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Dissocial behavior the 5HTTLPR polymorphism and maltreatment in women with bulimic syndromes.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:128 –130 (2008)
Brief Research Communication
Dissocial Behavior, the 5HTTLPR Polymorphism,
and Maltreatment in Women With Bulimic Syndromes
Howard Steiger,1,2,3* Jodie Richardson,1,3,4 Ridha Joober,2,3 Mimi Israel,1,2,3 Kenneth R. Bruce,1,2,3
N.M.K. Ng Ying Kin,2,3 Heidi Howard,2,3 Annelie Anestin,1 Cathy Dandurand,1 and Lise Gauvin3,5
1
Eating Disorders Program, Douglas Institute, Montreal, Quebec, Canada
Psychiatry Department, McGill University, Montreal, Quebec, Canada
3
Research Centre, Douglas Institute, Montreal, Quebec, Canada
4
Psychology Department, McGill University, Montreal, Quebec, Canada
5
Department of Social and Preventive Medicine and Groupe de Recherche Interdisciplinaire en Sante´ (GRIS), University of Montreal,
Montreal, Quebec, Canada
2
We recently reported that, among bulimic women,
previously abused carriers of the 5HTTLPR S
allele showed special propensities towards novelty seeking (implying recklessness or impulsivity)
and interpersonal insecurity. We subsequently
re-analyzed our data, to examine the bearing of
the 5HTTLPR polymorphism and prior sexual or
physical maltreatment upon validated, higherorder personality-traits. Ninety women with bulimic syndromes were genotyped for 5HTTLPR
‘‘short’’ (S) and ‘‘long’’ (LG and LA) alleles, and then
assessed for eating symptoms, history of sexual or
physical abuse, and the higher-order personality
traits Emotional Dysregulation, Dissocial Behavior, Inhibition, and Compulsivity. With a classification based on a biallelic model of 5HTTLPR
(i.e., presence or absence of at least one S-allele
copy), multiple regression indicated a significant
proportion of variance in Dissocial Behavior to
be explained by an abuse genotype interaction—
greater psychopathology occurring in abused
S-allele carriers. A parallel analysis applying
a triallelic model of 5HTTLPR (i.e., presence
or absence of at least one copy of presumably
low-function S or LG alleles) produced a similar
pattern, but no statistically significant effect
The finding that bulimic 5HTTLPR S-allele
carriers who are previously abused display elevations on Dissocial Behavior corroborates previous
observations concerning phenomenological correlates of traumatic stress in 5HTTLPR S allele
carriers.
ß 2007 Wiley-Liss, Inc.
KEY WORDS: bulimia nervosa; personality;
genes; serotonin; abuse
Grant sponsor: Quebec Government’s Joint CQRS-FRSQ-MSSS
Program in Mental Health; Grant number: SR-4306; Grant
sponsor: Canadian Institutes for Health Research; Grant number:
MOP-57929.
*Correspondence to: Howard Steiger, Ph.D., Eating Disorders
Program, Douglas Institute, 6875 LaSalle Blvd., Montreal
(Verdun) Quebec, Canada H4H 1R3.
E-mail: stehow@douglas.mcgill.ca
Received 9 April 2007; Accepted 4 June 2007
DOI 10.1002/ajmg.b.30579
ß 2007 Wiley-Liss, Inc.
Please cite this article as follows: Steiger H, Richardson
J, Joober R, Israel M, Bruce KR, Ng Ying Kin NMK,
Howard H, Anestin A, Dandurand C, Gauvin L. 2008.
Dissocial Behavior, the 5HTTLPR Polymorphism,
and Maltreatment in Women With Bulimic Syndromes.
Am J Med Genet Part B 147B:128–130.
Individuals with syndromes in the spectrum of bulimia
nervosa (BN) display heterogeneous psychopathological traits,
with descriptors applied to different subgroups ranging from
‘‘dysregulated (impulsive)’’ to ‘‘over-regulated (compulsive)’’ to
‘‘psychologically intact’’ [Westen and Harnden-Fischer, 2001;
Wonderlich et al., 2005]. Various factors have been thought
to account for sub-phenotypic variations. Among these, the
‘‘dysregulated’’ characteristic has been thought to implicate
greater exposure to childhood abuse [Westen and HarndenFischer, 2001; Steiger, 2004] and more pronounced deficits
in central serotonin (5-hydroxytryptamine, 5-HT) functioning
[Steiger, 2004; Steiger et al., 2005]. In keeping with such
trends, two studies in bulimic women have linked the
low-function (S) allele of the serotonin transporter promoter
polymorphism, 5HTTLPR, with increased proneness to affective instability, harm avoidance, or borderline traits [Steiger
et al., 2005; Monteleone et al., 2006]. Furthermore, suggesting
the possibility of an interaction between traumatic stress
and genetic vulnerability, a recent study by our group found
previously abused bulimic women with the 5HTTLPR S allele
to show elevations on measures of Sensation Seeking (implying
recklessness or impulsivity) and Insecure Attachment [Steiger
et al., in press]. Although our results had precedents in the
form of earlier findings associating variations in 5HTTLPR
and life stress to increased depression in general-population
cohorts [Caspi et al., 2003; Zalsman et al., 2006], we remained
concerned about the possibility of spurious results, related to
the sheer number of personality-trait dimensions we had
examined. We therefore re-analyzed our data, this time
using empirically validated ‘‘higher-order’’ personality factors
[Livesley et al., 1998; Bagge and Trull, 2003] that permitted the
aggregation of specific trait dimensions into a small number of
higher-order factors.
The 5HTTLPR polymorphism has been traditionally
conceptualized as ‘‘biallelic’’—long (L) and short (S) allele
variants thought to correspond to relatively high or low
production of 5-HT transporter protein [Lesch et al., 1996].
However, some recent data suggest the existence of a lowfrequency LG-allele variant (with A ! G SNP in its sequence)
whose functioning may be akin to that of the S allele [Hu et al.,
2006; Zalsman et al., 2006]. In other words, 5HTTLPR may be
5HTTLPR, Maltreatment, and Dissocial Behavior
‘‘triallelic.’’ As the functional significance of the variations
described yet needs to be ascertained, we tested models
consistent with biallelic and triallelic formulations.
Participating women were recruited through a specialized
Eating Disorders (ED) program using the criteria: Body
Mass Index (BMI) of 17.5–30, meeting criteria for a ‘‘bulimiaspectrum’’ ED in DSM-IV [American Psychiatric Association,
1994], but not Binge Eating Disorder, and not anorexic. After
exclusions, we completed assays in 90 women, 69 (76.7%)
of whom met DSM-IV criteria for BN-Purging subtype, 4 (4.4%)
for BN-Nonpurging subtype, and 17 (18.9%) a bulimiaspectrum Eating Disorder Not Otherwise Specified (because
they binged or purged at less than the requisite twice weekly).
Mean age and BMI (kg/m2) in the sample were 25.29 (6.40)
and 22.39 (2.67), respectively. Limiting recruitment to
unmedicated patients was impractical (and undesirable on
grounds of representativeness), and we therefore included
24 women (26.7% of the sample) who were on a psychoactive
medication. Statistical procedures controlled for potential
confounding effects of medications.
We assessed eating-disorder diagnoses and symptoms
using the Eating Disorders Examination [EDE; Fairburn and
Cooper, 1993], and applied the Dimensional Assessment of
Personality Pathology-Basic Questionnaire [DAPP-BQ; Livesley et al., 1992] to obtain the validated, higher-order personality factors, Emotional Dysregulation, Dissocial Behavior,
Inhibition, and Compulsivity [Livesley et al., 1998; Bagge and
Trull, 2003]. We also used the Childhood Trauma Interview
[CTI; Fink et al., 1995] to isolate experiences of physical or
sexual maltreatment occurring at or before age 18. Sexual
abuse was defined as ‘‘sexualized experiences involving
repeated sexual contacts occurring at least three times within
1 year, or more extreme experiences (e.g., oral sex or penetration), happening at least once. Physical abuse was defined as
‘‘experiences of blatant hitting, occurring at least three times
within 1 year, or at least one instance of extreme physical
abuse, implicating such acts as indiscriminate hitting with an
object’’. Procedures for genotyping DNA, obtained from whole
blood are conventional ones, fully described by Steiger et al.
[2005; in press].
Given evidence for the dominance of low-function alleles
[Lesch et al., 1996; Zalsman et al., 2006], and preliminary
tests consistent with such trends, our main statistical
analyses applied dichotomous ‘‘high-function’’ versus ‘‘lowfunction’’ classifications for the genotype (G) variable, according to both biallelic (S/S or S/L vs. L/L) and triallelic (S/S, S/LG,
S/LA, LG/LA or LG/LG vs. LA/LA) conceptualizations. To explore
effects of genotype (G) and abuse (A: present/absent) on trait
dimensions, while accounting for possible effects of medications (M: medicated or unmedicated), we applied hierarchical
multiple regressions on each variable of interest. Each
regression successively tested the G main effect (Step 1), the
A main effect (Step 2), the G A interaction (Step 3), and then
controlled for the M main effect (Step 4).
Treating 5HTTLPR in a biallelic fashion, frequencies of S/S,
S/L, and L/L genotypes, respectively, occurring in 18 (20.0%),
41 (45.6%), and 31 (34.4%) of our participants, were in
conformity with Hardy–Weinberg equilibrium (X2 (1) ¼ 0.43,
n.s.). With a triallelic model, we observed S/S, S/LG, S/LA, LG/
LA, LG/LG, and LA/LA genotypes, respectively, to occur in
18 (20.0%), 8 (8.9%), 33 (36.7%), 8 (8.9%), 2 (2.2%), and
21 (23.3%) of our participants. Frequencies of individuals who
were carriers of two, one or no ‘‘low-function’’ (i.e., S or LG)
alleles were also in conformity with Hardy–Weinberg equilibrium (X2 (1) ¼ 0.62, n.s.). When crossed with the abuse factor,
the biallelic model led to the groups: not abused, no-S allele
(n ¼ 18); not abused, S-allele (n ¼ 36); abused, no S allele
(n ¼ 13); and abused, S allele (n ¼ 23). The triallelic model led to
the groups: not abused, no S or LG (n ¼ 12); not abused, S or LG
129
(n ¼ 42); abused, no S or LG (n ¼ 9); and abused, S or LG (n ¼ 27).
These groups did not differ as to mean age or BMI, according to
one-way ANOVAs. Results on eating symptoms owing to main
and interaction effects of G, A, and M factors are provided in a
previous report [Steiger et al., in press], and are therefore not
presented in detail here. We note, however, that no main or
interaction effects were obtained, whether with biallelic or
triallelic G models.
On trait measures, G, A, or G A effects were also generally
absent. However, using a biallelic (S vs. no-S) classification, a
significant G A effect was obtained on Dissocial Behavior.
The G A interaction yielded a significant 4.4% increment
in variance accounted for (Fchange (1,86) ¼ 4.27, P < 0.05), and
resulted in a significant regression equation at that step
(F(3,86) ¼ 3.44, P < 0.03). The nonstandardized coefficient
associated with the G A effect was 0.51 (SE ¼ 0.25,
P < 0.05). Total variance explained by G, A, and G A effects
was 10.7%. Results indicated pathological elevations in
abused, S-allele carriers, as illustrated by mean Dissocial
Behavior scores: not abused, no-S allele ¼ 2.41 (0.49); not
abused, S-allele ¼ 2.29 (0.53); abused, no S allele ¼ 2.36
(0.75); and abused, S allele ¼ 2.75 (0.48). The analysis
described also confirmed independence of effects from those
attributable to psychoactive medications (M). Although results
obtained with a ‘‘triallelic’’ G classification had a similar
form—not abused, no-S allele ¼ 2.34 (0.52); not abused,
S-allele ¼ 2.33 (0.52); abused, no S allele ¼ 2.58 (0.81); and
abused, S allele ¼ 2.62 (0.55)—no G, A, or G A effects or
trends were obtained. Finally, a significant M effect showed
patients who were more symptomatic of Emotional Dysregulation to be (predictably) more likely to be medicated (nonstandardized coefficient ¼ 0.42; SE ¼ 0.16, P (biallelic) < 0.01;
P (triallelic) < 0.05).
What processes might explain increased Dissocial Behavior
in abused, S-allele carriers? Dissocial Behavior aggregates
DAPP-BQ subscales measuring Stimulus Seeking, Conduct
Problems, Rejection, and Callousness, and hence implies the
convergence of such traits as recklessness, impulsivity,
hostility and oppositionality. The idea that such tendencies
coincide with altered serotonin activity and prior abuse has
several precedents: findings have linked serotonergic anomalies (especially those consistent with reduced 5-HT transporter
function) with increased expressions of an impulsive or hostile
type [Coccaro et al., 1996; Steiger, 2004; Steiger et al., 2005, in
press]. Furthermore, studies in various populations associate
the 5HTTLPR S allele with proneness towards reckless or
antisocial behavior [e.g., Sander et al., 1998; Anguelova et al.,
2003; Liao et al., 2004]. As for gene–environment interaction
effects implicating prior trauma, it has been noted that adult
males who were abused during childhood, and who carry a
polymorphism influencing monoamine oxidase A activity
(as would indirectly impact serotonin activity) show greater
antisocial behavior [Caspi et al., 2002]. Finally, it has been
observed (in bulimic and nonbulimic women) that prior abuse
is associated with more pronounced serotonergic anomalies
[Steiger, 2004].
Based on such evidence, we specifically postulated that
‘‘dysregulated’’ variants of BN may often involve amplification,
due to developmental stressors, of latent genetic (5-HT
mediated) propensities towards a behaviorally, interpersonally, and affectively unstable phenotype [Steiger, 2004;
Steiger et al., in press]—that is, trauma sequelae might
increase latent propensities towards behavioral dysregulation
associated with the 5HTTLPR S allele [Lesch et al., 1996;
Anguelova et al., 2003]. Although the preceding is viable, it
remains possible that interaction effects like those observed
here [and by Reference Steiger et al., in press] actually reflect
the opposite direction of causality—the S allele actually
increasing risk of abuse—through such possible correlates as
130
Steiger et al.
heightened ‘‘dissocial’’ tendencies (in potentially abusive,
genetically disposed parents), or heightened precociousness
or risk taking (in genetically disposed children). Such effects,
too, could account for an observed interaction between a
genetic propensity (associated with 5HTTLPR) and exposure
to abuse.
Although the size of the gene–environment interaction
effect obtained in this study asks for restraint, lest the
importance of the results be overstated, interactions of the
type we observe in this study, if replicable, would have various
clinical and theoretical potentials: such findings corroborate
the existing view that subphenotypic variations occurring
within [Westen and Harnden-Fischer, 2001; Steiger, 2004] and
beyond [Caspi et al., 2002, 2003] the bulimic population imply
different underlying genetic and developmental substrates.
Furthermore, while the gene–environment effect we observe
here is not large, neither is it negligible—and this raises
the hope that it may eventually become possible to cogently
apply genetic and environmental data so as to better understand potentially important heterogeneities occurring within
broadly defined phenotypes (such as ‘‘bulimia nervosa’’). In
addition, attention to gene–environment interactions may be
important if we are to explain inconsistencies in the available
literature on candidate-gene effects in BN. In this literature,
with only rare exceptions, environmental influences upon gene
expression are ignored.
We add a final note on the point that, as do the results
of previous studies in other populations [Lesch et al., 1996;
Anguelova et al., 2003; Caspi et al., 2003] our findings localize
phenotypic differences to differences between S and no-S
variants of 5HTTLPR genotypes. Despite recent findings
suggesting that clinically relevant differences occur between
carriers of a presumably high-function 5HTTLPR LA allele and
of low-function S and LG alleles [Zalsman et al., 2006], G or
G A effects studied here were nonsignificant when patients
were classified according to a triallelic (S and LG vs. LA) model.
We assume that discrepant results obtained using biallelic or
triallelic models may be simple artefacts of limited statistical
power, related to our sample size. If so, then the actual
functional and clinical significances of 5HTTLPR alleles, and
the relative merits of biallelic or triallelic models, will need
further study.
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ACKNOWLEDGMENTS
This research was supported by grant no. SR-4306, awarded
to Drs. Steiger and Joober by the Quebec Government’s Joint
CQRS-FRSQ-MSSS Program in Mental Health, and by grant
no. MOP-57929, awarded to Dr. Steiger by the Canadian
Institutes for Health Research. Preliminary results from this
study were presented at the annual meeting of the Academy for
Eating Disorders, Baltimore MD, May 2, 2007.
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