive genetic influences, twin studies There are multiple informative measures of nicotine
can also be used to estimate the role of non-additive/ dependence, including the DSM-IV [48] diagnosis of
dominance genetic influences (denoted by D). D is shared nicotine dependence, the Fagerstrom Tolerance Question-
100% and 25% by MZ and DZ twins, respectively. naire (FTQ) [49], the Fagerstrom Test for Nicotine Depen-
However, when working with MZ and DZ twins alone, it is dence (FTND) [50], the Heaviness of Smoking Index (HSI)
not possible to identify simultaneously the effects of D and [51] and the Nicotine Dependence Syndrome Scale
C. [Let us assume that the correlation between members (NDSS) [52]. Irrespective of construct, there is substan-

© 2008 The Authors. Journal compilation © 2008 Society for the Study of Addiction Addiction, 103, 1069–1081
Genetic studies of addiction 1073

Alcoholism

Nicotine Dependence

Cannabis use disorders

Any illicit drug use disorders

Heritability (% of total variance)


80
70
60
50
40
30
20
10
0

s
s
s

s
s

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Figure 2 Heritability estimates for alco-

tw
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tw
tw
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a

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holism, nicotine dependence, cannabis

ad
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D
Vi

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Fi

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and other illicit drug use disorders across
na

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Au
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Vi

samples of twins

tial evidence from twin studies that nicotine dependence studies of cannabis-related phenotypes and noted that
is a heritable phenotype. Kendler et al. [53] reported a existing studies have produced estimates of the heritabil-
heritability of 72% for a factor score that combined items ity of cannabis dependence that ranged from 34% to 78%
from the FTQ and DSM-IV. Lessov et al. [54] report similar [64]. For example, in a study of US male twins, Kendler &
estimates for DSM-IV (56%) and the HSI (71%), as do Prescott estimated that 58% of the variance in cannabis
Haberstick et al. [55] for FTND (52%) and HSI (61%). dependence could be attributed to additive genetic factors
Heritabilities of similar magnitude have also been [65], while a parallel study of female twins estimated that
reported elsewhere: DSM-IIIR (60%) [56], FTND (75%) 62% of the variance in cannabis dependence could be
[57] and NDSS (30%) [58]. Across these studies, there attributed to heritable factors [65]. While these findings
has been no support for the role of shared environmental provided no evidence to suggest sex differences in herita-
influences on nicotine dependence; however, McGue et al. bility of cannabis dependence, another study of male and
[59] report that both heritable (44%) and shared envi- female like and unlike sex pairs could not distinguish
ronmental (37%) influences may contribute to twin between a model assuming no sex differences in the heri-
correlations for nicotine dependence in adolescents. The tability of cannabis dependence (estimated at 45%) and
emerging importance of heritable factors (Fig. 2) during one assuming additive genetic influences on cannabis
development from adolescence to adulthood is well docu- dependence only in men [66]. Since the publication of
mented and discussed in the subsequent section. this previous research, Kendler et al. [67] have reported
From a public health perspective we are also interested heritability of cannabis (and other substance) use dis-
in heritable influences on persistent smoking, which is orders from a Norwegian sample, a study of particular
correlated highly with nicotine dependence. There is sub- interest as the prevalence of cannabis and other illicit
stantial evidence across a number of studies to suggest drug use is substantially lower in Norway than in the
that 50–70% [60–63] of the total variance in smoking United States or Australia, where the bulk of previously
persistence is due to heritable influences. Similar to nico- reported twin studies of cannabis dependence have
tine dependence, there is no consistent evidence in favor been conducted. Despite the lower prevalence of abuse/
of shared environmental influences on persistence. dependence diagnoses (1.6%) or any symptoms of
abuse/dependence (2.9%), univariate genetic modeling
indicated substantial additive genetic influences on both
CANNABIS AND OTHER ILLICIT DRUG
abuse/dependence diagnoses [77%, 95% confidence
ABUSE/DEPENDENCE
interval (CI) = 46–93] and any symptoms of abuse/
Relative to the accumulated literature on tobacco and dependence (75%, 95% CI = 11–47).
alcohol, there is somewhat less research employing the There have also been a relatively small number of
twin methodology to examine heritable influences on studies examining abuse/dependence on other illicit
illicit drug use disorders. We recently reviewed twin drugs, including cocaine and heroin. For example, in the

© 2008 The Authors. Journal compilation © 2008 Society for the Study of Addiction Addiction, 103, 1069–1081
1074 Arpana Agrawal & Michael T. Lynskey

Vietnam era twin sample, Tsuang et al. reported that 33% suggests that nearly 60–90% of the latent genetic influ-
of the variance in stimulant abuse/dependence, 27% of ences on substance dependence overlap with those influ-
the variance in sedative abuse/dependence, 54% of the encing substance use, suggesting limited specificity of
variance in heroin abuse/dependence and 26% of the genetic influences on later stages. For example, Kendler
variance in abuse/dependence of psychedelics could be and colleagues [53] demonstrated that the heritability of
attributed to genetic factors [68,69]. Similar estimates nicotine dependence was 22% after accounting for the
have also been reported by Kendler et al. in a sample of 59% overlap between earlier stages of smoking and later
male US twins: 87% of the variance in sedative depen- dependence. Similar observations have also been made
dence, 79% of the variance in both cocaine and the hal- for illicit drug use and dependence. For instance, authors
lucinogen dependence, 87% of the variance in sedative have demonstrated that nearly 65% of the liability to
dependence but only 22% of the variance in stimulant illicit drug dependence is due to factors contributing to a
dependence was attributed to additive genetic factors life-time history of illicit drug use [78]. Recently, a study
[70,71]. There have been relatively fewer studies of the of adolescent twins (the Cardiff Study of all Wales and
heritability of illicit drug dependence in female samples. North West of England Twins: CaStNET) [79] revealed
Available studies, finding that 65% of the variance in that while, in general, there was considerable evidence for
cocaine dependence in women can be attributed to addi- greater genetic influences on later (i.e. heavier, non-
tive genetic factors [70] and that there are no sex differ- diagnostic use) use versus initiation of alcohol, cigarette
ences in the heritability of stimulant abuse/dependence and cannabis use, the overlap across the two stages was
symptoms [72], suggest significant genetic influences on considerable [80]. For cigarettes and cannabis, there was
illicit drug abuse/dependence in women that are of a only modest support for genetic factors specific to pro-
similar magnitude to those observed in men. It should be gression. Interestingly, some aspects of problem alcohol
noted that the relatively low prevalence of these disorders use, including heavier drinking, binge drinking and being
within general population samples of twins means that it in situations due to drinking that were regretted later,
is difficult to detect potential gender or other subgroup were influenced by genetic influences that were largely
differences in the heritability of these behaviors with unshared with the earlier stage of initiation.
confidence.

DIFFERENT DRUGS, SAME OR


STAGE-SEQUENTIAL NATURE OF DIFFERENT GENES
ADDICTION
Emerging evidence from population-based studies of
In our efforts to characterize the role of genetic influences adolescents and adults indicates that common genetic
on addictive behavior/addiction it is essential to recognize factors may influence population variation for a number
its stage-sequential nature, with the later stages of addic- of substance use disorders. Research in the male-only
tion, such as abuse and dependence, being contingent sample of Vietnam Era Twins [37,69] and in adult
upon earlier stages such as availability, experimentation men and women from the Virginia Twin Registry [81]
and regular use. While we focus upon heritable influences suggested that common heritable factors contribute to
for later stages of addiction, there is a substantial body of abuse/dependence on a number of illicit drugs. None the
literature supporting the role of genetic factors on earlier less, results from both studies suggested that substance-
stages as well [59,73,74]. Therefore, the genetic influ- specific genetic factors appeared to be of some impor-
ences on substance abuse/dependence need to be tance to opiate dependence. Evidence for genetic overlap
partitioned into those genetic factors that (i) predispose has also been reported in an adolescent sample, although
individuals to exposure to a substance and to experimen- due to power these multivariate twin analyses focused
tation with it; (ii) influence both initiation and later stages upon dimensions of problem substance use. Young et al.
of addiction; and (iii) specifically influence liability to [82] reported that nearly 25–36% of the genetic influ-
dependence. We might posit that drug availability and ences of alcohol, nicotine and cannabis problem use were
initiation of drug use would be correlated with some attributable to overlapping factors. Whether these find-
aspects of novelty seeking, and hence a gene encoding a ings suggest a more prominent role of substance-specific
dopaminergic receptor (DRD2, for instance), which is genetic factors when examining alcohol and tobacco
involved in reward dependence, may be important at this with illicit drugs, or whether they suggest an etiological
early stage. On the other hand, drug metabolizing genes, distinction in common versus specific heritable factors
such as the aldehyde dehydrogenase genes (ALDH), may during adolescence, or are merely a consequence of
be associated with risk for regular alcohol use and the sample size, is unknown as there are currently no
progression to addiction [75–77]. Are there, then, published studies of alcohol and tobacco and illicit drug
genetic factors specific to addiction? The twin literature dependence in adult twin samples.

© 2008 The Authors. Journal compilation © 2008 Society for the Study of Addiction Addiction, 103, 1069–1081
Genetic studies of addiction 1075

CAN HERITABILITY CHANGE? consequently explains a greater proportion of the vari-


ance, hence leaving less variance to be attributed to
As discussed before, heritability is specific to the popula-
genetic factors. Then, we may presume that during ado-
tion under study. Therefore, the role of genetic influences
lescence, genetic and environmental influences act on
may vary across populations, by gender, by age, over time,
risk for substance use. Through normative change in sub-
by cultural composition and as a function of multiple
stance use status across developmental milestones, this
other factors. Of these possible contributors to changes in
variation in substance use will, first, decrease (i.e. more
heritability, we focus upon three key population charac-
normative to drink/smoke during adulthood) and sec-
teristics: sex, age and culture.
ondly, this reduced variance will more probably be a
result of individual-specific (non-shared environmental)
Sex differences factors. Rose reviews this concept elegantly as it relates to
Kendler et al. [83] reported that, in a population of adult the genetics of alcoholism [84]. For smoking, Madden
women, about 50–60% of the population variation in et al. [61] have reported that smoking initiation in
alcohol dependence was attributable to genetic factors. In 18–25-year-old women was due, in equal parts, to
a subsequent study, this group reported that genetic genetic (43%) and shared environmental (48%) factors,
factors explained 48–58% of the risk for alcoholism in whereas in those aged 36–46 years, genetic and shared
men as well [36]. Similarly, Heath and colleagues [46] environmental factors explained 59% and 16% of the
reported that heritable factors explain about 64% of the total variance, respectively. The evidence for lower herita-
variance in alcoholism in both sexes. For smoking persis- bility of alcohol, tobacco and illicit drug use, in favor of
tence as well, Madden et al. [61] found only modest evi- shared environment, is also seen in studies of 8–16-year-
dence for higher heritability (24% versus 37%) in men, old twins from Virginia [85], in 17-year-old Minnesota
but only in those aged 26–35 years, although an earlier twins [59] and in 12–19-year-old twins from Colorado
study by Heath et al. [62] did note significant sex differ- [86]. However, a majority of these studies also examined
ences. In contrast, a few studies have reported sex differ- problem use or dependence and found that, even during
ences in the heritability of illicit drug abuse/dependence. adolescence, the risk for drug dependence was mediated
In the twin design, these sex differences may be of two largely by genetic and non-shared environmental factors.
forms—(i) quantitative, or referring to a difference in the
magnitude of genetic influence in men versus women Cultural characteristics
(e.g. Madden et al. [61] for smoking persistence) and (ii)
qualitative, or different genetic factors, with a similar/ Just as the high variability in the adolescent’s environ-
different magnitude of influence, contributing to risk in ment reduces the influence of genetic factors on sub-
men versus women. The latter hypothesis can be exam- stance use, the imposition of social constraints can
ined with data on dizygotic male–female twin pairs. reduce environmental variation and thus allow genetic
Lynskey et al. [66] report a reduced probandwise concor- factors to emerge dramatically. For instance, in cultures
dance of 16.8 in DZ brother–sister pairs than in DZ where cigarette smoking in women is considered socially
brother–brother (31.1%) and sister–sister (28.9%) pairs. inappropriate, population variation in women’s smoking
Overall, several studies have concluded that genetic may have a relatively stronger genetic underpinning. This
influences on addiction, especially later stages of abuse/ is because the women who continue to smoke despite
dependence, are of equal importance in both men and social sanctions may carry a high loading of genetic sus-
women. ceptibility. Madden et al. [63] compared twins from Aus-
tralia, Finland and Sweden and found limited evidence for
cross-cultural differences in regular smoking in men but
Age differences
none for smoking persistence. Whitfield et al. [87] have
Heritability is a function of variation—if there is no vari- shown that despite a somewhat lower prevalence of
ability in a behavior, then even if it is influenced geneti- cigarette smoking in African American versus European
cally its heritability cannot be examined. For instance, in American girls, the quantity smoked was under consid-
western adult populations it is not meaningful to estimate erable (43%) genetic influence. Ehlers et al. [88,89] have
the extent of heritable influences on any life-time use of found estimates of heritability for substance use and
alcohol, as almost everyone reports consuming alcoholic abuse to be comparable across European American and
beverages at least once. Additionally, heritability is Southwest California Native American populations.
modified by the increasing or decreasing importance of Research in this area is, unfortunately, lacking, due to
corresponding environmental influences—therefore, it availability of relatively few culturally diverse samples.
is not necessarily the case that genes become more or Most samples used for comparison are either representa-
less important but that the environment is modified and tive of greater permissiveness (e.g. smoking in Chinese

© 2008 The Authors. Journal compilation © 2008 Society for the Study of Addiction Addiction, 103, 1069–1081
1076 Arpana Agrawal & Michael T. Lynskey

men [90]) or are inter-related through common Euro- [96] reported recently that unmarried individuals were
pean cultural practices. Future studies that capitalize on more likely than married individuals to carry the high-
the cultural diversity in social attitudes towards sub- risk genotype for a polymorphism in the GABRA2 gene
stance use in Hispanic or Southeast Asian women versus (G–E correlation) but also that married individuals were
European women may prove to be of considerable at significantly increased risk for alcoholism when they
interest. carried the high-risk genotype. Therefore, the protective
influence of marriage on risk for alcoholism was dimin-
ished by the action of this high-risk genotype. Substance
EXTENSIONS TO THE INTERACTION OF
use itself can act as an environmental moderator of
GENETICS AND THE ENVIRONMENT
genetic predisposition. Caspi and colleagues [97] showed
We are currently at a stage in behavior genetic studies of that carriers of the Valine-coding allele (Met/Val) of the
addiction where the concept of nature versus nurture is COMT gene were at increased risk for psychosis only if
obsolete. Indeed, there is little evidence that genes (latent they had used cannabis during their adolescence. Unlike
or measured) and environment act independently of each the previous study by Dick et al., neither the risk for ado-
other [91]. Within the context of twin studies of sub- lescent cannabis use nor for psychosis was associated, in
stance use disorders, a majority of tests of unmeasured itself, with the high-risk genotype.
genotype ¥ measured environmental interaction has
focused upon alcoholism. As early as 1989, Heath and
colleagues [92] reported that the heritability of alcohol RECENT ADVANCES IN GENETIC
dependence was substantially higher in older unmarried STUDIES OF ADDICTION
(76%) versus younger married (30%) women. The
Children-of-twins and G ¥ E
authors suggest that marriage may serve to buffer the
impact of genetic predisposition to alcoholism. Using Despite progress made in the arena of addiction research,
data from adolescent Finnish twins, Rose et al. [93] dem- the study of twins reared together is limited in power and
onstrated higher heritability (34–62% versus 18–49%) design in its ability to examine G ¥ E [98–100]. The
for alcohol consumption frequency in 16–17-year-old children-of-twins (COT) design is emerging as a study
twins living in urban versus rural neighborhoods. The design that provides an opportunity to disentangle G ¥ E
authors posit that this socio-regional moderation of heri- from gross heritability estimates that ignore the effect of
table factors may be due to higher religiosity and social environmental moderation. This novel design utilizes
contact with the co-twin in rural neighborhoods, thereby information on the twins themselves, their genetic simi-
increasing the role of shared environment in rural neigh- larity to their offspring and, more importantly, avuncular
borhoods. Consequently, the diversity afforded by urba- genetic similarity between offspring of twins and their MZ
nicity may allow for expression of genetic predisposition (genetically identical to parents) and DZ aunts/uncles.
in those populations. Subsequently, Dick et al. [94] found Consequently, these children can be classified broadly as
that in urban environments, with greater numbers of (i) at high genetic risk and high environmental risk, when
youth and higher alcohol sales, there was an almost five- the parent is affected; (ii) at high genetic risk but reduced
fold increase in heritable influences on alcohol consump- environmental risk, when the parent is unaffected but the
tion. The authors argue that the restricted variation and MZ aunt/uncle is affected; (iii) at intermediate genetic risk
low migration rates in rural environments lead to a but reduced environmental risk, when the parent is unaf-
dampening of genetic susceptibility. Dick and colleagues fected but the DZ aunt/uncle is affected; and (iv) at low
[95] recently documented an important genotype ¥ envi- genetic and low environmental risk, when neither parent
ronment (G ¥ E) interaction for adolescent cigarette nor MZ/DZ aunt/uncle are affected [99].
smoking in Finnish twins. In this sample of 14-year-olds, A comparison of outcomes, such as alcohol problems,
an increase in heritability of experimentation with across these groups afford several ‘degrees of freedom’ to
cigarettes corresponded with increased time spent with detect not only genetic transmission, but also the envi-
parents. In contrast, as parental supervision decreased, ronmental consequences of parental substance use that
heritability of cigarette smoking decreased, suggesting a may modify offspring genetic risk (gene ¥ familial envi-
masking of genetic risk in restricted environments of ronment) but remain undetected in the traditional twin
high parental monitoring. There still remains a consider- study design. Applying this methodology, Knopik et al.
able need for further research on the influence of G ¥ E on [101] reported increased risk of attention deficit hyperac-
risk for drug use disorders. tivity disorder (ADHD) in children of (i) alcoholic mothers
Researchers have also begun to identify the moderat- and (ii) unaffected mothers but with an affected MZ aunt,
ing influence of some of these environmental influences suggesting a genetic mode of transmission of risk from
on measured genotype. For instance, Dick and colleagues alcoholism to ADHD. A recent study also used this design

© 2008 The Authors. Journal compilation © 2008 Society for the Study of Addiction Addiction, 103, 1069–1081
Genetic studies of addiction 1077

to find that while genetic factors explained transmission isolate the actual gene, perhaps even a mutation of
of conduct problems in female offspring, the mode of some modest effect? We posit that twin studies will con-
transmission in their male counterparts was environ- tinue to serve as the sturdy foundation upon which
mentally mediated [102]. these complex studies of genotype are constructed. First,
in order to estimate the variance explained by one func-
Other family-based designs tional polymorphism, one needs an understanding of
how much genetic variance there is to explain—namely,
Two additional designs warrant mention—twins reared heritability. This is more so in the case of linkage studies,
apart and the novel design of virtual twins. The former, where misspecifications of heritability of a quantitative
although limited severely by sample size, capitalizes on measure can bias findings markedly [118]. Thus, today’s
the graded genetic similarity of MZ and DZ twins who are genomic research is dependent upon years of careful
adopted into different familial environments, therefore twin analyses. Secondly, as genomic studies aim to
providing a test of variations in rearing environment identify genes involved in specific stages of addiction
against a matched genetic background [103]. Using data (e.g. nicotine withdrawal), they will probably return to
on 32 pairs of MZ twins from the Minnesota Twin Study twin studies for information on the genetic relationship
of Twins Reared Apart, Grove and colleagues [104] found between specific components of dependence and the
evidence for heritability of drug-related problems. In con- global construct of dependence itself. Indeed, Pergadia
trast, virtual twins refer to same-aged unrelated adoptive et al. [119], have found that 19–23% of the variance in
siblings, who are matched for rearing environment but nicotine withdrawal is due to specific genetic factors that
not (directly) for genetic relatedness [105]. This method do not influence related stages of progression and quan-
(especially, when combined with MZ/DZ twins reared tity smoked (see also [55]). In general, twin studies
together) presents a more refined estimate of familial are critical for understanding the etiological role of
environment. We are not aware of published virtual twin common and specific genetic risks in the multi-stage
studies of addiction. process of addiction. Thirdly, and perhaps most impor-
tantly, data from family and twin studies are critical for
The transition from heritability to genomics studying the environment, and its interactions with
We are transitioning rapidly into an era of measured genotype. The study of genetically identical (MZ) twins
genes, and this progression from population-wide herita- discordant for some aspect of substance use allows us to
bility to individual-specific polymorphisms has been wit- examine the role of the environment in addiction. The
nessed across numerous genomic studies of alcoholism application of this method to the relationship between
[106], nicotine dependence [107,108] and general early-onset cannabis use and the use of other illicit
substance abuse vulnerability [109,110]. This field drugs [64,120–123] demonstrate its utility.
bears its own challenges, a primary one being that of
non-replication [111]. However, a gene that is now
receiving widespread attention is GABRA2, the gamma- CONCLUSIONS
aminobutyric acid receptor A-subunit 2 gene. The asso-
ciation between polymorphisms in a highly conserved The convergence of findings from a range of genetically
region of this gene and risk for alcoholism has been informative research designs, including adoption, family
replicated across several diverse samples with varying and twin studies, provides compelling evidence suggest-
ascertainment strategies [112–116]. Despite concen- ing that alcohol, nicotine, cannabis and other illicit drug
trated gene-mapping efforts, currently identified candi- dependence are influenced by heritable factors. Despite
date genes for addiction explain only exceedingly modest this, there is nothing deterministic about the genetic
proportions (less than 5%) of the total genetic variance. basis (or the environmental basis, for that matter) to
However, with the rapid decrease in costs for large-scale, addiction. There is no single gene that causes addiction
high-density genotyping [117], we anticipate accelerated but multiple genes of modest, cumulative and interac-
identification of allelic variants that confer risk for sub- tive effect that shape the liability to addictive behaviors.
stance use disorders. With rapid advances in technology (and reductions in
cost), gene discovery efforts are likely to accelerate in the
near future. Identification of specific genes conveying
Family/twin studies in the post-genomic era
increased risks have promise not only for understanding
In this exciting time of gene discovery, critics may ques- the causes and potential treatments for disease, but
tion the continued need for family or twin studies. It is a also for increasing our understanding of how genetic
fair question: why continue to estimate a latent variance and environmental risks interact to shape liability to
component (i.e. heritability) when one has the ability to addiction.

© 2008 The Authors. Journal compilation © 2008 Society for the Study of Addiction Addiction, 103, 1069–1081
1078 Arpana Agrawal & Michael T. Lynskey

Acknowledgements alcoholics. The Stockholm Adoption Study. Recent Dev


Alcohol 1985; 3: 37–51.
Drs Agrawal and Lynskey receive support from grants 18. Heath A. C., Lynskey M. T., Waldron M. Substance use. In:
DA023668 and DA18660. Dr Lynskey is also supported Rutter M., Taylor E., editors. Handbook of Child and Adoles-
by grant DA18267. cent Psychiatry. London: Blackwell; 2007. in press.
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