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. Author manuscript; available in PMC: 2012 Oct 1.
Published in final edited form as: Psychiatr Genet. 2011 Oct;21(5):240–248. doi: 10.1097/YPG.0b013e3283457c15

5-HTTLPR as a Potential Moderator of the Effects of Adverse Childhood Experiences on Risk of Antisocial Personality Disorder

Kara Douglas a, Grace Chan a, Joel Gelernter c,d, Albert J Arias a, Raymond F Anton e, James Poling c, Lindsay Farrer f, Henry R Kranzler a,b
PMCID: PMC3119731  NIHMSID: NIHMS279676  PMID: 21399568

Abstract

INTRODUCTION

Antisocial personality disorder (ASPD) frequently co-occurs with substance dependence (SD). A functional polymorphism (5-HTTLPR) in the serotonin transporter gene has been widely studied as a risk factor for a variety of psychopathologic conditions, including aggressive/violent behavior. Childhood abuse is an important predictor of ASPD. We examined 5-HTTLPR genotype and adverse childhood events (ACEs) as risk factors for ASPD in a SD sample.

METHOD

Study participants [602 European Americans (EAs) and 779 African Americans (AAs)] were interviewed to obtain lifetime diagnoses of ASPD and SD and information on ACEs. Tri-allelic genotypes for 5-HTTLPR were obtained using standard methods. We used logistic generalized estimating equations (GEE) regression to examine ACEs and 5-HTTLPR genotype and their interaction as predictors of ASPD, separately by population group.

RESULTS

There were 203 (14.7%) participants diagnosed with ASPD. The frequency of the low-activity 5-HTTLPR S’ allele did not differ by ASPD diagnosis, and there was no overall 5-HTTLPR × ACE interaction. However, among EAs, male sex (OR=3.36; p<0.001) and ACE history (OR=1.47; p=0.002) were significant predictors of ASPD. Among AAs, there was a significant interaction of sex × 5-HTTLPR genotype × ACEs (χ2=13.92, p<0.001). Among AA men, each additional ACE significantly increased the odds of ASPD irrespective of genotype, while among AA women, the effect of ACEs on ASPD was significant only among S’ homozygotes. However, these results are limited by the small sample size in each subgroup, (particularly AA women with S’S’ genotype; N=7) and require replication.

CONCLUSIONS

Childhood maltreatment contributes to the risk of antisocial personality disorder, an effect for which there is preliminary evidence of moderation by 5-HTTLPR genotype in AA women.

Keywords: Serotonin Transporter Gene, SLC6A4, Child Abuse, Antisocial Personality Disorder, gene × environment

INTRODUCTION

Antisocial personality disorder (ASPD) is characterized by a pattern of aggression, deceitfulness, impulsivity, and unlawful behavior (American Psychiatric Association, 2000). In the United States, the lifetime population prevalence of ASPD has been estimated to be 3.6% (Compton et al., 2005), though it is higher among individuals with substance use disorders (SUDs) (Anthony and Helzer, 1991; Goldstein et al., 2007a; Goldstein et al., 2007b). Among individuals with SUDs, the presence of ASPD is associated with an earlier onset of substance-related problems, a more severe clinical course, and poorer treatment outcomes (Bucholz et al., 2000; Cottler et al., 1995; Goldstein et al., 2007a; Goldstein et al., 2007b; Kranzler et al., 1996; Rounsaville et al., 1987).

Childhood abuse is an important environmental risk factor for the development of antisocial behavior (Bierer et al., 2003; Hosser et al., 2007; Luntz and Widom, 1994). In a prospective study of 699 individuals, including 416 subjects abused and/or neglected as children, childhood abuse was a significant predictor of an ASPD diagnosis and of the number of lifetime ASPD symptoms endorsed (Luntz and Widom, 1994). A retrospective history of physical and/or sexual abuse was also associated with an increased likelihood of ASPD in a sample of adults (Bierer et al., 2003). A study of 1,526 incarcerated men showed a correlation between a history of maltreatment in childhood and increased levels of self-reported violence (Hosser et al., 2007).

In addition to the effects observed among the victims of childhood abuse, witnessing a traumatic event (e.g., domestic violence, violent crime) in childhood can also contribute to psychopathology, including antisocial behavior (Finkelstein and Yates, 2001; Knapp, 1998). However, studies often fail to differentiate between being a victim of violence and witnessing violence perpetrated against others. Knapp (1998) concluded that children who observe the battering of their mothers are at increased risk of violence later in life. Similarly, Malmquist (1986) found that boys who observe violence against their mothers, committed by their fathers, have a ten-fold risk of committing abuse against their own spouses as adults.

Adoption studies have shown that both environmental and genetic factors and their interaction effects may contribute to risk of antisocial behavior (for reviews see Raine, 2002 and Rhee and Waldman, 2002). The heritability of ASPD has been estimated to be 30-50% (Maes et al., 2007; Slutske, 2001), with gene × environment effects being important determinants of risk. In a study of 862 male Swedish adoptees, 40% of individuals with both inherited and environmental risk factors for criminality had histories of such behavior, compared to 12.1% with genetic factors only, 6.7% with environmental risk only, and 2.9% with neither risk factor (Cloninger et al., 1982). A study of female adoptees also showed a similar interactive effect of genetics and environment on the likelihood of antisocial behavior (Cloninger and Gottesman, 1987). Cadoret et al. (1995) found that an antisocial biological parent and an adverse adoptive home environment were independent predictors of antisocial behaviors in adopted-away men and women, and these two factors (genetic and environmental) interacted significantly to predict increased aggression and conduct disorder.

From a neurochemical point of view, serotonergic neurotransmission has been implicated in impulsive and aggressive behavior and may be relevant to the observed effects of childhood adversity on risk of antisocial behavior. Cerebrospinal fluid (CSF) concentrations of the serotonin metabolite 5-hydroxindole acetic acid (5-HIAA) are inversely related to aggressive and impulsive behavior in non-human primates (Higley et al., 1992; Mehlman et al., 1994) and humans (Brown et al., 1979; Linnoila et al., 1983; Roy and Linnoila, 1988). The serotonin transporter (5-HTT), which is responsible for the reuptake of serotonin, plays an important role in the regulation of serotonergic tone (Ramamoorthy et al., 1993). A functional insertion-deletion polymorphism (5-HTTLPR) in the 5′ promoter region of SLC6A4, the gene that encodes 5-HTT, has been widely studied for its contribution to the risk for a variety of psychopathologic conditions. The long (L) allele of 5-HTTLPR was associated with greater transcriptional efficiency than the short (S) allele (Heils et al., 1996; Lesch et al., 1996). The presence of a single nucleotide polymorphism (A/G) in the L allele modifies its function, such that the transcriptional rate of the LG allele is similar to that of the S allele (Hu et al., 2006). This tri-allelic polymorphism thus consists of two low-activity alleles (S and LG, referred to here as S’) and a high-activity allele (LA, referred to here as L’).

Some pre-clinical evidence suggests that early life experience may interact with serotonin transporter genotype to produce lasting effects on serotonin neurotransmission (Bennett et al., 2002; Higley et al., 1991). In rhesus monkeys, the rh-HTTLPR polymorphism (which is orthologous to the human 5-HTTLPR polymorphism) was associated with reduced CSF 5-HIAA concentrations only in animals with adverse early rearing experiences (Higley et al., 1991). A meta-analysis of 5-HTTLPR genotype and 5-HIAA concentrations in humans showed a significant inverse relationship of 5-HIAA concentrations with antisocial behavior (Moore et al., 2002). Williams et al. (2003) also examined the 5-HTTLPR polymorphism in relation to CSF 5-HIAA levels, with stratification by population group and sex. They found that, among Caucasians and men, individuals homozygous for the low-activity allele had lower 5-HIAA levels, while the opposite effect was seen among African Americans (AAs) and women.

Clinical studies have shown an association of the 5-HTTLPR polymorphism with aggressive and violent behaviors. Specifically, low-activity 5-HTTLPR alleles have been associated with conduct disorder (CD) in adolescents (Sakai et al., 2006), antisocial personality disorder in alcoholics (Hallikainen et al., 1999), violence in male criminals (Liao et al., 2004), physical violence in men (Retz et al., 2004), and violence in heroin-dependent men (Gerra et al., 2004). In a study of 96 low-income young adults, including 34 individuals with ASPD or borderline personality disorder, the number of 5-HTTLPR S alleles was significantly associated with ASPD (Lyons-Ruth et al., 2007). However, a significant relationship between the L allele and violent/aggressive traits has also been reported (Twitchell et al., 2001; Zalsman et al., 2001). Two studies of aggressive children found no relationship between 5-HTTLPR genotype and aggression (Beitchman et al., 2003; Davidge et al., 2004) and a longitudinal study in adolescents showed no significant relationship between 5-HTTLPR genotype and conduct problems or delinquency (Sakai et al., 2007). More recently, Sadeh et al. (2010) examined youth from two different studies with respect to the relations between two dimensions of psychopathy and 5-HTTLPR genotype. They found a significant main effect of genotype, such that individuals homozygous for the S’ allele showed higher levels of impulsivity, as well as a significant interaction effect in which decreasing socioeconomic status was associated with greater callous-unemotional and narcissistic traits, but only among individuals homozygous for the L’ allele. These findings suggest that although the S’/S’ genotype is associated with impulsivity, the L’/L’ genotype may increase the risk of emotional deficits among disadvantaged populations. Thus, both genotypes could potentially confer risk for antisocial behavior, but under different circumstances.

Mixed results on the association of antisocial behavior with 5-HTTLPR may have resulted from differences in statistical power or sample characteristics or the failure to consider gene by environment effects. The latter possibility is supported by the findings of Reif et al. (2007), who despite not finding a main effect of 5-HTTLPR, reported that adverse childhood experiences (ACEs) were associated with violent behavior among subjects with one or two copies of the low-activity S allele.

In the present study, we examined the main and interactive effects of 5-HTTLPR and ACEs on risk for ASPD in a sample of individuals with SD. We hypothesized that ACEs would be a risk factor for ASPD and that individuals with one or two low-activity 5-HTTLPR S’ alleles and a history of ACEs would show the highest rates of ASPD.

MATERIALS AND METHODS

Recruitment and Assessment Procedures

We recruited 1,381 subjects [602 European Americans (EAs) and 779 AAs] dependent on alcohol, cocaine, or opioids at four sites: 709 from Yale University (New Haven, CT), 518 from the University of Connecticut Health Center (Farmington, CT), 107 from McLean Hospital (Belmont, MA), and 47 from the Medical University of South Carolina (Charleston, SC).

The study was conducted in accordance with the Declaration of Helsinki, with review and approval of the study protocol and informed consent documents by the institutional review board at each of the participating institutions. Subjects provided written informed consent after receiving a complete description of the study and were paid for their participation. The study sample was selected from among subjects recruited to participate in family-based linkage or association studies of the genetics of substance dependence (Gelernter et al., 2007; Gelernter et al., 2005; Gelernter et al., 2006). The family-based sample was ascertained through two or more siblings affected with cocaine and/or opioid dependence. The association sample consisted of unrelated individuals with alcohol, cocaine, or opioid dependence. Once an individual was identified as eligible to participate in either a family-based linkage or an association study, all of his or her first-degree family members were invited to participate irrespective of whether they had a SUD diagnosis.

Subjects included 1,040 individuals (86.7%) with no other family members, 141 (11.8%) with 1 other member, 15 (1.3%) with 2 other members, 1 (0.1%) with 3 other members, and 2 (0.2%) with 4 other members. The study sample overlapped substantially with the sample reported on by us (Xie et al., 2009) in which the 5-HTTLPR polymorphism moderated the effects of adverse childhood events on risk for posttraumatic stress disorder (PTSD).

Genotyping

DNA was extracted from whole blood or immortalized cell lines. Polymerase chain reaction (PCR) amplification was used to differentiate the S allele from the L allele of the insertion-deletion polymorphism. PCR conditions are described in detail in Gelernter et al., (1997). To genotype the A/G SNP (rs25531) present at the sixth nucleotide of the first of two of the 22-bp repeat elements in the 16-repeat L allele (Hu et al., 2005), the PCR product was digested by MspI and size-fractionated on agarose gel (Stein et al., 2006). This differentiates the two subtypes of the 16-repeat variant into LA or LG. The S and LG (i.e., S’) alleles have a 2-fold lower level of gene expression than the A-allele variant (LA or L’) (Hu et al., 2006). Eight percent of genotypes for both polymorphisms were selected at random and repeated with no discrepancies.

To detect admixture, we genotyped a set of 38 ancestry-informative markers (AIMs) (Yang et al. 2005) to generate African ancestry proportions using the program STRUCTURE (Pritchard et al. 2000, Falush et al. 2003). We used the ancestry proportion scores to determine concordance (as measured using the κ statistic) of the predominant genetic ancestry (EA or AA) with self-reported population group. We also entered the African ancestry proportion as a covariate in the GEE regression models to exclude admixture effects.

Measures

All participants were evaluated using an electronic version of the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA), which provides information on demographics, diagnostic criteria for substance use and a variety of psychiatric disorders, as well as the childhood home environment. A detailed description of the SSADDA, its administration methods, and its reliability are provided elsewhere (Feinn et al., 2009; Pierucci-Lagha et al., 2005; Pierucci-Lagha et al., 2007). The test–retest and inter-rater reliability of ASPD diagnoses were κ=0.52 and κ=0.57, respectively.

Of specific relevance here, the SSADDA includes a 44-item assessment tailored to address the 7 DSM-IV diagnostic criteria for ASPD (aggression, impulsivity, lack of remorse, etc.) and questions about childhood behavior to determine the presence of CD. Subjects meeting three or more of the adult diagnostic criteria and full criteria for a diagnosis of CD were diagnosed with ASPD. Information on the childhood home environment included 3 items on ACEs: 1) violent crime exposure, which was defined by the response to the question: “Did you witness or experience a violent crime, like a shooting or a rape, by age 13?” 2) sexual abuse, which was defined by the response to the question: “By the time you were age 13, were you ever sexually abused?” 3) physical abuse was defined as being beaten by an adult so severely before age 13 that medical care was needed or marks on the body remained for more than 30 days. Based on the number of types of adverse event endorsed by each participant, we created the variable “ACE score,” which is a summary that ranges from 0–3. The test–retest and inter-rater reliability of the three items used in defining the ACE score ranged from κ=0.84-0.99 and κ=0.69-0.82, respectively. Some of the same items were utilized in our earlier report on PTSD (Xie et al., 2009).

Analysis

We used logistic regression models to examine the association of ASPD with 5-HTTLPR genotype, ACE score, and their interaction, after controlling for sex. For each population group, we started with a model that included sex, age, 5-HTTLPR genotype, and ACE score as main effects, the 3 2-way interactions of sex, 5-HTTLPR genotype and ACE score, and their three-way interaction. We used a hierarchical backward elimination procedure (with alpha = 0.05) to determine the most parsimonious model. Because age was not a significant covariate, it was removed from the analyses. Because genotype frequencies differed by population (see below), we examined AAs and EAs in separate models. To account for the dependence among family members, we applied generalized estimating equations (GEE) with an exchangeable correlation structure to fit the logistic regression models in SAS version 9.2. 5-HTTLPR was analyzed under an additive model, i.e., as a 3-level categorical predictor (0–2) based on the number of low-activity S’ alleles.

RESULTS

Sample Characteristics

Among the 1,381 participants, 203 (14.7%) met criteria for ASPD, which did not differ by population group (χ2 = 0.48, df = 1, p = 0.49) (Table 1). The frequency of ACEs in the study population is shown in Table 2; Table 3 shows the frequency of ACEs among individuals with ASPD. Although the population groups did not differ significantly on the number of types of ACEs (χ2 = 0.57, df = 1, p = 0.45), EAs were significantly less likely to have experienced violent crime, but more likely to have been abused, both sexually and physically. EAs were significantly more likely than AAs to be diagnosed with alcohol and opioid use disorders, but AAs were more likely to have a cocaine use disorder.

Table 1.

Descriptive Statistics by Population

Variable European-
American
N = 602 (43.6%)		 African-
American
N = 779 (56.4%)		 Test
Statistic2 		P-value
Sex 0.83 (df=1) 0.36
  Male 362 (60.1%) 452 (58.0%)
Age 19.58 (df=1) < 0.001
  Mean ± S.E.1 38.23 ± 0.45 40.96 ± 0.30
5-HTTLPR genotype 29.28 (df=5) < 0.001
  LA-LA
  (0 S’ allele)		 157 (26.1%) 219 (28.1%)
  LA-LG
  (1 S’ allele)		 42 (7.0%) 180 (23.1%)
  LA-S
  (1 S’ allele)		 256 (42.5%) 213 (27.3%)
  LG-LG
  (2 S’ allele)		 5 (0.8%) 43 (5.5%)
  LG-S
  (2 S’ allele)		 31 (5.2%) 77 (9.9%)
  S-S
  (2 S’ allele)		 111 (18.4%) 47 (6.0%)
5-HTTLPR allele frequency 1.71 (df=1) 0.19
  f(L’) 50.8% 53.3%
  f(S’) 49.2% 46.7%
ASPD 0.48 (df=1) 0.49
  Positive 93 (15.5%) 110 (14.1%)
ACEs
  Violent Crime 92 (15.3%) 214 (27.5%) 28.66 (df=1) < 0.001
  Sexual Abuse 117 (19.4%) 113 (14.5%) 5.82 (df=1) 0.016
  Physical Abuse 82 (13.6%) 73 (9.4%) 5.55 (df=1) 0.018
ACE score 0.57 (df=1) 0.45
  Mean ± S.E.1 0.48 ± 0.03 0.51 ± 0.03
Alcohol use disorder 8.86 (df=2) 0.012
  Dependence 431 (71.6%) 588 (75.6%)
  Abuse 100 (16.6%) 79 (10.2%)
Cocaine use disorder 15.31 (df=2) < 0.001
  Dependence 409 (67.9%) 620 (79.6%)
  Abuse 29 (4.8%) 11 (1.4%)
Opioid use disorder 85.30 (df=2) < 0.001
  Dependence 332 (55.2%) 183 (23.5%)
  Abuse 8 (1.3%) 11 (1.4%)
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1

S.E.: standard error

2

Type III GEE Wald χ2 test statistic

Table 2.

Number of Adverse Childhood Experiences Among All Participants

N (column %) European-American (N=602) African-American (N=779)
Number of ACEs Male (N=362) Female (N=240) Male (N=452) Female (N=327)
0 275 (76.0) 143 (59.6) 290 (64.2) 206 (63.0)
1 60 (15.6) 47 (19.6) 127 (28.1) 62 (19.0)
2 15 (4.1) 32 (13.3) 28 (6.2) 43 (13.2)
3 12 (3.3) 18 (7.5) 7 (1.6) 16 (4.9)
≥1 87 (24.0) 97 (40.4) 162 (35.8) 121 (37.0)
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Table 3.

Number of Adverse Childhood Experiences Among Participants with ASPD

N (column %) European-American (N=93) African-American (N=110)
Number of ACEs Male (N=73) Female (N=20) Male (N=79) Female (N=31)
0 49 (67.1) 8 (40.0) 31 (39.2) 13 (41.9)
1 13 (17.8) 4 (20.0) 37 (46.8) 10 (32.3)
2 7 (9.6) 7 (35.0) 9 (11.4) 4 (12.9)
3 4 (5.5) 1 (5.0) 2 (2.5) 4 (12.9)
≥1 24 (32.9) 12 (60.0) 48 (60.8) 18 (58.1)
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Table 4 presents the genotype frequencies by sex and ASPD diagnosis within each population group. Although there was a significant difference in genotype frequency by population group when considering the distribution of the 6 tri-allelic genotypes (χ2 = 29.28, df = 5, p < 0.001), the frequencies of S’ and L’ alleles did not differ significantly (χ2 = 1.71, df = 1, p = 0.19). All allele frequencies were consistent with Hardy-Weinberg equilibrium, irrespective of whether the bi-allelic or tri-allelic genotype data were considered (all p’s > 0.05).

Table 4.

5-HTTLPR Genotype and Allele Frequencies by Population, ASPD Diagnosis and Sex

European-American
(N = 602)		 African-American
(N = 779)
ASPD
N = 93 (15.5%)		 Non-ASPD
N = 509 (84.5%)		 ASPD
N = 110 (14.1%)		 Non-ASPD
N = 669 (85.9%)
Male
N = 73
(78.5%)		 Female
N = 20
(21.5%)		 Male
N = 289
(56.8%)		 Female
N = 220
(43.2%)		 Male
N = 79
(71.8%)		 Female
N = 31
(28.2%)		 Male
N = 373
(55.8%)		 Female
N = 296
(44.3%)
Genotype LA-LA 20
(27.4%)		 5
(25.0%)		 67
(23.2%)		 65
(29.5%)		 19
(24.1%)		 8
(25.8%)		 104
(27.9%)		 88
(29.7%)
LA-LG 7
(9.6%)		 2
(10.0%)		 18
(6.2%)		 15
(6.8%)		 19
(24.1%)		 6
(19.3%)		 93
(24.9%)		 62
(21.0%)
LA-S 26
(35.6%)		 7
(35.0%)		 130
(45.0%)		 93
(42.3%)		 23
(29.1%)		 10
(32.3%)		 100
(26.8%)		 80
(27.0%)
LG-LG 1
(1.4%)		 0
(0.0%)		 2
(0.7%)		 2
(0.9%)		 5
(6.3%)		 2
(6.5%)		 17
(4.6%)		 19
(6.4%)
LG-S 5
(6.8%)		 1
(5.0%)		 13
(4.5%)		 12
(5.5%)		 8
(10.1%)		 4
(12.9%)		 38
(10.2%)		 27
(9.1%)
S-S 14
(19.2%)		 5
(25.0%)		 59
(20.4%)		 33
(15.0%)		 5
(6.3%)		 1
(3.2%)		 21
(5.6%)		 20
(6.8%)
Allele f(L’) 50.0% 47.5% 48.8% 54.1% 50.6% 51.6% 53.7% 53.7%
f(S’) 50.0% 52.5% 51.2% 45.9% 49.4% 48.4% 46.3% 46.3%
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There was no association between the number of S’ alleles and the frequency of an ASPD diagnosis in either population group overall (EAs: χ2 = 0.99, df = 2, p = 0.61; AAs: χ2 = 0.82, df = 2, p = 0.66) or when analyzed by sex (EA males: χ2 = 0.93, df = 2, p = 0.63; EA females: χ2 = 1.76, df = 2, p = 0.42; AA males: χ2 = 0.54, df = 2, p = 0.76; AA females: χ2 = 0.18, df = 2, p = 0.92)

Adjusted Relationship Between Outcome and Risk Factors by Population Group

In EAs, logistic GEE regression analysis showed that only male sex and the number of types of ACEs were significantly associated with an ASPD diagnosis (Table 5). In AAs, the three-way interaction of sex × number of S’ alleles × ACE score was significantly associated with an ASPD diagnosis (Table 6). Decomposition of the interaction revealed that among AA men, each additional ACE significantly increased the odds of ASPD irrespective of the number of 5-HTTLPR S’ alleles. However, among AA women, the effect of ACE score on ASPD was significant only for those with 2 S’ alleles.

Table 5.

Logistic GEE Regression Analysis: European Americans

Initial Model Final Model
χ 2 df p-value p-value or
order of elimination
Sex 12.89 1 < 0.001 < 0.001
5-HTTLPR 1.12 2 0.57 − 5
ACE score 9.60 1 0.002 0.002
Sex × 5-HTTLPR 1.62 2 0.45 − 3
ACE score × 5-HTTLPR 2.23 2 0.33 − 4
ACE score × Sex 0.05 1 0.82 − 2
Sex × 5-HTTLPR × ACE score 1.40 2 0.50 − 1
Final Model ORs
OR 95% CI p-value
Sex (Male) 3.34 1.91 – 5.84 < 0.001
ACE score (+1) 1.47 1.15 – 1.87 0.002
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Table 6.

Logistic GEE Regression Analysis: African Americans

Initial (and Final) Model
χ 2 df p-value
Sex 7.60 1 0.006
5-HTTLPR 7.01 2 0.03
ACE score 33.97 1 < 0.001
Sex × 5-HTTLPR 5.58 2 0.06
ACE score × 5-HTTLPR 9.17 2 0.01
ACE score × Sex 0.04 1 0.85
Sex × 5-HTTLPR × ACE score 13.82 2 < 0.001
Final Model ORs
OR 95% CI p-value
ACE score (+1)
  Male 0 S’ allele 2.80 1.53 – 5.15 < 0.001
1 S’ allele 1.94 1.20 – 3.14 0.007
2 S’ alleles 1.75 1.03 – 2.98 0.04
  Female 0 S’ allele 1.36 0.67 – 2.76 0.39
1 S’ allele 0.98 0.57 – 1.70 0.95
2 S’ alleles 6.16 3.15 – 12.03 < 0.001
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Although the frequency of the S’ allele did not differ by sex either for EAs (men: 51.0%; women: 53.5%) or AAs (men: 46.8%; women: 46.5%), other features varied as a function either of the main or two-way interaction effects of genotype, sex, and population group. Men had a higher prevalence of ASPD (18.7% vs. 9.0%) and an alcohol use disorder (90.8% vs. 81.1%) than women. Women reported having experienced more ACEs (mean ± SE = 0.64 ± 0.04 vs. 0.41 ± 0.02), particularly sexual abuse (27.9% vs. 8.9%), than men. EA men were more likely than EA women to have experienced or witnessed a violent crime (11.9% vs. 8.1%), but both were less likely to report such an experience than both AA men (29.2%) and AA women (25.1%). The lifetime prevalence of opioid use disorder was higher among AA men than AA women (28.5% vs. 19.9%), but AAs had lower prevalence rates of this disorder than either EA men (54.6%) or women (59.6%).

Admixture as a Potential Confound

Ancestry proportions calculated for all participants showed a high degree of concordance with self-reported population group. Specifically, 595 (98.8%) of the 602 self-reported EAs had an African ancestry proportion < 0.5 and 775 (99.5%) of the 779 self-reported AAs had an African ancestry proportion > 0.5. The concordance rate (κ) for this cross-tabulation was 0.98 (95% confidence interval = 0.97-0.99). Further, the addition of African ancestry proportion as a covariate in the GEE logistic regression model was not significant, so it was removed from the equations.

DISCUSSION

This study examined genetic and environmental risk factors for the development of ASPD in a sample of substance-dependent individuals, among whom the prevalence of ASPD far exceeded that in the general population (Compton et al. 2005; Kessler et al., 1994; Robins et al., 1984). Consistent with epidemiological studies, ASPD was much more prevalent among men than women (Compton et al. 2005; Kessler et al., 1994; Robins et al., 1984). As hypothesized, we found a significant main effect of ACEs on risk of ASPD, consistent with a substantial literature showing that adverse experiences in childhood are predictive of subsequent antisocial behavior. We also found that AA women homozygous for the low-activity S’ 5-HTTLPR allele were significantly more likely than any of the other subgroups to manifest ASPD in the context of having experienced ACEs. This finding partially supports the hypothesis that the 5-HTTLPR polymorphism contributes to risk for the development of ASPD, but only among a small number of AA women with the S’S’ genotype (n = 73), including only 7 AA women diagnosed with ASPD. Although analysis of other potential predictors provided no evidence that they confounded the moderating effect of genotype, this finding requires replication in a larger sample.

Among AA individuals, recent research examining 5-HTTLPR genotype and antisocial behavior has produced mixed results. A recent study (Beaver et al. 2010) evaluated approximately 150 AA males for several “high-risk” polymorphisms (including 5-HTTLPR) and also assessed parental involvement and attachment in childhood. Although there were no main effects of genetic and environmental variables, the interaction of genotype with early rearing experiences significantly predicted some of the variation in the risk of antisocial behavior. A family study of 641 AA adolescents followed for 29 months showed that one or two copies of the low-activity 5-HTTLPR allele significant predicted risk behavior (i.e., the ingestion of alcoholic beverages and marijuana and participation in sexual intercourse) (Brody et al., 2009). Interestingly, this study also showed that participation in a family intervention program attenuated the genetic risk.

In contrast, a regression analysis of data from 1,736 Caucasian adolescents showed no significant relationship between the low-activity 5-HTTLPR genotype and categorical or continuous measures of conduct problems, controlling for sex, age, and family effects (Sakai et al., 2007). Further, in this study, there was no interaction effect of genotype and self-reported childhood maltreatment on the risk of conduct problems.

Mixed results have also been reported for 5-HTTLPR genotype and early childhood experiences with regard to other negative health outcomes, including substance use (Laucht et al., 2009; Gerra et al., 2007). For example, Laucht et al. (2009) found that an interaction of the high-activity, LL genotype with early psychosocial adversity predicted more hazardous drinking in adulthood, an effect that was limited to males. A study of cocaine users (Gerra et al., 2007) showed that the frequency of the SS genotype was significantly higher among drug users than controls and the risk that an SS individual would become a cocaine user was nearly three times that of individuals with the LL genotype. Greater scores on the parental care measure rendered the relationship between genotype and cocaine use non-significant, consistent with a mediating effect of parenting on this relationship (Gerra et al., 2007).

We focused our analysis on DSM-IV ASPD rather than the association of 5-HTTLPR with adult antisocial behavioral syndrome (AABS; (Goldstein et al., 1998)). AABS has been proposed as a diagnosis for individuals who meet full adult criteria for antisocial behavior without a history of CD. Its estimated lifetime prevalence in the United States is 12.3% (Compton et al., 2005). Although several studies suggest that AABS and ASPD are essentially the same disorder (Black and Braun, 1998; Goldstein et al., 2007a; Goldstein et al., 2007b; Goldstein et al., 1998; Langbehn and Cadoret, 2001), initial analyses (data not shown) showed that AABS subjects in our sample more closely resembled subjects without ASPD, differing significantly from the ASPD group on many relevant variables. Consequently, we chose to group the AABS subjects with the non-ASPD subjects.

The present study was limited by several factors. First, because of the small number of AA women who were S’ homozygotes, the observed association has to be viewed as tentative. Similarly, the failure to observe some other effects may have resulted from inadequate statistical power, particularly among women. Second, because the sample was comprised of drug-dependent individuals, it is not representative of the general population. Third, we collected ACE data using the SSADDA, rather than a more widely used assessment in childhood abuse research, such as the Childhood Trauma Questionnaire (Bernstein et al., 1994) or the Early Trauma Inventory (Bremner et al., 2000). Lastly, we obtained diagnostic and ACE data via retrospective recall by subjects, potentially introducing errors and biases in reporting. A study of the validity of retrospective reporting for childhood sexual abuse, which used medical records as a criterion measure, showed a response bias toward underreporting (Edwards et al., 2001). Therefore, although it is likely that we underestimated the incidence of ACEs in our sample, there is no reason to suspect that this bias would differ by genotype and skew our results. It could, however, have reduced statistical power and obscured effects that might exist in the data.

Other serotonin-related genes have been studied in relation to risk of ASPD. Variation in MAOA, the gene encoding the enzyme monoamine oxidase A (which, among other activities, metabolizes serotonin to 5-HIAA), and its interaction with childhood abuse, has been the focus of a number of studies of antisocial behavior (Caspi et al., 2002; Ducci et al., 2008; Foley et al., 2004; Haberstick et al., 2005; Huizinga et al., 2006; Kim-Cohen et al., 2006; Widom and Brzustowicz, 2006). A meta-analysis of this research supports a modest interaction effect, with individuals possessing the high-risk MAOA genotype and having experienced childhood maltreatment showing a greater risk for ASPD than those with either condition alone (Taylor and Kim-Cohen, 2007).

Other biological risk factors (e.g., cortical underarousal, neuropsychological deficits) have also been implicated in the development of ASPD (Brennan and Raine, 1997; Moffitt, 1990; Raine and Venables, 1981). It is possible that such measures mediate the effects of genetic variation in ASPD risk and the use of mediational models that include genetic information could contribute to a fuller understanding of the etiology and development of the disorder. For example, a recent study of 69 newborn-caregiver pairs showed that infants homozygous for the S’ allele expressed greater emotionality and fear in response to the “strange situation” test of attachment. Because the effect was seen as early as 12 months of age, there appears to be an early effect of genotype on complex emotional behaviors (Pauli-Potts et al., 2009). Other genetic and environmental factors that could differ by sex and population group to influence the expression of ASPD in the context of ACEs are important topics for subsequent study.

ACKNOWLEDGMENTS

Supported by NIH grants DA12690, DA12849, DA18432, AA03510, AA11330, AA13736, and AA017435. The authors thank the interviewers and laboratory personnel who conducted the study, and the study participants at all of the participating sites. Kathleen Brady, M.D., Ph.D. of the Medical University of South Carolina and Roger Weiss, M.D. of McLean Hospital and Harvard Medical School oversaw study recruitment at their respective sites.

Footnotes

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