Yong-Kyu Kim

Editor

Handbook of Behavior
Genetics

123
Editor
Yong-Kyu Kim
University of Georgia
Athens, GA
USA
yongkyu@arches.uga.edu

ISBN 978-0-387-76726-0 e-ISBN 978-0-387-76727-7

DOI 10.1007/978-0-387-76727-7

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Chapter 30
Genetic Analysis of Conduct Disorder and Antisocial Behavior
Soo Hyun Rhee and Irwin D. Waldman
Introduction
In this chapter, we examine the evidence for genetic influ-
ences on conduct disorder and antisocial behavior. First,
we present results from a meta-analysis of twin and adop-
tion studies estimating the relative magnitude of genetic
and environmental influences on antisocial behavior (Rhee
& Waldman, 2002). Second, we discuss recent studies
that have examined several interesting issues in the eti-
ology of antisocial behavior, including genotype × envi-
ronment interactions, co-occurrence with other psychiatric
disorders, the etiology of psychopathy, and the etiology
of adolescent-limited versus life-course-persistent antisocial
behavior. Third, we review association studies examining the
influence of specific candidate genes on antisocial behav-
ior and linkage studies conducting genome-wide screens for
quantitative trait loci (QTLs) influencing antisocial behavior.
In this review, we focused on phenotypes directly related
to conduct disorder or antisocial behavior. Studies were
included if they clearly examined antisocial personality dis-
order, conduct disorder, criminality, or aggression; if there
was empirical evidence suggesting that the measure of anti-
social behavior used in the study successfully discriminated
an antisocial group from a control group; or if there was
empirical evidence suggesting that the measure used in the
study is significantly related to a more established opera-
tionalization of antisocial behavior.
Studies examining four operationalizations of antisocial
behavior were included. First, studies examining psychiatric
diagnoses of antisocial personality disorder (ASPD) and con-
duct disorder (CD) were included. The Diagnostic and Statis-
tical Manual of Mental Disorders, fourth edition (DSM-IV;
American Psychiatric Association [APA], 1994), describes
the essential features of ASPD as “a pervasive pattern of dis-
S.H. Rhee (B)
Institute for Behavioral Genetics, University of Colorado, Boulder, CO
80309, USA
e-mail: Soo.Rhee@colorado.edu
Y.-K. Kim (ed.), Handbook of Behavior Genetics,
DOI 10.1007/978-0-387-76727-7 30,  c Springer Science+Business Media, LLC 2009
regard for, and violation of, the rights of others that begins
in childhood or early adolescence and continues into adult-
hood” (p. 645). A diagnosis of ASPD requires a history of
CD before the age of 15 and three or more of the following
criteria: failure to conform to social norms with respect to
lawful behaviors (i.e., as indicated by repeatedly performing
acts that are grounds for arrest), deceitfulness, impulsivity,
irritability and aggressiveness, reckless disregard for safety,
consistent irresponsibility, and lack of remorse. Conduct dis-
order, a criterion for the diagnosis of ASPD, is described
by the DSM-IV as “a repetitive and persistent pattern of
behavior in which the basic rights of others or major age-
appropriate societal norms or rules are violated” (p. 90,
APA, 1994). It usually occurs in childhood or early ado-
lescence and is manifested as aggression toward people and
animals, destruction of property, deceitfulness or theft, and
serious violations of rules. Second, studies examining crim-
inality (an unlawful act that leads to arrest, conviction, or
incarceration) and delinquency (unlawful acts committed as
a juvenile) were included. Third, we included studies exam-
ining aggression, which is usually studied as a personal-
ity characteristic and assessed with measures such as the
Adjective Checklist (Gough & Heilbrun, 1972). Fourth, stud-
ies examining an omnibus operationalization that includes
aggression and delinquency items, such as the externalizing
scale from the Child Behavior Checklist (Achenbach & Edel-
brock, 1983), were included.
Current Issues and Research
A Meta-analysis of Twin and Adoption Studies
Examining Antisocial Behavior
More than a hundred twin and adoption studies of antiso-
cial behavior have been published. Nonetheless, it is diffi-
cult to draw clear conclusions regarding the magnitude of
genetic and environmental influences on antisocial behav-
ior given the current literature. The main reason for this
455
456
difficulty is the considerable heterogeneity of the results in
this area of research, with published heritability estimates
(i.e., the magnitude of genetic influences) ranging from very
low (e.g., 0.00; Plomin, Foch, & Rowe, 1981) to very high
(e.g., 0.71; Slutske et al., 1997). It is important to remember
that there is not a fixed, absolute heritability for antisocial
behavior. The heritability estimate describes the magnitude
of genetic influences in a particular population at a particular
time (Plomin, DeFries, McClearn, & McGuffin, 2001), and
it is possible that the heterogeneity in the results of behavior
genetic studies of antisocial behavior may reflect real, sub-
stantive differences as well as those due to methodological
variations across studies. In the literature, various hypotheses
have been proposed to explain these heterogeneous results
across studies, including differences in the age of the sample
(e.g., Cloninger & Gottesman, 1987), the age of onset of anti-
social behavior (e.g., Moffitt, 1993), and the measurement of
antisocial behavior (e.g., Plomin, Nitz, & Rowe, 1990).
We conducted a meta-analysis of twin and adoption stud-
ies in order to provide a clearer and more comprehen-
sive picture of the magnitude of genetic and environmental
influences on antisocial behavior. Given previous hypothe-
ses proposed to explain the heterogeneity in the results, we
examined the possible moderating effects of three study char-
acteristics (i.e., the operationalization of antisocial behavior,
assessment method, and zygosity determination method) and
two participant characteristics (i.e., the age and sex of the
participants) on the magnitude of genetic and environmental
influences on antisocial behavior.
We tested the operationalization of antisocial behavior
as a possible moderator given the evidence that antiso-
cial personality disorder, conduct disorder, criminality, and
aggression are distinct but related constructs (e.g., Robins &
Regier, 1991). We examined four levels of operationaliza-
tion, which included diagnosis (ASPD or CD), criminality,
aggression, and antisocial behavior (an omnibus operational-
ization that included aggression and delinquency items). We
tested assessment method and zygosity determination as
moderators because of evidence suggesting that these are
potential methodological confounders (e.g., Plomin, 1981;
McCartney, Harris, & Bernieri, 1990). We compared five
assessment methods, including self-report, report by oth-
ers (i.e., parent and teacher report), official records, objec-
tive measures, and reactions to aggressive material as well
as three zygosity determination methods, including blood
grouping, questionnaires, and a combination of blood group-
ing and questionnaires. Sex was examined given the con-
sistent evidence that antisocial behavior is more prevalent
in males than females (e.g., Hyde, 1984; Wilson & Herrn-
stein, 1985). Age was examined because of the potential to
test an interesting hypothesis regarding the development of
antisocial behavior by comparing studies that included chil-
dren, adolescents, and adults. DiLalla and Gottesman (1989)
S.H. Rhee and I.D. Waldman
and Moffitt (1993) have suggested that antisocial individuals
can be divided into a smaller group whose antisocial behav-
ior is persistent throughout the life course and caused pre-
dominantly by genetic influences and a larger group whose
antisocial behavior is limited to adolescence and caused pre-
dominantly by environmental influences. If their hypothesis
is correct, the magnitude of genetic influences on antisocial
behavior should be lower in adolescence than in childhood or
adulthood. We also compared the results of twin and adop-
tion studies. Twin and adoption studies have unique assump-
tions or biases that can make interpretations of their results
difficult. Comparing the results of twin and adoption studies
can help determine whether the results of behavior genetic
studies have been influenced by these unique assumptions or
biases. To the degree that the results of twin and adoption
studies are similar, it is more likely that the results reflect
the true magnitude of genetic and environmental influences.
One cannot rule out the possibility, however, that the results
of twin and adoption studies are similar because they share
similar biases to some extent that influence their results in
the same direction.
Two types of adoption studies were included in the present
meta-analysis: (1) parent–offspring adoption studies (i.e.,
comparing the correlation between adoptees and their adop-
tive parents with the correlation between adoptees and their
biological parents) and (2) sibling adoption studies (i.e.,
comparing the correlation between adoptive siblings with
the correlation between biological siblings). When interpret-
ing the results of parent–offspring data, it is important to
consider the possibility that the correlations between the
parents and the offspring may be reduced by the age dif-
ference between the two generations and that the magnitude
of familial (i.e., genetic and shared environmental) influ-
ences may be underestimated. Genetic influences on a trait
may differ from one generation to another because the genes
affecting the same trait may differ in their expression across
age due to genotype–environment interaction. For exam-
ple, genetic influences in the younger generation may be
increased because of environmental facilitation of antisocial
behavior, e.g., via secular increases in substance use and
less-stringent parenting practices (e.g., Lykken, 1997). Also,
there may be cohort-specific shared environmental influences
other than the cultural transmission from parents to offspring.
Therefore, each type of adoption study was compared to the
twin studies separately.
One hundred forty-one twin and adoption studies of anti-
social behavior were identified by examining the PsycInfo
and Medline databases and contacting authors of unpub-
lished manuscripts identified by abstracts of the Behavior
Genetics Association meetings and searching the Disserta-
tion Abstracts and ERIC databases. After excluding stud-
ies that were unsuitable given inadequate construct validity,
inability to calculate effect sizes given lack of information,
30 Genetic Analysis of Conduct Disorder and Antisocial Behavior
and simultaneous assessment of related disorders, such as
alcoholism, 96 studies remained. Non-independence among
these studies was addressed by either choosing the effect
size from the largest sample when non-independent sam-
ples had differing sample sizes or by averaging the effect
sizes across the samples when non-independent samples
had the same sample size. After addressing the problem of
non-independence, 10 independent adoption samples and 42
independent twin samples remained. The meta-analysis was
conducted on these 52 independent samples. The studies
included in the meta-analysis are marked with an asterisk (∗ )
in the References section.
Effect sizes were determined in one of three ways. First,
some adoption and twin studies used a continuous variable
to measure antisocial behavior and reported either Pearson
product moment or intraclass correlations, which were the
effect sizes used from these studies in the meta-analysis. Sec-
ond, a dichotomous variable was used, and concordances,
percentages, or a contingency table (including the number
of twin pairs with both twins affected, one twin affected, and
neither twin affected) was reported. The information from the
concordances or percentages was transformed into a contin-
gency table, which was then used to estimate the tetrachoric
correlation (i.e., the correlation between the latent contin-
uous variables that are assumed to underlie the observed
dichotomous variables). For these studies, the tetrachoric
correlation was the effect size used in the meta-analysis.
Third, we were able to directly estimate the tetrachoric cor-
relation from the raw data for some studies because we had
access to the data (e.g., Slutske et al., 1997; Waldman, Levy,
& Hay, 1995).
Alternative models positing that antisocial behavior is
affected by additive genetic influences (A), shared environ-
mental influences (C), non-additive genetic influences (D),
and nonshared environmental influences (E) were tested. The
ACE model, the AE model, the CE model, and the ADE
model were compared. Given that the ACDE model can be
tested only when both twin and adoption studies are included
in the analysis, it was only possible to estimate c2 and d2
simultaneously when analyzing all of the data included in
the meta-analysis. For other analyses (i.e., the comparison
between twin and adoption studies and the tests of modera-
tors), both twin and adoption studies were not always avail-
able across different types of studies. Therefore, we were
limited to comparing the ACE, AE, CE, and ADE models
for analyses other than those that included all data included
in the meta-analysis.
Overview of the Results
When all available data from both twin and adoption studies
were analyzed together and the magnitude of non-additive
457
genetic influences was estimated in addition to the magnitude
of shared environmental influences, the best fitting model
was the ACDE model. Based on this analysis, there were
moderate additive genetic (a2 = 0.32), non-additive genetic
(d2 = 0.09), shared environmental (c2 = 0.16), and non-
shared environmental (e2 = 0.43) influences on antisocial
behavior.
Operationalization was a significant moderator of the
magnitude of genetic and environmental influences. This
means that there was a statistically significant difference
between a model that constrained the parameter estimates
to be the same across the different levels of the moderator
and a model that allowed the parameter estimates to dif-
fer across the different levels of the moderator. The ACE
model was the best fitting model for diagnosis (a2 = 0.44,
c2 = 0.11, e2 = 0.45), aggression (a2 = 0.44, c2 = 0.06,
e2 = 0.50), and antisocial behavior (a2 = 0.47, c2 = 0.22,
e2 = 0.31), whereas the ADE model was the best fitting
model for criminality (a2 = 0.33, d2 = 0.42, e2 = 0.25).
Within the operationalization of diagnosis, the a2 estimate
was higher in studies examining CD (a2 = 0.50, c2 = 0.11,
e2 = 0.39), whereas the e2 estimate was higher in studies
examining ASPD (a2 = 0.36, c2 = 0.10, e2 = 0.54).
Assessment method also was a significant moderator, with
the ACE model fitting best for self-report (a2 = 0.39, c2 =
0.06, e2 = 0.55) and report by others (a2 = 0.53, c2 = 0.22,
e2 = 0.25), whereas the AE model fit best for reaction to
aggressive stimuli (a2 = 0.52, e2 = 0.48). All of the stud-
ies using the assessment method of records were also studies
examining criminality, for which the ADE model fits best
(a2 = 0.33, d2 = 0.42, e2 = 0.25).
Age was a significant moderator, with the ACE model fit-
ting best for children (a2 = 0.46, c2 = 0.20, e2 = 0.34),
adolescents (a2 = 0.43, c2 = 0.16, e2 = 0.41), and adults
(a2 = 0.41, c2 = 0.09, e2 = 0.50). The magnitude of famil-
ial influences (a2 and c2 ) decreased with age, whereas the
magnitude of non-familial influences (e2 ) increased with age.
Operationalization, assessment method, and age were fre-
quently confounded in the studies included in the meta-
analysis. For example, parent report was more frequently
used in studies examining antisocial behavior than in stud-
ies examining diagnosis or aggression, as well as in studies
examining children than in studies examining adolescents or
adults. The results of analyses examining age as a signifi-
cant moderator were not consistent with DiLalla and Gottes-
man’s hypothesis that the magnitude of genetic influences
should be higher in childhood and adulthood than in ado-
lescence. In contrast, the magnitude of genetic influence was
lower in both adolescence and adulthood than in childhood.
Nonetheless, the presence of confounding among the moder-
ators must be considered, implying that the higher heritabil-
ity for childhood may actually reflect the higher heritability
for parent report.
458
Zygosity determination method was a significant moder-
ator, such that the ADE model was the best fitting model
for studies using blood grouping (a2 = 0.14, d2 = 0.33,
e2 = 0.53), whereas the ACE model was the best fitting
model for studies using the questionnaire method (a2 = 0.43,
c2 = 0.27, e2 = 0.30) and a combination of the two meth-
ods (a2 = 0.39, c2 = 0.11, e2 = 0.50). These parameter
estimates are difficult to interpret, given that studies using
the most stringent method of zygosity determination (i.e.,
blood grouping) and the least stringent method of zygosity
determination (i.e., questionnaire) yielded higher estimates
of genetic influences (broad h2 = 0.43–0.47) than studies
using a combination of the two methods (broad h2 = 0.39).
Although sex was a significant moderator when data from all
studies were analyzed, there were no statistically significant
sex differences in studies that included both sexes (males:
a2 = 0.43, c2 = 0.19, e2 = 0.38; females: a2 = 0.41,
c2 = 0.20, e2 = 0.39).
Parent–offspring adoption studies found a lower magni-
tude of familial influences on antisocial behavior (i.e., lower
a2 and c2 and higher e2 ) than the twin and sibling adoption
studies. There are several possible reasons for this result.
First, the age difference between the children and their par-
ents may lead to lower correlations, given that there may be
age- or cohort-specific genetic and/or environmental influ-
ences. This age difference is absent in the twin studies
and smaller in the sibling adoption studies, thus supporting
this explanation. Second, because of the practical obstacles
involved in conducting an adoption study, in several stud-
ies different operationalizations and methods of assessment
were used in the adoptees and their parents (e.g., criminality
via official records in the parents and aggression via self-
report in the adoptees).
There was no statistically significant difference between
the results of twin studies and the sibling adoption studies.
This result should be interpreted cautiously considering the
fact that 42 independent twin samples were compared with
only 3 independent sibling adoption samples. Although the
power to detect a statistically significant difference between
the two types of studies may have been limited by the small
number of sibling adoption studies, the parameter estimates
for the twin studies (a2 = 0.45, c2 = 0.12, e2 = 0.43) and
the sibling adoption studies (a2 = 0.48, c2 = 0.13, e2 =
0.39) were very similar.
Additional Issues in the Etiology of Antisocial
Behavior
Several interesting issues in the etiology of antisocial behav-
ior were beyond the scope of the meta-analysis, or we were
unable to conduct a quantitative review of these issues given
S.H. Rhee and I.D. Waldman
the small number of studies addressing them in the liter-
ature. Below, studies examining genotype × environment
interaction, co-occurrence with other psychiatric disorders,
the etiology of psychopathy, and the etiology of adolescent-
limited versus life-course-persistent antisocial behavior are
reviewed.
Genotype × Environment Interaction
In addition to estimating the main effects of genes and envi-
ronments on various forms of antisocial behavior, researchers
also have examined whether genes and the environment inter-
act to influence antisocial behavior using both the adoption
design and the twin design, which have differing advantages
and disadvantages. The adoption study is the ideal method
for testing genotype–environment interactions because the
genetic and environmental influences on a trait are disen-
tangled and can be measured distinctly. Unfortunately, the
power to test the genotype × environment interaction term
may be reduced in adoption studies of antisocial behavior
because of range restriction in the variables used to indi-
cate the environmental and/or genetic influences on antiso-
cial behavior. McClelland & Judd (1993) demonstrated that
restricting the range of the predictor variables will reduce the
residual variance of the product of the two predictors and, in
turn, the statistical power to detect an interaction. The prob-
lem with range restriction is especially a concern in adoption
studies of antisocial behavior because the chance of adoptees
being placed in adoptive homes with criminal or antisocial
adoptive parents is very low. Therefore, the statistical diffi-
culties of detecting interactions should be considered in inter-
preting adoption studies examining gene–environment inter-
actions. In contrast, genotype–environment interactions are
more difficult to test in twin studies because the genetic and
environmental influences on a trait are likely to be correlated.
On the other hand, range restriction is less of a problem in
twin studies, where the samples are more representative of
the general population.
Data from several adoption studies (Cadoret, Cain, &
Crowe, 1983; Cloninger, Sigvardsson, Bohman, & von Knor-
ring, 1982; Mednick, Gabrielli, & Hutchings, 1983) show
evidence of genotype–environment interaction for antisocial
behavior. Mednick et al. (1983) conducted a cross-fostering
analysis of Danish adoptees. Among adoptees who had a
criminal background in both their biological and adoptive
parents, 24.5% of them became criminal themselves. This is
in comparison to 20% of adoptees who have a criminal back-
ground only in their biological parents, 14.7% of adoptees
who have a criminal background only in their adoptive par-
ents, and 13.5% of adoptees with no criminal background.
Cloninger et al. (1982) found similar results for petty crim-
inality in Swedish adoptees when they considered both bio-
30 Genetic Analysis of Conduct Disorder and Antisocial Behavior
logical variables (i.e., criminal biological parents) and envi-
ronmental variables (i.e., negative rearing experiences and
adoptive placement). Among adoptees with both biologi-
cal and environmental risks, 40% were criminal. This is in
comparison to 12.1% of those with only biological risk fac-
tors, 6.7% of those with only environmental risk factors, and
2.9% of those with neither biological nor environmental risk
factors. Also, in a sample of adoptees from Iowa, Cadoret
et al. (1983) found that when both genetic and environmen-
tal risk factors were present, they accounted for a greater
number of antisocial behaviors than an additive combination
of the two kinds of risk factors acting independently. The
genotype–environment interactions were not statistically sig-
nificant in Cloninger et al. (1982) or Mednick et al. (1983),
most likely given reduced power to test an interaction in the
presence of range restriction.
More recently, several twin studies have examined the
interaction between genes and specific environmental influ-
ences. Rowe, Almeida, and Jacobson (1999) examined the
interaction between genetic influences and family warmth
on aggression and reported that heritability increased and
the magnitude of shared environmental influences decreased
with greater family warmth. Rowe et al. suggested the
possibility that greater genetic influences are required for
the expression of aggression in more benign environments,
whereas social norms and peer models may lead to the
expression of aggression in individuals without genetic pre-
disposition in more adverse environments. A recent study
by Button, Scourfield, Martin, Purcell, and McGuffin (2005)
supports Rowe et al.’s findings. They examined the interac-
tion between genes and family dysfunction and concluded
that the heritability of antisocial behavior decreased and
the magnitude of both shared environmental and nonshared
environmental influences increased as family dysfunction
increased.
Jaffee et al. (2005) examined the effect of the interac-
tion between genetic influences and physical maltreatment
on conduct problems in a different way. They divided their
twin sample into four groups based on levels of genetic risk
as a function of their co-twin’s conduct disorder status and
the pair’s zygosity (i.e., lowest risk – MZ co-twin with no
CD diagnosis; low risk – DZ co-twin with no CD diagno-
sis; high risk – DZ co-twin with CD diagnosis; highest risk
– MZ co-twin with CD diagnosis) and absence/presence of
maltreatment. The maltreated group with the highest genetic
risk had the highest probability of a CD diagnosis. There was
a significant interaction between genetic risk and maltreat-
ment, but the conclusions are different from those reached
by Rowe et al. (1999) and Button et al. (2005). In the non-
maltreated group, there was a 44.2% increase in the probabil-
ity of a CD diagnosis from the lowest (1.9%) to the highest
(46.1%) genetic risk group. In the maltreated group, there
was a 66.1% increase in the probability of a CD diagnosis
459
from the lowest (3.5%) to the highest (69.6%) genetic risk
group. That is, genetic risk had less effect on conduct prob-
lems in the non-maltreated group (i.e., the more benign envi-
ronment) than in the maltreated group (i.e., the less benign
environment).
The Jaffee et al. (2005) study differs from the Rowe
et al. (1999) and Button et al. (2005) studies in several
ways, including the specific environmental variable exam-
ined and the analytical method used. It is possible that
the effects of the interaction between genes and family
warmth/dysfunction on antisocial behavior are different from
those of the interaction between genes and physical mal-
treatment. Additional studies examining genotype × specific
environmental influence interactions on antisocial behavior
are needed.
Co-occurrence with Other Psychiatric Disorders
Antisocial behavior co-occurs with several other psy-
chiatric disorders such as major depressive disorders,
attention-deficit/hyperactivity disorder (ADHD), and drug
dependence. In recent years, many researchers have exam-
ined the degree to which the covariance between antisocial
behavior and other psychiatric disorders is due to common
genetic or environmental influences.
There is evidence of significant co-occurrence between
conduct disorder (CD) and ADHD, which occur together in
30–50% of the cases in both epidemiological and clinical
samples (Biederman, Newcorn, & Sprich, 1991). The results
of several multivariate behavior genetic studies examining
the co-occurrence between ADHD and CD are largely con-
sistent, with most studies (Dick, Viken, Kaprio, Pulkkinen, &
Rose, 2005; Nadder, Rutter, Silberg, Maes, & Eaves, 2002;
Nadder, Silberg, Eaves, Maes, & Meyer, 1998; Silberg
et al., 1996; Thapar, Harrington, & McGuffin, 2001; Wald-
man, Rhee, & Levy, 2001) reporting a substantial overlap
between the genetic influences on ADHD and the genetic
influences on CD. An exception was Burt, Krueger, McGue,
and Iacono’s (2001) examination of ADHD, oppositional
defiant disorder (ODD), and CD, in which a single shared
environmental factor was the largest contributor to the
covariation among ADHD, ODD, and CD.
Researchers also have noted the high rate of co-
occurrence between CD and MDD, with reported rates of
co-occurrence between depression and CD/ODD ranging
from 21 to 83% (Angold & Costello, 1993). There are three
published studies examining the etiology of the occurrence
between CD and MDD or the broader constructs of exter-
nalizing and internalizing behavior/disorders, and the results
of these studies are conflicting. Gjone and Stevenson (1997)
examined the covariance between parent reports of inter-
nalizing and externalizing behavior problems in adolescent
460
twins and concluded that although there are both common
genetic and shared environmental influences on the covari-
ance between internalizing and externalizing behavior, there
is more consistent evidence for common shared environ-
mental influences. O’Connor, McGuire, Reiss, Hetherington,
and Plomin (1998) examined the covariation between anti-
social behavior and depressive symptoms assessed using a
composite of parent report, self-report, and observers’ report
in adolescents and found that there were moderate genetic,
shared environmental, and nonshared environmental influ-
ences on the covariation between the two symptom domains.
In Kendler, Prescott, Myers, and Neale’s (2003) examina-
tion of self-reported internalizing and externalizing disorders
in adults, the authors found that genetic factors influencing
externalizing disorders had little influence on internalizing
disorders, and genetic factors influencing internalizing disor-
ders had little influence on externalizing disorders. (They did
not find a clear distinction for shared environmental influ-
ences and nonshared environmental influences on external-
izing and internalizing disorders.) Several methodological
differences among these studies may explain their differing
conclusions, including the specific constructs examined, the
assessment methods used, and the age of the participants.
Conduct disorder also commonly co-occurs with sub-
stance use and substance use disorders. For example, Reebye,
Moretti, and Lessard (1995) reported that 52% of adoles-
cent inpatients with CD also had a substance use disor-
der. Researchers have concluded that there are genetic influ-
ences on the co-occurrence between antisocial behavior and
substance use/substance use disorders across a range of
substances. Silberg, Rutter, D’Onofrio, and Eaves (2003)
found significant common genetic influences on smoking
and conduct disturbance. Slutske et al. (1998) reported that
genetic influences accounted for most of the covariance
(with nonshared environmental influences accounting for the
remainder) between CD and alcohol dependence. Miles, van
den Bree, and Pickens (2002) found evidence of moder-
ate common genetic influences and low common nonshared
environmental influences on CD and marijuana use. Grove
et al. (1990) found significant genetic correlations between
illegal drug problems and both childhood and adult antisocial
behavior. Recently, Button et al. (2006) reported that there
were moderate genetic, shared environmental, and nonshared
environmental influences on the covariance between CD and
polysubstance dependence vulnerability. These studies are
consistent in suggesting that common genetic influences play
a significant role in the substantial co-occurrence of conduct
problems and substance use and/or dependence.
The Etiology of Psychopathy
Psychopathy is a personality-based construct characterized
by superficial charm, lack of empathy, lack of guilt, egocen-
S.H. Rhee and I.D. Waldman
tricity, and dishonesty. Personality characteristics are empha-
sized in this condition, rather than overt antisocial acts.
Researchers hypothesize that psychopathic individuals, who
represent a subset of individuals diagnosed with CD or
ASPD, may be those who are most likely to engage in life-
course-persistent antisocial behavior (Viding, Blair, Mof-
fitt, & Plomin, 2005) and instrumental aggression (Blair,
Peschardt, Budhani, Mitchell, & Pine, 2006), both of which
are particularly heritable.
Recently, Waldman and Rhee (2006) presented the results
of a meta-analysis of the small number of behavior genetic
studies examining psychopathy. These included the stud-
ies reviewed in the earlier Rhee & Waldman (2002) meta-
analysis (Brandon & Rose, 1995; DiLalla, Carey, Gottes-
man, & Bouchard, 1996; Gottesman, 1963, 1965; Loehlin
& Nichols, 1976; Loehlin, Willerman, & Horn, 1987; Taylor,
Iacono, and McGue, 2000; Torgersen, Skre, Onstad, Edvard-
sen, & Kringlen, 1993) as well more recent results from
Taylor, Loney, Bobadilla, Iacono, and McGue (2003) and
Blonigen, Carlson, Krueger, and Patrick (2003). In contrast
to the aforementioned overall results for antisocial behavior
(a2 = 0.32, d2 = 0.09, c2 = 0.16, e2 = 0.43), there is little
evidence for shared environmental influences on psychopa-
thy, and the AE model fits best (h2 = 0.49, e2 = 0.51).
The results from an interesting study by Viding
et al. (2005) were not included in the meta-analysis because it
examined the magnitude of genetic and environmental influ-
ences on extreme status on psychopathy (whereas the other
studies examined the etiology of psychopathy in the general
population). Viding et al.’s study is also the first examina-
tion of the etiology of psychopathy in children. They exam-
ined a sample of 7-year-old twin pairs in the general popu-
lation and then selected probands based on extremely high
scores on antisocial behavior and callous-unemotional traits.
Their results are similar to those from the Waldman and
Rhee meta-analysis. Extreme antisocial behavior accompa-
nied by extreme callous-unemotional traits was highly heri-
table (h2 g = 0.81) with no evidence of shared environmen-
tal influences, but extreme antisocial behavior unaccompa-
nied by extreme callous-unemotional traits was less heritable
(h2 g = 0.30) and affected by shared environmental influ-
ences (c2 g = 0.34).
Recently, Larsson, Andershed, and Lichtenstein (2006)
published a twin study examining the etiology of psychopa-
thy in adolescents. Twins aged 16–17 years were assessed via
the Youth Psychopathic Traits Inventory (YPI). Their results
are also consistent with those of previous studies examining
the etiology of psychopathy, as they found moderate genetic
and nonshared environmental influences and little evidence
of shared environmental influences on all three YPI dimen-
sions (grandiose/manipulative – a2 = 0.51, c2 = 0.03,
e2 = 0.46; callous/unemotional – a2 = 0.43, c2 = 0.00,
e2 = 0.57; impulsive/irresponsible – a2 = 0.56, c2 = 0.00,
e2 = 0.44). A common pathway model (where the covari-
30 Genetic Analysis of Conduct Disorder and Antisocial Behavior
ance among the three YPI dimensions is represented by an
intermediate latent variable) fits the data well, and the her-
itability of the latent psychopathic personality factor was
slightly higher (h2 = 0.63, c2 = 0.00, e2 = 0.37) than those
of the three YPI dimensions.
Another recent paper by Blonigen, Hicks, Krueger,
Patrick, and Iacono (2005) examined the co-occurrence
between psychopathic traits and internalizing and externaliz-
ing psychopathology. They found evidence of genetic influ-
ences on two distinct psychopathic traits, fearless dominance
(which is characterized by social potency, stress immu-
nity, and fearlessness) and impulsive antisociality (which
is characterized by negative emotionality and low behav-
ioral constraint). Genetic influences on fearless dominance
were negatively correlated with those on internalizing
psychopathology, whereas genetic influences on impulsive
antisociality were positively correlated with those on exter-
nalizing psychopathology.
Genetic Influences on Adolescent-Limited Versus
Life-Course-Persistent Antisocial Behavior
In a seminal review paper in 1993, Moffitt hypothesized
that there are two developmental types of antisocial behavior
that have different etiologies. Life-course-persistent antiso-
cial behavior begins in early childhood, continues throughout
the child’s lifetime, and is posited to show stronger genetic
influences and greater deficits in neuropsychological func-
tioning. In contrast, adolescent-limited antisocial behavior is
posited to be more affected by environmental influences such
as antisocial peer models. Therefore, Moffitt hypothesizes
that the magnitude of genetic influences should be higher for
antisocial behavior occurring in childhood or adulthood than
in adolescence.
The results of the meta-analysis do not support this
hypothesis, as the magnitude of genetic influences on antiso-
cial behavior was lower in both adolescence and adulthood
than in childhood. However, it is possible that this result is
due to the presence of confounding between age and assess-
ment method (i.e., most studies that examined the heritabil-
ity of antisocial behavior in childhood used parent reports,
and most studies that examined the heritability of antisocial
behavior in adolescence and adulthood used self-reports).
Given that studies that use parent reports have yielded higher
heritabilities than studies that use self-reports, the higher her-
itability for antisocial behavior in childhood may thus reflect
the higher heritability for parent report.
Several studies that have examined adolescent-limited and
life-course-persistent antisocial behavior in the same sam-
ple using the same assessment method have reported results
supporting Moffitt’s hypothesis. Lyons et al. (1995) con-
trasted the etiology of adult and juvenile antisocial traits and
reported that adult antisocial traits had significant genetic
461
influences, whereas juvenile antisocial traits were largely
influenced by shared environmental influences. Taylor,
Iacono, and McGue (2000) examined antisocial behavior
in the co-twins of probands with early-onset and late-onset
delinquency. Monozygotic co-twins of probands with early-
onset delinquency were more antisocial than dizygotic co-
twins of probands with early-onset delinquency, but the
monozygotic and dizygotic co-twins of probands with late-
onset delinquency had similar levels of antisocial behav-
ior. Finally, Jacobson, Neale, Prescott, and Kendler (2001)
reported that adolescent antisocial behavior had a lower
heritability and a greater magnitude of shared environmen-
tal influences in their subsample of youth whose antisocial
behavior did not persist into adulthood than in their subsam-
ple of youth whose antisocial behavior did persist into adult-
hood.
Examination of the Influence of Specific Genes
and QTLs on Antisocial Behavior
Given the evidence of moderate genetic influences on con-
duct disorder and antisocial behavior, many researchers have
investigated the relations of specific genes with antisocial
behavior in linkage and association studies. The number of
association and linkage studies examining antisocial behav-
ior is far fewer than those examining disorders or phenotypes
that are often comorbid with antisocial behavior, such as
ADHD, alcoholism, and suicidality. Thus, many researchers
examining these overlapping phenotypes also have examined
the evidence for association of specific genes with antiso-
cial behavior in clinical samples with ADHD (e.g., Thapar
et al., 2005), alcoholism and drug abuse (e.g., Soyka, Preuss,
Koller, Zill, & Bondy, 2004), suicidality (e.g., Zalsman
et al., 2001), and schizophrenia (e.g., Strous et al., 2003). In
the present review, we focused on studies of antisocial behav-
ior in the general population, clinical samples with antisocial
behavior, or general psychiatric samples, given the possibil-
ity that some of the conflicting results and failures to replicate
across studies may be due to sample differences.
Broadly speaking, there are two general strategies for
identifying quantitative trait loci (QTLs) that contribute to
the etiology of a disorder or trait, namely linkage and asso-
ciation. The purpose of a linkage study is to test whether the
putative risk-inducing gene is at a particular chromosomal
locus, whereas the purpose of an association study is to test
whether a particular allele of a candidate gene is associated
with the disorder or trait.
In genome scans, evidence for linkage between a disorder
or trait and evenly spaced DNA markers distributed across
the entire genome is evaluated. Evidence for linkage between
any of these DNA markers and the trait or disorder of interest
implicates a broad segment of the genome that may contain
hundreds of genes, and lack of evidence for linkage can, in
462
some cases, be used to exclude genomic segments. Subse-
quent fine-grained linkage analyses can then use a new set of
more tightly grouped markers within the implicated genomic
region to locate the functional mutation. Thus, genome scans
may be thought of as exploratory searches for putative genes
that contribute to the etiology of a disorder. The fact that
major genes have been found for many medical diseases via
genome scans without a priori knowledge of those genes’
function or etiological significance is a testament to the use-
fulness of this method. Unfortunately, the power of linkage
analyses in genome scans is typically quite low, making it
very difficult, if not impossible, to detect QTLs that account
for less than ∼15% of the variance in a disorder. There-
fore, the promise for linkage-based genome scans of complex
traits remains largely unknown.
In contrast to linkage, association has the statistical power
to detect QTLs that account for a relatively small percent-
age of the variance in a disorder. A disadvantage of asso-
ciation is that a QTL cannot be detected unless the marker
being examined is very close to the QTL. Therefore, many
more DNA markers would be needed to conduct a genome
scan using association, which has been made possible by
recent advances in array-based genotyping technologies.
Until recently, researchers have used association solely to
conduct candidate gene studies.
In many ways, candidate gene studies are polar opposites
of genome scans. In contrast to the exploratory nature of
genome scans, well-conducted candidate gene studies repre-
sent a targeted test of the role of specific genes in the etiology
of a disorder as the location, function, and etiological rele-
vance of candidate genes are most often known or strongly
hypothesized a priori. Thus, an advantage of well-conducted
candidate gene studies in comparison with genome scans is
that positive findings are easily interpretable because one
already knows the gene’s location, function, and etiological
relevance, even if the specific polymorphism(s) chosen for
study in the candidate gene is not functional and the func-
tional mutation(s) in the candidate gene is as yet uniden-
tified. There are also disadvantages to the candidate gene
approach given that only previously identified genes can be
studied. Thus, one cannot find genes that one has not looked
for or have yet to be discovered, and because there are rela-
tively few strong candidate genes for psychiatric disorders,
the same genes are examined as candidates for almost all
psychiatric disorders, regardless of how disparate the disor-
ders may be in terms of their symptomatology or conjectured
pathophysiology.
In well-designed studies, however, knowledge regarding
the biology of the disorder is used to select genes based on
the known or hypothesized involvement of their gene product
in the etiology of the trait or disorder (i.e., its pathophysio-
logical function and etiological relevance). With respect to
antisocial behavior, genes underlying various aspects of the
S.H. Rhee and I.D. Waldman
dopaminergic and serotonergic neurotransmitter pathways
may be conjectured based on several lines of converging evi-
dence suggesting a role for these neurotransmitter systems
in the etiology and pathophysiology of these traits and their
relevant disorders.
Association Studies
Dopamine transmission. There is significant co-occurrence
between CD and ADHD, with 30–50% of cases having
both disorders in both epidemiological and clinical sam-
ples (Biederman et al., 1991). Also, several twin studies
examining the co-occurrence between the two disorders sug-
gest that there are genetic influences common to both (Dick
et al., 2005; Nadder et al., 1998, 2002; Silberg et al., 1996;
Waldman et al., 2001). Therefore, specific genes associated
with ADHD also may influence CD.
There are several lines of evidence suggesting that the
dopamine transporter gene is associated with ADHD. The
dopamine transporter is the site of action of stimulant med-
ications effective in the treatment of ADHD (Winsberg &
Comings, 1999), and dopamine transporter levels are approx-
imately 70% higher in the brains of individuals with ADHD
than those of controls (Dougherty et al., 1999). “Knock-
out” mice with a deletion of both copies of the dopamine
transporter are hyperactive (Giros, Jaber, Jones, Wightman,
& Caron, 1996) and in humans, a VNTR polymorphism in
the 3 untranslated region of the dopamine transporter gene
has shown association with ADHD in previous studies, with
the more common 10-repeat allele being the risk allele (e.g.,
Cook et al., 1995; Faraone et al., 2005; Mill et al., 2005;
Waldman et al., 1998).
Given such evidence, two studies have examined the
evidence of association between this polymorphism of the
dopamine transporter gene and externalizing behavior in
children. Jorm, Prior, Sanson, Smart, Zhang, and East-
eal (2001) examined the association between the DAT1 gene
and externalizing behavior problems and associated temper-
ament traits in a longitudinal study of children from age
3 to 16 in the general population. They examined whether
children with the 10-repeat/10-repeat, 10-repeat/non 10-
repeat, and non 10-repeat/non 10-repeat genotypes differed
in the mean level of behavior problems but found no evi-
dence of association between the DAT1 gene and any of the
phenotypes examined, including parent reports of hostile-
aggressive behavior, conduct disorder, socialized aggression,
or oppositional behavior, at any age.
Young et al. (2002) examined the association between
the same VNTR polymorphism of the DAT1 gene and par-
ent reports of externalizing behavior at ages 4, 7, and 9.
A community sample of children from twin and adoption
studies was examined, using a sibling-based association
30 Genetic Analysis of Conduct Disorder and Antisocial Behavior
method (Fulker, Cherny, Sham, & Hewitt, 1999) that sepa-
rates the allelic effect into between-family effects (that may
include possible population stratification effects) and within-
family effects (where population stratification is controlled
by the inclusion of siblings). In contrast to evidence from
ADHD studies suggesting that the 10-repeat allele is the risk-
inducing allele, Young et al. found that the 9-repeat was the
risk-inducing allele for externalizing behavior at ages 4 and
7, but not at age 9. Young et al. cite that the less frequent
9-repeat allele has been shown to be the risk-inducing allele
for other phenotypes correlated with externalizing behavior,
such as alcohol dependence (Sander et al., 1997; Schmidt,
Harms, Kuhn, Rommelspacher, & Sander, 1998) and cocaine
intoxication (Gelernter, Kranzler, Satel, & Rao, 1994).
Serotonin transmission. Several lines of evidence suggest
that genes influencing serotonergic neurotransmission
may be associated with conduct disorder and antisocial
behavior. Low cerebrospinal fluid concentrations of
5-hydroxyindoleacetic acid, the major metabolite of
serotonin, are found in aggressive subjects (e.g., Kruesi
et al., 1990; Lidberg, Tuck, Asberg, Scalia-Tomba, &
Bertilsson, 1985). Also, pharmacological challenge trials
suggest an association between low serotonin functioning
and violence or aggression. For example, aggression is
associated with blunted prolactin (PRL) responses to
the treatment of 5-HT releaser, d-fenfluramine (Coccaro,
Kavoussi, Cooper, & Hauger, 1997; Coccaro et al., 1987).
Given this evidence, researchers have examined the
association between antisocial behavior and several genes
involved in serotonergic transmission, including the
serotonin transporter gene, the HTR1B gene, and the
tryptophan hydroxylase gene.
The serotonin transporter is known to influence seroton-
ergic transmission and several researchers have examined a
polymorphism in the promoter area with two allelic vari-
ants that differ in transcriptional activity (5-HTTLPR). The
S or short allele of the polymorphism has lower transcrip-
tional activity (Heils et al., 1996) and is associated with a
blunted response in fenfluramine-induced prolactin release
pharmacological challenges (e.g., Reist, Mazzanti, Vu, Tran,
& Goldman, 2001), whereas serotonin transporter availabil-
ity is higher in individuals with the L or long allele than in
those with the S allele (Heinz et al., 2000).
Baca-Garcia et al. (2004) examined the association
between the serotonin transporter gene promoter linked
region and impulsivity and aggressive behavior among sui-
cide attempters and a control group of blood donors and
found no difference among the SS, SL, and LL geno-
types in the level of impulsivity or history of aggressive
behavior in either group. In contrast, Retz, Retz-Junginger,
Supprian, Thome, and Rösler (2004) found a significant asso-
ciation between the serotonin transporter gene and violent
behavior in a sample of adult males referred for a forensic
463
examination. Retz et al. divided the subjects into a vio-
lent and nonviolent group and found that the S allele was
significantly over-represented in the violent group. More
recently, Sakai et al. (2006) found that the S allele is a risk
allele for conduct disorder with aggression in a case–control
study comparing conduct-disordered adolescents and non-
conduct-disordered controls as well as in a transmission dis-
equilibrium test examining conduct-disordered adolescents
and their parents. Beitchman et al. (2006) reported similar
results in a study examining three alleles of the 5-HTTLPR
polymorphism (i.e., S, Lg, and La; La is “high transcrib-
ing”; Lg is “low transcribing”, similar to S); they found
that the “low-expressing” genotypes of the 5-HTTLPR poly-
morphism (S/S, Lg/S, Lg/Lg) are associated with childhood
aggression in a case–control study.
In an adoption study sample, Cadoret et al. (2003) found a
complex pattern of association between the serotonin trans-
porter gene and externalizing behavior (i.e., aggressivity,
conduct disorder, and attention-deficit/hyperactivity disor-
der). In the presence of antisocial biological parents, the
L allele was associated with increased externalizing behav-
ior, whereas in the presence of alcoholism in the biological
parents, the S allele was associated with increased external-
izing behavior. The authors also found a significant genotype
by gender interaction, with the S allele being associated with
higher externalizing behavior in males and the S allele being
associated with lower externalizing behavior in females.
Haberstick, Smolen, and Hewitt (2006) also reported mixed
findings. Family-based association tests were conducted in a
twin sample, examining parent and teacher reports of aggres-
sive behavior at ages 7, 9, 10, 11, and 12, with teacher reports
also available at age 8. A statistically significant result was
obtained only for teacher reports of aggressive behavior at
age 9, with the S allele being the risk allele.
Given research suggesting that genes involved in sero-
tonin functioning may be candidate genes for aggression and
the evidence that 5-HT1B knockout mice show increased
aggression (Saudou et al., 1994), New et al. (2001) examined
the association between a common polymorphism caused by
a silent G to C substitution in the HTR1B gene and self-
reported impulsive aggression in a sample of subjects with
one or more personality disorders but found no evidence of
association.
Tryptophan hydroxylase (TPH) is the rate-limiting
enzyme in the serotonin pathway in the conversion of trypto-
phan into 5-hydroxytryptophan, the direct precursor of 5-HT.
Researchers have examined two common SNPs in intron 7
of the TPH gene, A218C and A779C, that are in strong link-
age disequilibrium. The genotypes of these two SNPs were
found to be identical in nearly 100% of the sample in one
Japanese study (Kunugi et al., 1999), with the 218A and
the 779A being linked and the 218C and 779C alleles being
linked.
464
The results of studies examining the association between
the TPH gene and antisocial behavior are conflicting. Two
studies suggest that the A allele of the A218C/A779C poly-
morphism is associated with increased antisocial behavior.
Manuck et al. (1999) examined association of the A218C
polymorphism of the TPH gene with aggression and anger-
related traits and found that the A allele was associated
with higher aggression, a tendency to experience unpro-
voked anger, and a tendency to express anger outwardly.
The A allele was also associated with attenuated peak
prolactin response to fenfluramine, although this relation-
ship was only found in men. Hennig, Reuter, Netter, Burk,
and Landt (2005) examined the association between the
TPH A779C polymorphism and aggression in a community
sample. They examined two different types of aggression
assessed by the Buss–Durkee hostility inventory, neurotic
hostility and aggressive hostility, and found that the A allele
of the A779C polymorphism of the TPH gene was associated
with aggressive hostility but not neurotic hostility. In con-
trast to Hennig et al. and Manuck et al., Staner et al. (2002)
found that the C allele of the A218C polymorphism was
associated with a higher level of impulsive aggression in
a sample of nonpsychotic, impulsive inpatients. Similarly,
New et al. (1998) examined the association between the
A218C polymorphism and impulsive aggression in a sam-
ple of patients with personality disorders and found that
the C allele was associated with higher levels of impulsive
aggression.
Staner et al. (2002) suggest that the differences in sam-
ple composition may account for the discrepancies in these
results, as the association with the C allele was found in
psychiatric samples (New et al., 1998; Staner et al., 2002)
and not in community samples (Manuck et al., 1999; Staner
et al., 2002). Hennig et al. (2005) suggest that differences
in the conclusions may be due to differences in the type of
aggression being examined, as they found evidence for asso-
ciation of the A allele with aggressive hostility, but not with
neurotic hostility, which was more similar to the measure of
impulsive aggression examined in New et al. (1998).
MAOA. Monoamine oxidase A is a degradative enzyme
that catalyzes deamination of serotonin, norepinephrine, and
dopamine. Two lines of evidence suggest that the gene
coding for MAOA may be related to antisocial behavior.
First, deletion of the gene encoding MAOA led to height-
ened aggression in transgenic mice (Cases et al. 1995). Sec-
ond, a rare MAOA point mutation resulting in no MAOA
enzyme was associated with mild mental retardation and
impulsive aggression in males in a large Dutch kindred
(Brunner, Nelson, et al., 1993; Brunner, Nelson, Breakefield,
Ropers, & van Oost, 1993). Although this mutation is rare
and unlikely to predict aggressive behavior in the general
population, other common allelic variations of the MAOA
gene may be associated with aggression. Several researchers
S.H. Rhee and I.D. Waldman
have examined a functional 30-bp variable number of tan-
dem repeat polymorphism in the promoter region of the
MAOA gene, for example, in which alleles 2 and 3 (i.e.,
3.5 or 4 repeats) have shown greater transcriptional activ-
ity than alleles 1 and 4 (i.e., 3 or 5 repeats; Sabol, Hu, &
Hamer, 1998).
Manuck, Flory, Ferrell, Mann, and Muldoon (2000) exam-
ined the association between the VNTR polymorphism of
the MAOA gene and aggression and impulsivity in a male
community sample. In contrast to the results expected based
on the findings from the Dutch kindred study (Brunner, Nel-
son, et al., 1993; Brunner, Nelen, et al., 1993) and the trans-
genic mouse study (Cases et al., 1995), individuals with the 1
and 4 alleles (i.e., with lower transcriptional activity) scored
lower on the composite measure of aggression and impul-
sivity than individuals with the 2 and 3 alleles (i.e., with
higher transcriptional activity). Also, individuals in the 1/4
allele group also showed more pronounced central nervous
system serotonergic responsivity than individuals in the 2/3
allele group in a neuropsychopharmacologic challenge (i.e.,
prolactin response to fenfluramine hydrochloride).
Caspi et al. (2002) examined the interaction between
the MAOA gene and maltreatment early in life, given evi-
dence that maltreatment in early life alters norepinephrine,
serotonin, and dopamine systems (e.g., Bremner & Vermet-
ten, 2001). They hypothesized that maltreated children with
a genotype that confers high levels of MAOA expression
would be less likely to develop antisocial behavior, and
tested this hypothesis in a longitudinal community sample
of male adolescents. The main effect of MAOA on antiso-
cial behavior was not significant, although the main effect
of maltreatment was significant. The effect of maltreatment
on antisocial behavior was much stronger in males with the
genotype conferring low MAOA activity than in males with
the genotype conferring high MAOA activity. This was a sig-
nificant finding, as it is one of the first demonstrations of an
interaction between a measured gene and a measured envi-
ronmental influence on a behavioral trait in humans. Caspi et
al.’s results are not necessarily in contrast to those of Manuck
et al., given that among individuals with no maltreatment
experience, those with the genotype conferring low MAOA
activity had lower antisocial behavior than those with the
genotype conferring high MAOA activity.
Since the publication of Caspi et al.’s results (2002),
several researchers have attempted to replicate the MAOA-
by-maltreatment interaction on antisocial behavior, with
varying results. Huang et al. (2004) found a significant inter-
action in a psychiatric sample, reporting that the high-activity
MAOA allele was associated with lower impulsivity in those
reporting early childhood abuse. However, this finding did
not extend to measures of aggression or hostility, and simi-
lar results were not found in females. In males, Huang et al.
found that childhood abuse was more common in individuals
30 Genetic Analysis of Conduct Disorder and Antisocial Behavior
with the low-activity MAOA allele, suggesting evidence of
evocative gene–environment correlation.
Foley et al. (2004) examined the interaction between
the MAOA gene and adverse childhood environment
(i.e., parental neglect, exposure to interparental violence,
and inconsistent parental discipline) on conduct disor-
der in a community twin sample. They replicated Caspi
et al.’s (2002) findings, reporting that the low MAOA activ-
ity allele was a risk factor for conduct disorder only in
the presence of adverse childhood environment. Most of
the power to detect this interaction came from the individ-
uals with extremely adverse childhood environment. Foley
et al. (2004) also examined the evidence for evocative
gene–environment correlation, but in contrast to Huang
et al. (2004), found that the low MAOA activity allele did not
predict exposure to childhood adversity. Nilsson et al. (2005)
found support for the initial Caspi et al. (2002) finding
in a study examining the interaction between MAOA and
a broader construct of psychosocial risk (i.e., dwelling in
multi-family housing and experiences with violent victim-
ization). They reported a stronger effect of psychosocial risk
on antisocial behavior in boys with the low-activity MAOA
genotype than in boys with the high-activity MAOA geno-
type. Widom and Brzustowicz (2006) attempted to replicate
the Caspi et al. (2002) finding in participants in a prospective
cohort design study. The interaction between MAOA geno-
type and abuse/neglect was replicated in Caucasians but not
in non-white participants.
Haberstick et al. (2005) also examined the interaction
between MAOA and maltreatment on antisocial behavior
in a community sample. Despite having adequate power,
they were not able to replicate Caspi et al.’s (2002) find-
ing. However, they found a nonsignificant trend in the
predicted direction, with individuals with the high-activity
MAOA allele having lower antisocial behavior in the mal-
treated group and individuals with the low-activity MAOA
allele having a lower level of antisocial behavior in the non-
maltreated group. Huizinga et al. (2006) examined the inter-
action between MAOA and self-reported physical abuse and
violent victimization in participants in the National Youth
Survey Family Study. Maltreatment by a parent was signifi-
cantly related to adolescent and adult antisocial and violence-
related behavioral problems, but the main effect of MAOA
and the MAOA-by-maltreatment interaction was not sig-
nificant. Similar results were found for violent victimiza-
tion. Young et al. (2006) examined the interaction between
MAOA and maltreatment in a group of adolescents being
treated for significant conduct and substance use problems.
They were unable to replicate Caspi et al.’s (2002) find-
ings, reporting that there were no significant differences
in the relationship between maltreatment and conduct dis-
order between the low- and high-activity MAOA geno-
types.
465
Recently, Kim-Cohen et al. (2006) reported replication of
the Caspi et al. (2002) findings in children assessed at age 5
and 7. As in Caspi et al., maltreatment had a stronger effect
on antisocial behavior in boys with the low MAOA activ-
ity genotype than in boys with the high-activity genotype.
In addition, Kim-Cohen conducted a meta-analysis of five
studies examining the maltreatment by MAOA interaction on
antisocial behavior (Caspi et al., 2002; Foley et al., 2004;
Haberstick et al., 2005; Kim-Cohen et al., 2006; Nilsson
et al., 2005) and found support for the original Caspi et al.
finding.
Linkage Studies
There are no linkage studies of conduct disorder examining a
general population sample or a clinical sample being treated
only for conduct problems. However, two recent linkage-
based genome-wide screens have been conducted in sam-
ples ascertained for substance use problems to search for loci
influencing conduct disorder.
Dick et al. (2004) published the first genome-wide link-
age scan of conduct disorder in an adult sample collected
as part of the Collaborative Study on Genetics of Alco-
holism (COGA). They examined retrospectively reported
childhood conduct disorder and conduct disorder symptoms
in a sample of alcoholic probands and their first-degree rel-
atives. They conducted nonparametric, multipoint linkage
analyses using affected sibling pairs, reporting lod scores
equal to or greater than 1.5 for CD diagnosis at chromo-
some 19p13 at 35 cM (lod score = 2.14), chromosome 2p11
at 136 cM (lod score = 1.65), chromosome 12q13 at 78
cM (lod score = 1.79), and chromosome 3q12 at 134 cM
(lod score = 1.60). For CD symptoms as a quantitative trait,
suggestive evidence for linkage was found at chromosome
1q32 at 34 cM (lod score = 2.17) and at chromosome 19q12
at 46 cM (lod score = 2.1).
Stallings et al. (2005) examined evidence for linkage for
conduct disorder symptoms in a clinical sample being treated
for comorbid substance use disorders and antisocial behav-
ioral problems. Using DeFries–Fulker linkage analysis, a
regression-based sibling pair linkage method, they found
two peaks yielding lod scores greater than 1 for conduct
disorder symptoms, one on chromosome 9q34 at 162 cM
(lod score = 1.76) and the other on chromosome 17q12 at
54 cM (lod score = 1.26). Unfortunately, there are no over-
laps between the suggestive linkage peaks reported in Dick
et al. (2004) and Stallings et al. (2005). Although Stallings
et al. (2005) found a suggestive peak on chromosome 3q24-
3q25 at 173 cM with a lod score of 1.63 for substance depen-
dence vulnerability, a similar peak was not found for conduct
disorder symptoms.
466
Future Directions
Twin and Adoption Studies
The results of Rhee & Waldman’s (2002) meta-analysis sug-
gest several future directions for twin and adoption studies
of antisocial behavior. First, there may be meaningful dis-
tinctions in the operationalizations of antisocial behavior that
need further examination, such as violent versus nonviolent
crime, criminality versus delinquency, relational versus overt
aggression, and instrumental versus reactive aggression. Sec-
ond, multivariate analyses examining the extent to which
the different operationalizations of antisocial behavior have
common or specific genetic and environmental influences
are needed. An example of such an analysis is Cloninger
& Gottesman’s (1987) finding that there is little genetic
overlap between violent and nonviolent crime. Such results
will be very important to consider in the search for spe-
cific genes influencing antisocial behavior. Related to this
goal is the clarification of the relation between antisocial
behavior and possible endophenotypes. Third, the results of
the meta-analysis show that there is significant confounding
between assessment method and operationalization and age
(e.g., criminality always being assessed using official records
and childhood externalizing behavior always being assessed
using parent report), suggesting that the assessment methods
used in future behavior genetic studies of antisocial behavior
should be diversified given the possibility that results may
reflect the assessment method rather than the operationaliza-
tion of antisocial behavior being assessed. One such example
is Arseneault et al.’s (2003) finding that there were strong
genetic influences on antisocial behavior when ratings agreed
across mother, teacher, observer, and self-report. Fourth, the
power to test genotype × environment interactions may be
limited by range restriction in adoption studies. Therefore,
future behavior genetic studies should consider alternative
research design strategies, such as over-sampling extreme
observations (McClelland & Judd, 1993). For example, such
studies may over-sample children with a low genetic pre-
disposition to antisocial behavior who are reared in envi-
ronments that predispose them to antisocial behavior. Fifth,
studies examining specific shared and nonshared environ-
mental influences while controlling for genetic influences are
needed.
Association and Linkage Studies
In comparison to other comorbid disorders such as ADHD
and alcoholism, there are few association and linkage studies
of conduct disorder and antisocial behavior. So far, there is
S.H. Rhee and I.D. Waldman
little consensus in the findings of these studies. There are
several possible reasons for conflicting results and failures
to replicate, including small sample sizes, differences in the
types of samples employed, differences in the range of phe-
notypes examined, differences in analytical approaches, and
the possibility of population stratification. Future directions
for association studies include the need to increase our under-
standing regarding how the various operationalizations of
antisocial behavior are related to each other and apply this
knowledge to the search for specific genes influencing antiso-
cial behavior. For example, a highly heritable common latent
phenotype or endophenotype for antisocial behavior may be
a better phenotype than conduct disorder symptoms, which
generally show moderate shared environmental influences.
The differences across studies suggest a need for increased
collaboration among researchers investigating the genetics
of antisocial behavior. Such collaboration among researchers
examining attention-deficit/hyperactivity disorder has been
productive (e.g., Kent, 2004). There are many possible can-
didate genes for antisocial behavior that have yet to be exam-
ined, and technological advances will allow more intensive,
systematic studies involving dense mapping or sequencing
of specific candidate genes and whole genome association
studies.
Knowledge regarding the neuro-cognitive dysfunctions
related to antisocial behavior from neuropsychological and
functional imaging studies has been increasing. For exam-
ple, Blair et al. (2006) recently reviewed the evidence for
two neural systems implicated in psychopathy, one involving
the amygdala and the other involving the orbital/ventrolateral
frontal cortex. As the evidence regarding specific genetic
effects on antisocial behavior becomes clearer, the applica-
tion of imaging genomics (i.e., combining neuroimaging and
genetic analysis to examine genes’ effects on brain informa-
tion processing) in the etiology of antisocial behavior will
become an important future direction.
The first evidence of a specific gene × measured environ-
ment interaction was found for antisocial behavior 4 years
ago (Caspi et al., 2002), resulting in considerable interest
in measured gene × environment interactions. Given the
large number of possible candidate genes and environmental
risk factors for antisocial behavior, the possibility of type I
errors and spurious findings should be considered carefully.
Recently, Moffitt, Caspi, and Rutter (2005) have encouraged
careful measured gene × environment interaction hypothesis
testing and have emphasized the importance of specifying a
priori theoretically plausible triads of a gene, an environmen-
tal pathogen, and a behavioral phenotype. They described
seven strategic steps needed to organize future hypothesis-
driven studies of measured gene × environment interaction,
which include (1) consulting the quantitative behavioral-
genetic literature, (2) identifying a candidate environmen-
tal pathogen for the disorder in question, (3) optimizing
30 Genetic Analysis of Conduct Disorder and Antisocial Behavior
environmental risk measurement, (4) identifying candidate
susceptibility genes, (5) testing for an interaction, (6) eval-
uating whether a measured gene × environment interaction
extends beyond the initially hypothesized triad of gene, envi-
ronmental pathogen, and disorder, and (7) replication and
meta-analysis.
Acknowledgment This work was supported in part by NIDA DA-
13956 and NIMH MH-01818.
Note: The asterisk denotes a study that was considered for
inclusion in the meta-analysis.
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