Dissocial behavior the 5HTTLPR polymorphism and maltreatment in women with bulimic syndromes.код для вставкиСкачать
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: firstname.lastname@example.org 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. 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