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

In 2000, the completion of the draft sequence of the
human genome was announced, with much fanfare, at a
joint press conference held by US President Clinton and
UK Prime Minister Blair [1–3]. Proponents highlighted
the potential of this work for revolutionizing the diagno-
sis and treatment of many illnesses [4,5], while others
urged caution, both questioning the potential of genomic
medicine [6] and highlighting potential ethical and social
challenges of this discovery [7]. This controversy has
been perhaps most acute in complex disorders, such as
alcohol and other drug dependence. Complex disorders
are both multi-factorial (where known environmental
and genetic influences are at play) and polygenic (i.e. any
genetic influences are likely to be spread over multiple
genes, each of which may make only minor contributions
to variance in disease risk) in nature. These aspects of
complex or non-Mendelian disorders have led some
disorders [8].
In considering the relative merit of attempts to iden-
tify genes conferring susceptibility to addictive diseases, a
necessary first step is to evaluate evidence concerning the
extent to which alcohol and other drug use disorders
(or ‘addiction’, for the scope of this review) may be influ-
enced by heritable factors. Such evidence can be derived
from a range of family-based genetically informative
research designs including adoption, twin and family
designs. The aim of the current paper is to review evi-
dence from such studies to address the central question of
whether there are heritable influences on liability to drug
abuse/dependence. A particular focus of this review is to
evaluate the contributions of the more commonly used
twin design. Particularly for the study of addiction, twin
studies have several advantages over both family and
adoption designs and, as such, are the foundation for
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
SUBSTANCE USE DISORDERS
Some early family-based studies provided initial clues
to potential heritable influences on addictive disorders
by examining the risk of substance use disorders in
the first-degree relatives of individuals either with or
without a substance use disorder. For example, in a
study of a large sample of individuals meeting criteria
for alcohol dependence and their siblings, Bierut et al.
[9] reported that, relative to a control individual, the sib-
lings of alcohol-dependent probands had elevated rates
of alcohol dependence (49.3–50.1% for men and 22.4–
25% for women, depending on the presence of comorbid
drug dependence). While additional substance use disor-
ders in the proband did not appear to increase risks of
alcohol dependence in siblings, there was some evidence
for substance-specific influences on drug dependence:
siblings of cannabis-dependent probands had an elev-
ated risk of developing cannabis dependence [relative
risk (RR), 1.78], siblings of cocaine-dependent pro-
bands had an elevated risk of developing cocaine depen-
dence (RR, 1.71) and siblings of habitual-smoking
probands had an elevated risk for habitual smoking
(RR, 1.77).
Similarly, in a study of the 1267 adult first-degree
relatives of 231 probands with dependence on opioids,
cocaine, cannabis and/or alcohol and 61 control
probands, Merikangas et al. [10] reported an eightfold
increased risk of drug disorders among the relatives of
probands with drug disorders across the range of sub-
stances studied, which was largely independent from the
familial aggregation of both alcoholism and antisocial
personality disorder. There was also evidence of specific-
ity of familial aggregation of the predominant drug of
abuse, suggesting that there may be risk factors that are
specific to particular classes of drugs as well as risk
factors that underlie substance disorders in general.
Similarly, studies have reported both that alcoholism is
familial [11] and that having an alcoholic parent is
associated with a fivefold increase in the risk of alcohol-
ism [12].
Family studies conclude that both alcoholism and sub-
stance use disorders cluster in families, due presumably to
heritable factors. The family design cannot distinguish
whether the causes of familial similarity are genetic or
environmental in nature. Further, for substance depen-
dence, there appear to be familial influences that confer a
non-specific risk for drug dependence. The scope of family
studies, while discussed briefly here, is influenced by strat-
egy for sample selection (e.g. via a proband from clinics,
community samples), for inclusion of relatives (e.g. must
have one or more affected siblings) and for exclusion of
relatives (e.g. age, non-participation, geography).
© 2008 The Authors. Journal compilation © 2008 Society for the Study of Addiction
ADOPTION STUDIES
Adoption studies are based on a comparison of the con-
cordance or correlation between offspring behavior
(e.g. alcohol dependence) and the characteristics of both
the biological and adoptive parents: similarity between
offspring and biological parents is suggestive of genetic
influences on that behavior, while similarity between off-
spring and adoptive parents is suggestive of environmen-
tal influences. Some highly influential adoption studies
have been conducted highlighting the importance of
genetic influences on substance dependence. In one of
the earliest of these studies, Goodwin et al. [13] compared
rates of alcohol problems and psychiatric treatment in 55
male children of biological parents with alcohol depen-
dence and 78 control children, all of whom were adopted
out within the first 6 weeks after being born and who had
no known contact with their biological parents. Rates of
psychiatric treatment (40% versus 24%), psychiatric hos-
pitalization (15% versus 3%), treatment for alcohol prob-
lems (9% versus 1%) and meeting criteria for alcoholism
(18% versus 5%) were all significantly higher in the
adopted-away children of parents with alcohol problems/
dependence, thus providing strong support for a genetic
component to alcohol dependence. Similarly, Cadoret
et al. [14–16] studied the etiological importance of bio-
logical parents’ alcohol problems and antisocial person-
ality (as indexed by hospital and prison records) on the
development of these behaviors in their adopted-away
offspring. Their analyses of data from 242 male and 201
female offspring provided an early demonstration of the
importance of genetic factors in the development of drug
abuse/ dependence and also identified two distinct path-
ways for the transmission of risk. The first mechanism
was where parental antisocial behavior increased risk for
offspring antisocial behavior, which in turn increased risk
for drug abuse. The second was characterized by parental
alcohol problems directly influencing risks of drug abuse
in their biological offspring, even in the absence of off-
spring antisocial behavior [16]. Two other features of this
study are noteworthy. First, comparison of results for
males and females suggested that genetic and environ-
mental risk mechanisms operate similarly across gen-
ders. Secondly, their results also highlighted the etiologi-
cal importance of some environmental influences—
particularly parental divorce and parental psychiatric
disorder in the adoptive families—in the development of
drug abuse. While the importance of these environmen-
tal influences had been recognized previously, this was
one of the first studies to be able to isolate the influence of
environmental exposures from potential genetic con-
founds, thus highlighting the utility of adoption and
other family designs for elucidating components of envi-
ronmental risk.
Addiction, 103, 1069–1081

The adoption study literature must be interpreted
with recognition of certain important limitations. First,
due to the challenges involved with accessing adoption
records, these studies are not common. Secondly, because
of the much higher prevalence of alcoholism in males
than females, particularly for earlier birth cohorts on
which the older adoption studies were based, the studies
have mainly been informative about outcomes associated
with paternal alcoholism, although the Swedish Adop-
tion study [17] provides some data on maternal alcohol-
ism. Similarly, neither biological nor adoptive parents or
adopted children may be representative of the popula-
tion: biological parents are likely to have higher rates of
drug dependence and psychiatric disorders while, con-
versely, adoptive parents are less likely to be disordered as
well as being, on average, older and relatively socially
advantaged. For example, in the Swedish adoption
samples, rates of temperance board registrations were
32% in biological fathers but only 4% in adoptive fathers,
relative to a population prevalence of 12% [17]. The use
of control adoptees from unaffected biological families
may have ameliorated some of these biases. Selective
placement, whereby adoptive families are selected on the
basis of sharing characteristics of the biological parents,
may be an overstated problem of the evaluations con-
ducted in the adoption process [18]. None the less,
environmental exposures occurring before adoptive
placement, including in utero environment, may inflate
estimates of heritable influences, while some have argued
[19] that the adoption process itself may be pathogenic
and account for at least some of the elevated rates of
psychopathology seen in adopted offspring [20].
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
twin pair different from each other (non-shared environ-
© 2008 The Authors. Journal compilation © 2008 Society for the Study of Addiction
Genetic studies of addiction 1071
ment). Shared environmental factors overlap 100%
between members of MZ and DZ twin pairs, under the
important assumption of equal environments (which is
discussed in some detail later). The measure of non-
shared environment includes the effects of measurement
error and is, by definition, uncorrelated between
members of a twin pair.
One way to conceptualize the information captured by
the twin model is by considering the path diagram (or
structural equation model) of MZ and DZ twins presented
in Fig. 1. In path analyses, latent measures are repre-
sented by circles and measured variables in rectangles—
hence, additive genetic (A), shared environment (C) and
non-shared environment (E) appear in circles with a
direct path (denoted by the single-headed directional
arrow) on addiction, which is measured/observed and,
therefore, denoted by a rectangle. The double-headed
arrows represent the extent to which A and C are corre-
lated between MZ and DZ twins.
Prior to reviewing twin findings in addiction, it is
important to consider the construct of heritability. Heri-
tability, in statistical terms, is that proportion of the total
phenotypic variance that can be attributed to genetic
factors (or A/A + C + E). The context for measurement of
heritability is the population and not the individual—
hence, the heritability in an individual is undefined. In
addition, there are some caveats to estimates from twin
studies that should be considered:
1 The premise that members of MZ and DZ twin pairs are
exposed to, and respond to, ‘shared environment’ to
the same extent constitutes the equal environments
assumption (EEA). If the EEA is violated (i.e. members
Figure 1 The classical twin model: path diagrams for monozygotic
(MZ) and dizygotic (DZ) twins
Addiction, 103, 1069–1081
1072 Arpana Agrawal & Michael T. Lynskey
of MZ twin pairs receive/perceive their shared environ-
ment more similarly than DZ twins, and that this
change influences concordance for addiction), then
this would inflate the heritability estimate (as any
increased similarity in MZ versus DZ twins is captured
by the genetic parameter). The EEA has been criticized
by some as an unrealistic notion [21–24]. However,
studies that examined twin physical similarity or
parental behavior towards twins as well as the effects of
perceived zygosity (where DZ twins were identified
incorrectly as MZ) and its association with personality
[25,26], eating attitudes [27], behavioral problems
[28] and psychiatric disorders [29–31] have concluded
largely that previous assertions of violations of EEA
may have been overstated. If the reason that MZ twins
are perceived more similarly then DZ twins is because
MZ twins are genetically more similar than DZ twins,
then this is not a violation of EEA.
2 Heritability encompasses only those genetic mecha-
nisms that make MZ twins systematically genetically
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
occur in one member of an MZ pair but not the other,
are not captured by A. Therefore, in the context of the
simple twin design, epigenetic change, albeit biologi-
cal, is estimated as individual-specific environment (E)
[32,33].
3 Twin studies also assume random mating—if,
however, parents of the twins under investigation
selected each other based on genetic predisposition for,
for instance, alcohol consumption, as documented by
twin studies [34,35], then the genetic correlation
between DZ twins is no longer simply 0.5A and
increases by m (a measure of assortative mating). If
there is non-random mating and it is ignored, this
excess similarity in DZ twins will inflate estimates of
shared environment, and possibly bias heritability
downwardly.
4 Genetic and environmental factors have direct (‘main’)
effects, and under the simple twin model do not inter-
act. In reality, this is rarely the case. Depending on the
effect of the interaction, ignoring gene–environment
interactions (and correlations) will bias heritability as
well as other estimates. Later in this review, we provide
a more detailed consideration of the importance of
gene–environment interplay.
In addition to additive genetic influences, twin studies
can also be used to estimate the role of non-additive/
dominance genetic influences (denoted by D). D is shared
100% and 25% by MZ and DZ twins, respectively.
However, when working with MZ and DZ twins alone, it is
not possible to identify simultaneously the effects of D and
C. [Let us assume that the correlation between members
© 2008 The Authors. Journal compilation © 2008 Society for the Study of Addiction
of MZ and DZ pairs for alcoholism is R1 and R2, respec-
tively. We also know that twin similarity is a consequence
of A, D and C (but not E, which contributes to variance
only)
R1 = A + D + C
R2 = 0.5A + 0.25D + C
These equations, when D and C are estimated jointly,
cannot be solved as a set of simultaneous equations.]
Keeping these limitations in mind, the following sec-
tions highlight the major findings from twin studies esti-
mating the extent to which genetic factors contribute to
the etiology of alcoholism (abuse/dependence), nicotine
dependence, cannabis abuse/dependence and abuse of, or
dependence on, other illicit drugs. Due to the incredible
wealth of information in this area our description, while
aiming to be comprehensive, cannot be as detailed as may
be desired. We urge readers to refer to the exciting empiri-
cal research papers cited in these sections for a detailed
discussion of findings.
ALCOHOLISM
There have now been numerous large twin studies
[36–39] of alcohol abuse, dependence and related drink-
ing behaviors conducted across several countries and
also several comprehensive reviews of these studies
[38,40,41]. As shown in Fig. 2, estimates of the herita-
bility of alcohol abuse/dependence have ranged from
50% to 70%. Additional studies have demonstrated a
similarly high level of heritability across a spectrum of
alcohol-related behaviors, including heavy consumption
[42] and problem drinking [42–44], with some sugges-
tion that the heritability may be higher for more severe
forms of alcohol problems [45]. Despite earlier sugges-
tions that alcohol dependence may be more heritable in
men than in women, more recent evidence has estab-
lished that a similar proportion of variation in liability to
alcohol dependence in men and women can be explained
by additive genetic factors. None the less, uncertainty
remains concerning the extent to which genetic sources
of variability in risk of alcohol dependence overlap fully
[46] or only partially [47] across men and women.
NICOTINE DEPENDENCE
There are multiple informative measures of nicotine
dependence, including the DSM-IV [48] diagnosis of
nicotine dependence, the Fagerstrom Tolerance Question-
naire (FTQ) [49], the Fagerstrom Test for Nicotine Depen-
dence (FTND) [50], the Heaviness of Smoking Index (HSI)
[51] and the Nicotine Dependence Syndrome Scale
(NDSS) [52]. Irrespective of construct, there is substan-
Addiction, 103, 1069–1081
 Genetic studies of addiction 1073

Alcoholism

Nicotine Dependence

Cannabis use disorders

Any illicit drug use disorders

Heritability (% of total variance)

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70
60
50
40
30
20
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Figure 2 Heritability estimates for alco-

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holism, nicotine dependence, cannabis

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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%
of the variance in stimulant abuse/dependence, 27% of
the variance in sedative abuse/dependence, 54% of the
variance in heroin abuse/dependence and 26% of the
variance in abuse/dependence of psychedelics could be
attributed to genetic factors [68,69]. Similar estimates
have also been reported by Kendler et al. in a sample of
male US twins: 87% of the variance in sedative depen-
dence, 79% of the variance in both cocaine and the hal-
lucinogen dependence, 87% of the variance in sedative
dependence but only 22% of the variance in stimulant
dependence was attributed to additive genetic factors
[70,71]. There have been relatively fewer studies of the
heritability of illicit drug dependence in female samples.
Available studies, finding that 65% of the variance in
cocaine dependence in women can be attributed to addi-
tive genetic factors [70] and that there are no sex differ-
ences in the heritability of stimulant abuse/dependence
symptoms [72], suggest significant genetic influences on
illicit drug abuse/dependence in women that are of a
similar magnitude to those observed in men. It should be
noted that the relatively low prevalence of these disorders
within general population samples of twins means that it
is difficult to detect potential gender or other subgroup
differences in the heritability of these behaviors with
confidence.
STAGE-SEQUENTIAL NATURE OF
ADDICTION
In our efforts to characterize the role of genetic influences
on addictive behavior/addiction it is essential to recognize
its stage-sequential nature, with the later stages of addic-
tion, such as abuse and dependence, being contingent
upon earlier stages such as availability, experimentation
and regular use. While we focus upon heritable influences
for later stages of addiction, there is a substantial body of
literature supporting the role of genetic factors on earlier
stages as well [59,73,74]. Therefore, the genetic influ-
ences on substance abuse/dependence need to be
partitioned into those genetic factors that (i) predispose
individuals to exposure to a substance and to experimen-
tation with it; (ii) influence both initiation and later stages
of addiction; and (iii) specifically influence liability to
dependence. We might posit that drug availability and
initiation of drug use would be correlated with some
aspects of novelty seeking, and hence a gene encoding a
dopaminergic receptor (DRD2, for instance), which is
involved in reward dependence, may be important at this
early stage. On the other hand, drug metabolizing genes,
such as the aldehyde dehydrogenase genes (ALDH), may
be associated with risk for regular alcohol use and the
progression to addiction [75–77]. Are there, then,
genetic factors specific to addiction? The twin literature
© 2008 The Authors. Journal compilation © 2008 Society for the Study of Addiction
suggests that nearly 60–90% of the latent genetic influ-
ences on substance dependence overlap with those influ-
encing substance use, suggesting limited specificity of
genetic influences on later stages. For example, Kendler
and colleagues [53] demonstrated that the heritability of
nicotine dependence was 22% after accounting for the
59% overlap between earlier stages of smoking and later
dependence. Similar observations have also been made
for illicit drug use and dependence. For instance, authors
have demonstrated that nearly 65% of the liability to
illicit drug dependence is due to factors contributing to a
life-time history of illicit drug use [78]. Recently, a study
of adolescent twins (the Cardiff Study of all Wales and
North West of England Twins: CaStNET) [79] revealed
that while, in general, there was considerable evidence for
greater genetic influences on later (i.e. heavier, non-
diagnostic use) use versus initiation of alcohol, cigarette
and cannabis use, the overlap across the two stages was
considerable [80]. For cigarettes and cannabis, there was
only modest support for genetic factors specific to pro-
gression. Interestingly, some aspects of problem alcohol
use, including heavier drinking, binge drinking and being
in situations due to drinking that were regretted later,
were influenced by genetic influences that were largely
unshared with the earlier stage of initiation.
DIFFERENT DRUGS, SAME OR
DIFFERENT GENES
Emerging evidence from population-based studies of
adolescents and adults indicates that common genetic
factors may influence population variation for a number
of substance use disorders. Research in the male-only
sample of Vietnam Era Twins [37,69] and in adult
men and women from the Virginia Twin Registry [81]
suggested that common heritable factors contribute to
abuse/dependence on a number of illicit drugs. None the
less, results from both studies suggested that substance-
specific genetic factors appeared to be of some impor-
tance to opiate dependence. Evidence for genetic overlap
has also been reported in an adolescent sample, although
due to power these multivariate twin analyses focused
upon dimensions of problem substance use. Young et al.
[82] reported that nearly 25–36% of the genetic influ-
ences of alcohol, nicotine and cannabis problem use were
attributable to overlapping factors. Whether these find-
ings suggest a more prominent role of substance-specific
genetic factors when examining alcohol and tobacco
with illicit drugs, or whether they suggest an etiological
distinction in common versus specific heritable factors
during adolescence, or are merely a consequence of
sample size, is unknown as there are currently no
published studies of alcohol and tobacco and illicit drug
dependence in adult twin samples.
Addiction, 103, 1069–1081

CAN HERITABILITY CHANGE?
As discussed before, heritability is specific to the popula-
tion under study. Therefore, the role of genetic influences
may vary across populations, by gender, by age, over time,
by cultural composition and as a function of multiple
other factors. Of these possible contributors to changes in
heritability, we focus upon three key population charac-
teristics: sex, age and culture.
Sex differences
Kendler et al. [83] reported that, in a population of adult
women, about 50–60% of the population variation in
alcohol dependence was attributable to genetic factors. In
a subsequent study, this group reported that genetic
factors explained 48–58% of the risk for alcoholism in
men as well [36]. Similarly, Heath and colleagues [46]
reported that heritable factors explain about 64% of the
variance in alcoholism in both sexes. For smoking persis-
tence as well, Madden et al. [61] found only modest evi-
dence for higher heritability (24% versus 37%) in men,
but only in those aged 26–35 years, although an earlier
study by Heath et al. [62] did note significant sex differ-
ences. In contrast, a few studies have reported sex differ-
ences in the heritability of illicit drug abuse/dependence.
In the twin design, these sex differences may be of two
forms—(i) quantitative, or referring to a difference in the
magnitude of genetic influence in men versus women
(e.g. Madden et al. [61] for smoking persistence) and (ii)
qualitative, or different genetic factors, with a similar/
different magnitude of influence, contributing to risk in
men versus women. The latter hypothesis can be exam-
ined with data on dizygotic male–female twin pairs.
Lynskey et al. [66] report a reduced probandwise concor-
dance of 16.8 in DZ brother–sister pairs than in DZ
brother–brother (31.1%) and sister–sister (28.9%) pairs.
Overall, several studies have concluded that genetic
influences on addiction, especially later stages of abuse/
dependence, are of equal importance in both men and
women.
Age differences
Heritability is a function of variation—if there is no vari-
ability in a behavior, then even if it is influenced geneti-
cally its heritability cannot be examined. For instance, in
western adult populations it is not meaningful to estimate
the extent of heritable influences on any life-time use of
alcohol, as almost everyone reports consuming alcoholic
beverages at least once. Additionally, heritability is
modified by the increasing or decreasing importance of
corresponding environmental influences—therefore, it
is not necessarily the case that genes become more or
less important but that the environment is modified and
© 2008 The Authors. Journal compilation © 2008 Society for the Study of Addiction
Genetic studies of addiction 1075
consequently explains a greater proportion of the vari-
ance, hence leaving less variance to be attributed to
genetic factors. Then, we may presume that during ado-
lescence, genetic and environmental influences act on
risk for substance use. Through normative change in sub-
stance use status across developmental milestones, this
variation in substance use will, first, decrease (i.e. more
normative to drink/smoke during adulthood) and sec-
ondly, this reduced variance will more probably be a
result of individual-specific (non-shared environmental)
factors. Rose reviews this concept elegantly as it relates to
the genetics of alcoholism [84]. For smoking, Madden
et al. [61] have reported that smoking initiation in
18–25-year-old women was due, in equal parts, to
genetic (43%) and shared environmental (48%) factors,
whereas in those aged 36–46 years, genetic and shared
environmental factors explained 59% and 16% of the
total variance, respectively. The evidence for lower herita-
bility of alcohol, tobacco and illicit drug use, in favor of
shared environment, is also seen in studies of 8–16-year-
old twins from Virginia [85], in 17-year-old Minnesota
twins [59] and in 12–19-year-old twins from Colorado
[86]. However, a majority of these studies also examined
problem use or dependence and found that, even during
adolescence, the risk for drug dependence was mediated
largely by genetic and non-shared environmental factors.
Cultural characteristics
Just as the high variability in the adolescent’s environ-
ment reduces the influence of genetic factors on sub-
stance use, the imposition of social constraints can
reduce environmental variation and thus allow genetic
factors to emerge dramatically. For instance, in cultures
where cigarette smoking in women is considered socially
inappropriate, population variation in women’s smoking
may have a relatively stronger genetic underpinning. This
is because the women who continue to smoke despite
social sanctions may carry a high loading of genetic sus-
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
none for smoking persistence. Whitfield et al. [87] have
shown that despite a somewhat lower prevalence of
cigarette smoking in African American versus European
American girls, the quantity smoked was under consid-
erable (43%) genetic influence. Ehlers et al. [88,89] have
found estimates of heritability for substance use and
abuse to be comparable across European American and
Southwest California Native American populations.
Research in this area is, unfortunately, lacking, due to
availability of relatively few culturally diverse samples.
Most samples used for comparison are either representa-
tive of greater permissiveness (e.g. smoking in Chinese
Addiction, 103, 1069–1081
1076 Arpana Agrawal & Michael T. Lynskey
men [90]) or are inter-related through common Euro-
pean cultural practices. Future studies that capitalize on
the cultural diversity in social attitudes towards sub-
stance use in Hispanic or Southeast Asian women versus
European women may prove to be of considerable
interest.
EXTENSIONS TO THE INTERACTION OF
GENETICS AND THE ENVIRONMENT
We are currently at a stage in behavior genetic studies of
addiction where the concept of nature versus nurture is
obsolete. Indeed, there is little evidence that genes (latent
or measured) and environment act independently of each
other [91]. Within the context of twin studies of sub-
stance use disorders, a majority of tests of unmeasured
genotype ¥ measured environmental interaction has
focused upon alcoholism. As early as 1989, Heath and
colleagues [92] reported that the heritability of alcohol
dependence was substantially higher in older unmarried
(76%) versus younger married (30%) women. The
authors suggest that marriage may serve to buffer the
impact of genetic predisposition to alcoholism. Using
data from adolescent Finnish twins, Rose et al. [93] dem-
onstrated higher heritability (34–62% versus 18–49%)
for alcohol consumption frequency in 16–17-year-old
twins living in urban versus rural neighborhoods. The
authors posit that this socio-regional moderation of heri-
table factors may be due to higher religiosity and social
contact with the co-twin in rural neighborhoods, thereby
increasing the role of shared environment in rural neigh-
borhoods. Consequently, the diversity afforded by urba-
nicity may allow for expression of genetic predisposition
in those populations. Subsequently, Dick et al. [94] found
that in urban environments, with greater numbers of
youth and higher alcohol sales, there was an almost five-
fold increase in heritable influences on alcohol consump-
tion. The authors argue that the restricted variation and
low migration rates in rural environments lead to a
dampening of genetic susceptibility. Dick and colleagues
[95] recently documented an important genotype ¥ envi-
ronment (G ¥ E) interaction for adolescent cigarette
smoking in Finnish twins. In this sample of 14-year-olds,
an increase in heritability of experimentation with
cigarettes corresponded with increased time spent with
parents. In contrast, as parental supervision decreased,
heritability of cigarette smoking decreased, suggesting a
masking of genetic risk in restricted environments of
high parental monitoring. There still remains a consider-
able need for further research on the influence of G ¥ E on
risk for drug use disorders.
Researchers have also begun to identify the moderat-
ing influence of some of these environmental influences
on measured genotype. For instance, Dick and colleagues
© 2008 The Authors. Journal compilation © 2008 Society for the Study of Addiction
[96] reported recently that unmarried individuals were
more likely than married individuals to carry the high-
risk genotype for a polymorphism in the GABRA2 gene
(G–E correlation) but also that married individuals were
at significantly increased risk for alcoholism when they
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
use itself can act as an environmental moderator of
genetic predisposition. Caspi and colleagues [97] showed
that carriers of the Valine-coding allele (Met/Val) of the
COMT gene were at increased risk for psychosis only if
they had used cannabis during their adolescence. Unlike
the previous study by Dick et al., neither the risk for ado-
lescent cannabis use nor for psychosis was associated, in
itself, with the high-risk genotype.
RECENT ADVANCES IN GENETIC
STUDIES OF ADDICTION
Children-of-twins and G ¥ E
Despite progress made in the arena of addiction research,
the study of twins reared together is limited in power and
design in its ability to examine G ¥ E [98–100]. The
children-of-twins (COT) design is emerging as a study
design that provides an opportunity to disentangle G ¥ E
from gross heritability estimates that ignore the effect of
environmental moderation. This novel design utilizes
information on the twins themselves, their genetic simi-
larity to their offspring and, more importantly, avuncular
genetic similarity between offspring of twins and their MZ
(genetically identical to parents) and DZ aunts/uncles.
Consequently, these children can be classified broadly as
(i) at high genetic risk and high environmental risk, when
the parent is affected; (ii) at high genetic risk but reduced
environmental risk, when the parent is unaffected but the
MZ aunt/uncle is affected; (iii) at intermediate genetic risk
but reduced environmental risk, when the parent is unaf-
fected but the DZ aunt/uncle is affected; and (iv) at low
genetic and low environmental risk, when neither parent
nor MZ/DZ aunt/uncle are affected [99].
A comparison of outcomes, such as alcohol problems,
across these groups afford several ‘degrees of freedom’ to
detect not only genetic transmission, but also the envi-
ronmental consequences of parental substance use that
may modify offspring genetic risk (gene ¥ familial envi-
ronment) but remain undetected in the traditional twin
study design. Applying this methodology, Knopik et al.
[101] reported increased risk of attention deficit hyperac-
tivity disorder (ADHD) in children of (i) alcoholic mothers
and (ii) unaffected mothers but with an affected MZ aunt,
suggesting a genetic mode of transmission of risk from
alcoholism to ADHD. A recent study also used this design
Addiction, 103, 1069–1081

to find that while genetic factors explained transmission
of conduct problems in female offspring, the mode of
transmission in their male counterparts was environ-
mentally mediated [102].
Other family-based designs
Two additional designs warrant mention—twins reared
apart and the novel design of virtual twins. The former,
although limited severely by sample size, capitalizes on
the graded genetic similarity of MZ and DZ twins who are
adopted into different familial environments, therefore
providing a test of variations in rearing environment
against a matched genetic background [103]. Using data
on 32 pairs of MZ twins from the Minnesota Twin Study
of Twins Reared Apart, Grove and colleagues [104] found
evidence for heritability of drug-related problems. In con-
trast, virtual twins refer to same-aged unrelated adoptive
siblings, who are matched for rearing environment but
not (directly) for genetic relatedness [105]. This method
(especially, when combined with MZ/DZ twins reared
together) presents a more refined estimate of familial
environment. We are not aware of published virtual twin
studies of addiction.
The transition from heritability to genomics
We are transitioning rapidly into an era of measured
genes, and this progression from population-wide herita-
bility to individual-specific polymorphisms has been wit-
nessed across numerous genomic studies of alcoholism
[106], nicotine dependence [107,108] and general
substance abuse vulnerability [109,110]. This field
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-
aminobutyric acid receptor A-subunit 2 gene. The asso-
ciation between polymorphisms in a highly conserved
region of this gene and risk for alcoholism has been
replicated across several diverse samples with varying
ascertainment strategies [112–116]. Despite concen-
trated gene-mapping efforts, currently identified candi-
date genes for addiction explain only exceedingly modest
proportions (less than 5%) of the total genetic variance.
However, with the rapid decrease in costs for large-scale,
high-density genotyping [117], we anticipate accelerated
identification of allelic variants that confer risk for sub-
stance use disorders.
Family/twin studies in the post-genomic era
In this exciting time of gene discovery, critics may ques-
tion the continued need for family or twin studies. It is a
fair question: why continue to estimate a latent variance
component (i.e. heritability) when one has the ability to
© 2008 The Authors. Journal compilation © 2008 Society for the Study of Addiction
Genetic studies of addiction 1077
isolate the actual gene, perhaps even a mutation of
some modest effect? We posit that twin studies will con-
tinue to serve as the sturdy foundation upon which
these complex studies of genotype are constructed. First,
in order to estimate the variance explained by one func-
tional polymorphism, one needs an understanding of
how much genetic variance there is to explain—namely,
heritability. This is more so in the case of linkage studies,
where misspecifications of heritability of a quantitative
measure can bias findings markedly [118]. Thus, today’s
genomic research is dependent upon years of careful
twin analyses. Secondly, as genomic studies aim to
identify genes involved in specific stages of addiction
(e.g. nicotine withdrawal), they will probably return to
twin studies for information on the genetic relationship
between specific components of dependence and the
global construct of dependence itself. Indeed, Pergadia
et al. [119], have found that 19–23% of the variance in
nicotine withdrawal is due to specific genetic factors that
do not influence related stages of progression and quan-
tity smoked (see also [55]). In general, twin studies
are critical for understanding the etiological role of
common and specific genetic risks in the multi-stage
process of addiction. Thirdly, and perhaps most impor-
tantly, data from family and twin studies are critical for
studying the environment, and its interactions with
genotype. The study of genetically identical (MZ) twins
discordant for some aspect of substance use allows us to
examine the role of the environment in addiction. The
application of this method to the relationship between
early-onset cannabis use and the use of other illicit
drugs [64,120–123] demonstrate its utility.
CONCLUSIONS
The convergence of findings from a range of genetically
informative research designs, including adoption, family
and twin studies, provides compelling evidence suggest-
ing that alcohol, nicotine, cannabis and other illicit drug
dependence are influenced by heritable factors. Despite
this, there is nothing deterministic about the genetic
basis (or the environmental basis, for that matter) to
addiction. There is no single gene that causes addiction
but multiple genes of modest, cumulative and interac-
tive effect that shape the liability to addictive behaviors.
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
increased risks have promise not only for understanding
the causes and potential treatments for disease, but
also for increasing our understanding of how genetic
and environmental risks interact to shape liability to
addiction.
Addiction, 103, 1069–1081
1078 Arpana Agrawal & Michael T. Lynskey
Acknowledgements
Drs Agrawal and Lynskey receive support from grants
DA023668 and DA18660. Dr Lynskey is also supported
by grant DA18267.
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