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Journal of Psychiatric Research 43 (2009) 1086–1094 Contents lists available at ScienceDirect j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / j p s y c h i r e s Association of trait-defined, eating-disorder sub-phenotypes with(biallelic and triallelic) 5HTTLPR variations Howard Steiger *, Jodie Richardson, Norbert Schmitz, Ridha Joober, Mimi Israel, Kenneth R. Bruce,Lise Gauvin, Cathy Dandurand, Annelie Anestin Eating Disorders Program, Douglas University Institute in Mental Health, 6875 LaSalle Blvd., Montreal (Verdun), Quebec, Canada H4H 1R3 Context: Efforts to classify eating-disordered individuals based on concurrent personality traits have consistently converged on a typology encompassing ‘‘over-regulated”, ‘‘dysregulated”, and ‘‘low psychopathology” subgroups. In various populations, evidence has associated personality variations of an ‘‘over-regulated/dysregulated” type with differences on serotonin-system indices, and specifically,with different loadings of serotonin transporter promoter regulatory region polymorphism (5HTTLPR)genotypes and alleles. We explored the extent to which an empirical, trait-defined typology of eating- disordered individuals coincided systematically with variations in 5HTTLPR, assayed using biallelic and Method: We tested 185 women with a DSM-IV eating disorder (108 with Bulimia Nervosa, 17 Anorexia Nervosa, and 60 an Eating Disorder Not Otherwise Specified) and 93 with no eating disorder on measures reflecting psychopathological traits and 5HTTLPR (biallelic and triallelic) genotypes and alleles.
Results: The highest-function, triallelic (LA/LA) genotype occurred significantly more frequently amongeating-disordered individuals than among controls. However, a more fine-grained analysis suggested thatthis association was attributable to the fact that, among eating-disordered participants, those displayingan ‘‘Inhibited/Compulsive” profile (derived using latent class analysis) were more likely than those of a‘‘Dissocial/Impulsive” or a ‘‘Low Psychopathology” group to carry the triallelic 5HTTLPR gain-of-functionLA allele and to be LA/LA homozygotes.
Discussion: This study’s empirically derived classes coincide with interpretable differences on geneticindices—associating an ‘‘Inhibited/Compulsive” group with 5HTTLPR gain-of-function genotypes (andalleles) that have elsewhere been linked to trait compulsivity. The findings, furthermore, suggest that5HTTLPR, by influencing personality-trait manifestations may, in turn, influence eating-disorder riskand symptom expression.
Ó 2009 Elsevier Ltd. All rights reserved.
lated subgroup. In eating- and non-eating-disordered populationsalike, traits of a ‘‘compulsive” or ‘‘impulsive” type have been asso- Evidence implies that concurrent psychopathological traits ciated with definable variations in serotonin (5-hydroxytrypta- demarcate clinically relevant sub-phenotypes within the eating- mine: 5-HT) system function (Cloninger et al., 1993; Hollander, disordered population. For example, factor- or cluster-analytic 1998; Steiger and Bruce, 2007; Steiger, 2004).
studies in the area yield consistent support for the occurrence ofcompulsive (‘‘over-regulated”), impulsive (‘‘dysregulated”), and 1.1. Psychopathological correlates of 5-HT ‘‘psychologically intact” eating-disorder (ED) subgroups (e.g., Wes-ten and Harnden-Fischer, 2001; Steiger and Bruce, 2007; Wonder- The 5-HT system regulates mood, social behavior, impulsivity lich et al., 2005). Anorexic ED variants (especially those of the and eating behavior (Steiger, 2004)—creating an obvious rationale ‘‘restricter” variety) tend to occur preferentially within the over- for the hypothesis that 5-HT has a role in ED pathogenesis. In sup- regulated subgroup, whereas bulimic variants, although heteroge- port, studies in eating-disordered individuals document disorder- neously distributed, tend to occur preferentially in the dysregu- relevant alterations in 5-HT metabolism, receptor sensitivity andtransporter activity (Steiger, 2004; Frank and Kaye, 2005). Usingsingle photon emission computer tomography, studies have shown * Corresponding author. Tel.: +1 514 761 6131x2895; fax: +1 514 888 4085.
E-mail address: stehow@douglas.mcgill.ca (H. Steiger).
reduced central 5-HT transporter availability in women with BN 0022-3956/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jpsychires.2009.03.009 H. Steiger et al. / Journal of Psychiatric Research 43 (2009) 1086–1094 (Tauscher et al., 2001). Likewise, using platelet measures, studies have suggested altered peripheral 5-HT reuptake in active anorex-ics and bulimics (Bruce et al., 2006; Steiger et al., 2005a), in binge– Our first goal was to develop an empirical classification of eat- purge free former bulimics (Steiger et al., 2005) and even in ED pa- ing-disordered individuals based on assessment of variations along tients’ unaffected relatives (Steiger et al., 2006). All of the preced- theoretically indicated, comorbid psychopathological traits. Fol- ing implicate altered 5-HT transporter kinetics in ED pathogenesis.
lowing from previous studies (e.g., Westen and Harnden-Fischer, Consistent with this notion, some candidate-gene studies associate 2001; Wonderlich et al., 2005), we anticipated finding ‘‘over-regu- low-function alleles of the 5-HT transporter promoter polymor- lated” (compulsive), ‘‘dysregulated” (impulsive) and ‘‘low psycho- phism (5HTTLPR)—called ‘‘low function” because they are associ- ated with lower levels of transcription of the transporter protein examine associations between empirically-derived sub-pheno- – with the EDs (Di Bella et al., 2000; Matsushita et al., 2004). Asso- types and 5HTTLPR variants. The available literature led us to ciation findings are, however, inconsistent (cf., Monteleone et al., anticipate that the ‘‘compulsive” subgroup might show stronger loadings of ‘‘high-function” (LA in the triallelic model, or L in the One basis for inconsistent association may be that 5HTTLPR, biallelic model) 5HTTLPR alleles than would other eating-disor- rather than conveying direct risk for ED development, influences dered or normal-eater groups, whereas the ‘‘impulsive” subgroup the expression of behavioral traits that indirectly impact suscepti- might show stronger loadings of the ‘‘low-function” (LG and/or S) bility to an ED. In non-eating disordered populations, data have supported the idea that traits of compulsivity and impulsivitymay have different rates of coincidence with 5HTTLPR low- andhigh-function alleles and genotypes. The low-function alleles have been associated with impulsivity (Lesch et al., 1996), novelty seek-ing (Sander et al., 1998), affective instability and suicidality (Ang- ‘‘dysregulation”—whereas the high-function alleles have been All participants in this institutional ethics-board approved linked to obsessive–compulsive disorder (OCD: Hu et al., 2006; study differed from those assessed by Wonderlich et al. (2005).
Baca-Garcia et al., 2005; Bengel et al., 1999) or ‘‘hyperfrontality” All gave informed consent. Eating-disordered participants were re- (Heinz et al., 2005)—both, arguably, associated with cortical cruited through a specialized Eating Disorders (ED) program in ‘‘over-regulation”. Suggesting that the same tendency may exist Montreal, Quebec, Canada. Given that diagnostic heterogeneity in an eating-disordered population, recent studies have shown that suited our interest in the spectrum of traits found in a broad, eat- bulimic individuals who carry low-function 5HTTLPR alleles are ing-disordered population, we included individuals with the DSM- more likely to display traits of affective instability, impulsivity IV ED diagnoses Anorexia Nervosa (AN), Bulimia Nervosa (BN) and (Steiger et al., 2005b), sensation seeking (Steiger et al., 2007), or Eating-Disorder Not Otherwise Specified (EDNOS). Our eating-dis- harm avoidance (Monteleone et al., 2006).
ordered sample consisted of 185 women, 99 (53.5%) meeting DSM- Despite the preceding, a recent study implicating 178 bulimic IV criteria for BN-Purging (BN-P) subtype, 9 (4.9%) for BN-Nonpur- women found no association between 5HTTLPR variations and la- ging (BN-NP) subtype, 9 (4.9%) for AN Restricting (AN-R) subtype, 8 tent profile analysis-derived personality clusters characterized as (4.3%) for AN binge-eating/purging (AN-BP) subtype, 47 (25.4%) for ‘‘low psychopathology”, ‘‘affective perfectionistic” and ‘‘impulsive” a bulimia-spectrum EDNOS (EDNOS-BN), and 13 (7.0%) for an anor- (Wonderlich et al., 2005). We felt a replication to be warranted, exia-spectrum EDNOS (EDNOS-AN/R or EDNOS-AN/BP). EDNOS partly in view of findings (noted earlier) showing positive associa- disorders were defined as follows: subjects (n = 47) with BMI of tion between 5HTTLPR variants and personality traits, partly be- 18 or more who binged or purged, but at less than the requisite cause the study’s sample included a disproportionate number of twice weekly (on average over the past 3 months), were regarded low-function allele carriers, and partly because the study relied as having a BN-spectrum EDNOS (EDNOS-BN); individuals (n = 7) upon a potentially imprecise ‘‘biallelic” conceptualization of who had lower body weight, and engaged in regular bingeing and/or purging, but either failed to meet AN criteria due to weightabove BMI of 17.5 or presence of menses were classified as having an AN Binge/Purge spectrum EDNOS (EDNOS-AN/BP); individuals(n = 6) who engaged in restriction and/or excessive exercise with- The 5HTTLPR polymorphism has (for many years) been con- out binging or purging, but who failed to meet AN criteria due to ceptualized as being biallelic, with long (L) and short (S) allele weight above BMI of 17.5 or presence of menses were classified variants thought, respectively, to correspond to relatively high as having an AN Restricting spectrum EDNOS (EDNOS-AN/R).
or low production of 5-HT transporter protein (Lesch et al., When interested in comparing anorexic versus bulimic disorders, 1996). However, recent data support the existence of a low-fre- we compared AN/R, AN/BP, EDNOS-AN/R and EDNOS-AN/BP quency L-allele variant, LG (an L allele with A ? G SNP in its groups to BN and EDNOS/BN groups. When interested in compar- sequence) whose functioning seems to be akin to that of the S ing ‘‘restricters” to ‘‘bingers/purgers”, we compared AN/R and ED- allele (Hu et al., 2006; Zalsman et al., 2006). Such data imply NOS-AN/R to BN, EDNOS/BN, AN/BP and EDNOS-AN/BP groups. A that 5HTTLPR may need to be conceptualized as being triallelic, major part of the sampling for this study was conducted through with S and LG alleles being comparable ‘‘low-function” variants, a project concerned with bulimia-spectrum disorders (to which and an LA allele conferring gain-of function. Recent findings consecutive, consenting patients with such eating syndromes were have, furthermore, associated the triallelic gain-of-function allele recruited), with patients with Anorexia Nervosa added in an ad hoc with obsessive–compulsive disorder (OCD), showing the LA/LA way. Therefore, proportions of cases with different diagnoses genotype and the overall frequency of the LA allele to be achieve a desired degree of heterogeneity as to ED diagnoses, but substantially increased in individuals with OCD (Hu et al., do not reflect actual patterns of referral to our program.
2006). Given an existent literature based on a biallelic 5HTTLPR We also recruited 93 normal-eater control women, drawn from assay, and new evidence that the polymorphism may be triall- an age group comparable to that of our ED sample, and with elic, we opted to examine effects of biallelic and triallelic recruitment through public media and school-based announce- ments, so as to produce a group that included comparable propor- H. Steiger et al. / Journal of Psychiatric Research 43 (2009) 1086–1094 tions of student and non-student participants to those found in our into four higher-order personality dimensions, based upon previ- ED sample. To be eligible for the normal-eater group, participants ously established factor analyses conducted on data from large had to be free of clinical ED symptoms according to the EDE, of a general, personality-disordered and twin samples (Livesley et al., history of ED according to initial screening, and to have BMI be- 1992; Bagge and Trull, 2003). The studies in question support the tween 18 and 34. So as not to skew the sample towards super-nor- validity of the higher-order dimensions Emotional Dysregulation malcy, we accepted 8 normal-eaters who emerged, on the (onto which load DAPP-BQ subscales measuring Anxiousness, structured interviews described below (see Section 2.2) as having Identity Problems, Social Avoidance, Affective Lability, Cognitive had an Axis-I disorder within the past 12 months. Disorders de- Distortion, Oppositionality, Submissiveness, Insecure Attachment, tected included major depressive disorder (n = 4), social phobia Suspiciousness and Narcissism), Dissocial Behavior (encompassing (n = 2), post-traumatic-stress-disorder (PTSD: n = 2), and cannabis Stimulus Seeking, Conduct Problems, Rejection, and Callousness), Inhibition (including Intimacy Problems and Restricted Expression) and Compulsivity (including the Compulsivity subscale alone). To complement our assessment, we added the Barrat Impulsivity 24.43 ± 6.24 for controls). Body Mass Index (BMI: Kg/m2) fell be- Scale (BIS, version 11: Patton et al., 1995) and the Centre for Epide- tween 12.5 and 34 for ED subjects (mean = 21.39 ± 3.89) and 18 miological Studies Depression (CES-D: Weissman et al., 1977), both and 34 for control subjects (mean = 22.00 ± 2.55). Predictably, widely-known and validated for the measurement of the intended AN-spectrum (AN-R, AN-BP and EDNOS-AN) cases had a signifi- cantly lower mean BMI (mean = 16.93 + 1.86) than did BN-spec- Screening for comorbid (past 12 months) DSM-IV Axis-I disor- ders in control subjects was accomplished using the Structured Clinical Interview for DSM-IV Axis-I disorders (SCID-I: First et al., df = 2, 275; p = .000]. AN-spectrum, BN-spectrum and control cases 1996), a computer-guided, interview-based version of the Diagnos- did not, however, differ as to mean Age. Limiting recruitment to tic Interview Schedule, Version IV (DIS4: Bucholz et al., 1991), and/ unmedicated individuals was impractical (and undesirable on or the Clinician-Administered Post-Traumatic Stress Disorder Scale grounds of representativeness), and we therefore included 77 ED (CAPS: Blake et al., 1995) – all ‘‘industry standard” measures, women (41.6% of the eating-disordered sample) and 1 normal-ea- exhibiting excellent reliability, and convergent and discriminant ter control who were taking a psychoactive medication when validity. (Variations in interviews applied reflected shifts in study tested. The pattern of results ruled out the possibility of confounds protocols occurring during the patient recruitment reported here).
associated with medication effects (see Section 3).
Elsewhere, we have evaluated agreement between DIS4 and SCID-I The Quebec population (from which this sample was drawn) is diagnoses, and obtained excellent Kappas (and percent agree- ethnically quite homogeneous. Consequently, our eating-disor- ments) for past 12-month presence of Axis-I disorders (Steiger dered sample included mainly individuals of West-European Cau- casian descent (158 individuals, or 85.4% of the sample). Therewere, however, an additional 8 (4.3%) of East-European Caucasian descent, 5 (2.7%) of South-European Caucasian descent, 4 (2.2%)of Middle-East Caucasian descent, 4 (2.2%) of Latin-American Cau- DNA samples, obtained from whole blood, were amplified by casian descent, 1 (0.5%) of mixed West-European Caucasian/Native polymerase chain reaction (PCR) in a total volume of 20 ll, which American (aboriginal) descent, 1 (0.5%) of mixed West-European contained 100 ng of genomic DNA, 200 lM of dNTPs, 10 pmol each Caucasian/Caribbean Black descent, 3 (1.6%) of Asian descent, and of the forward and reverse primer, 1 U of Taq DNA Polymerase 1 (0.5%) of mixed West-European Caucasian/ Asian descent. As eth- (Qiagen, Alameda, CA), 1 Â PCR buffer, and 1 Â Q solution (Qiagen).
nic distributions did not allow for meaningful comparisons across The forward primer (50-ATG CCA GCA CCT AAC CCC TAA TGT-30) ethnic groups, we instead simply conducted ancillary analyses, and reverse primer (50-GG ACC GCA AGG TGG GCG GGA-30) were repeating main investigations into associations between genotypes used to amplify a region encompassing 5HTTLPR; long and short and phenotypes (as described in the results), but excluding those alleles were then resolved on a 2% agarose gel. The PCR protocol in- participants who were not of clearcut, Caucasian descent. Despite volved preheating the samples at 94° C for 5 min, followed by 35 reduced sample size (and power) in these secondary analyses, cycles of denaturation at 94° C (30 s), annealing at 64° C (30 s), the gist of main effects was preserved. We did not have full ethnic- and extension at 72° C (45 s), as well as a final hold of 5 min at ity data on all the normal-eater participants, and therefore did no corresponding subject deletion in this group. However, as main G and LA alleles were subsequently studied by enzy- matic digestion of 7 ll of the above mentioned PCR product using analyses concerned differences occurring within trait-defined, eat- 5 U of MspI and incubating at 37° C for a minimum of 3 h. The L ing-disordered sub-samples, uncontrolled ethnic variations among normal-eater controls were unlikely to represent a serious A alleles were then resolved on a 2% agarose gel.
The latent structure of psychopathology in individuals with EDs ED diagnoses and symptoms were assessed using the widely was examined using latent class analysis (LCA) applied to scores used Eating Disorders Examination (EDE: Fairburn and Cooper, for the four higher-order DAPP dimensions, the BIS and the CES- 1993) interview. We also computed Body Mass Index (BMI: Kg/m2).
D. LCA models associations between observed variables and a To achieve a comprehensive, dimensional assessment of per- non-observable (latent) variable, aiming to identify the smallest sonality pathology, while limiting the number of variables impli- number of latent classes that adequately describes associations cated, we applied established, higher-order factors obtained from among dimensions entered. Models were fitted by means of an the Dimensional Assessment of Personality Pathology-Basic Ques- Expectation Maximization (EM) algorithm, with the program La- tionnaire (DAPP-BQ: Livesley et al., 1992). The DAPP-BQ is an tent Gold 3.0 (Vermunt and Magidson, 2000). To identify the empirically derived, self-report measure that systematically de- best-fitting model, we compared successive models by the Bayes- scribes personality traits using 290 items, organized into 18 ‘‘trait” ian information criterion (BIC), Akaike information criterion subscales. In the present study, DAPP subscales were aggregated (AIC), and percentage classification error. BIC and AIC information H. Steiger et al. / Journal of Psychiatric Research 43 (2009) 1086–1094 statistics are global measures that weight the fit and parsimony of the model; lower observed values indicate better fit. Latent classmodels were applied to successively test 1- to 6-class solutions.
Table 2 shows results of Chi-Squared tests (and frequency val- (The upper limit of 6 was used to ensure an adequate number of ues) comparing the 3 LCA-based classes with respect to ED diagno- observations in each class.) To address the problems of local min- ses (AN-spectrum disorder, Restricter subtypes, past history of AN) ima and starting values and to ensure that a true maximum likeli- and medication use. In addition, ANOVAS (and mean values) for hood solution had been reached, we estimated the model 100 Age, BMI, Binge Days per Month, and Monthly Binge, Vomit and times using different random starting values to select the optimal Purge Frequencies (the latter including episodes of vomiting, or solution. Cases were assigned to latent classes by modal assign- laxative or diuretic misuse) are provided. Chi-squared tests indi- ment (i.e., assignment to the latent class for which the a posteriori cated a difference across classes with respect to AN-spectrum probability was the highest). Once formed, LCA-based groups were and Restricter diagnoses, and a trend with respect to history of compared for ED diagnoses and symptoms using either ANOVAs or AN spectrum disorders, with the Inhibited/Compulsive class al- Chi-Squared tests as appropriate. In addition, frequencies of geno- ways including largest proportions of AN-spectrum (AN-R, AN-BP types and alleles were compared across eating-disordered groups and EDNOS-AN) diagnoses, Restricter (AN-R and EDNOS-AN/R) (organized to reflect diagnostic and trait differences of interest) subtypes, or past AN disorders. A final chi-squared analysis indi- and normal-eater groups using Chi-Squared tests.
cated members of the Low Psychopathology class to receive signif-icantly less psychoactive medication than did members of eitherthe Dissocial/Impulsive or Inhibited/Compulsive classes. The pre- ceding tendency helps confirm that lower psychopathologicalexpression in the Low Psychopathology group was not due to con- founding effects of medication (i.e., disproportionately highermedication use) that cancelled symptoms in this group.
Criteria indicated a 3 latent-class model to provide best fit to One-way ANOVAs indicated no significant group differences as our data (BIC values: 1 class: 4406.33; 2 classes: 4320.04; 3 clas- to Age. However, in line with the finding of an increased number of ses: 4308.96; 4 classes: 4328.17; 5 classes: 4352.35; 6 classes: AN cases in the Inhibited/Compulsive class, there was a tendency 4391.41). Analysis of classification errors also supported a 3-class for this class to have a lower mean BMI relative to that in other eat- model. To rule out potentially confounding effects of ED diagnosis ing-disordered groups. Potential group differences (eating-disor- on model estimation, we re-ran the LCA twice, once with a covar- dered groups only) as to frequencies of binge and purge iate differentiating individuals with AN-spectrum disorders (AN-R, symptoms were examined using ANOVAs. Outliers on variables AN-BP, EDNOS-AN/R or EDNOS-AN/BP) from those with BN-spec- recording frequencies of binge, vomit and purge episodes were trum disorders (BN-P, BN-NP, or EDNOS-B), and a second time with transformed to the mean plus two standard deviations and, due a covariate differentiating individuals who binged and/or purged to deviations from normality, square-root transformations were (i.e., with AN-BP, EDNOS-AN/BP, BN-P, BN-NP, or EDNOS-B diagno- performed. (Table 2 shows actual, rather than transformed, values ses) from those who did not (i.e., AN-R or EDNOS-AN/R diagnoses).
since both analyses revealed similar results.) Again, in line with the Although the covariate always emerged as a significant predictor of finding of an increased number of AN cases in the Inhibited/Com- classification, both analyses yielded best-fitting 3-class solutions pulsive class, this class reported lowest monthly binge days and that differed in no substantive way from the original (no-covariate) episodes. At a statistical trend level, the Inhibited/Compulsive analysis. (For brevity’s sake, we report results from the original group also reported fewer monthly purging episodes than did Table 1 shows means on the six scale scores entered into the LCA. Three classes were indicated which, in decreasing order of group size, encompassed individuals who showed elevated (a) Dis-social Behavior, Impulsivity, Emotional Dysregulation and Depres- Treating 5HTTLPR in a conventional (biallelic) fashion, frequen- sion (n = 80, or 43.2% of the sample), (b) None of the pathological cies (and percentages) of S/S, S/L, and L/L genotypes, respectively indices (n = 73, or 39.5%), or (c) Inhibition, Compulsivity, Emotional occurring in 42 (22.7%), 84 (45.4%) and 59 (31.9%) of our eating- Dysregulation and Depression (n = 32, or 17.3%). As both ‘‘psycho- disorder participants and 17 (18.3%), 54 (58.1%) and 22 (23.7%) of pathological” groups (‘‘a” and ‘‘c”) showed heightened affectivity, a our control participants, were in conformity with Hardy-Weinberg pattern similar to that noted by Wonderlich et al. (2005), we as- equilibrium [ED: v2 ¼ 1:31, n.s.; Control: v2 ¼ 2:53, n.s.]. With a sumed emotional reactivity to be a non-specific characteristic, triallelic model, frequencies (and percentages) of groups who were and opted to assign labels according to the more-unique character- carriers of two, one or no ‘‘low-function” (i.e., S or LG) alleles, 58 istics. Correspondingly, we named the three LCA derived groups (31.4%), 80 (43.2%) and 47 (25.4%), respectively in ED participants, ‘‘Dissocial/Impulsive”, ‘‘Low Psychopathology”, and ‘‘Inhibited/ and 27 (29.3%), 53 (57.6%) and 12 (13.0%), respectively in controls, were also in conformity with Hardy-Weinberg equilibrium [ED: Table 1 also provides mean values for members of the control v2 ¼ 3:23, n.s.; Control: v2 ¼ 3:09, n.s.].
group on the six trait/symptom scores, along with results obtained Our next data-analytic step aimed to detect any differences in in univariate ANOVAs that tested for group differences on each var- genotype or allele frequencies that corresponded to the presence iable. Results indicate mean scores of eating-disordered individuals or absence of an eating disorder. To do so, we first compared geno- to have generally been higher (in a pathological direction) than type and allele frequencies occurring in the overall group of eating- those of normal-eater controls (significantly so on Emotional Dys- disordered individuals to those obtained in normal-eaters (see Ta- regulation, Inhibition, and Depression.) Dissocial-Impulsive group ble 3). Analyses were set up to examine rates of biallelic genotypes members had higher scores than did all other groups on Emotional and alleles (see Table 3a and b), triallelic genotypes and alleles (see Dysregulation, Dissocial Behavior, and Impulsivity, reflecting these Table 3c and d), and finally triallelic genotypes organized into low individuals’ uniquely ‘‘dysregulatory” propensities. In contrast, function homozygotes, heterozygotes, or high-function homozyg- indicating a unique connection with ‘‘over-regulation”, ‘‘Inhib- tes, and triallelic allele frequencies when rates of low-function ited/Compulsive” group members’ scores exceeded those of all and high-function alleles were compared (see Table 3e and f). A other groups on Inhibition and Compulsivity.
significant difference emerged in the analysis contrasting carriers H. Steiger et al. / Journal of Psychiatric Research 43 (2009) 1086–1094 Table 1Mean scores (and standard deviations) for each latent-class derived cluster of eating-disordered patients and for normal-eater controls on Emotional Dysregulation, DissocialBehavior, Inhibition, Compulsivity, Impulsivity and Depression scales. Contribution of scale scores to cluster classifications is reflected by Wald test values (betas are equal amongclasses). One-way ANOVAs reflect differences between actual group means (including controls). Values with different letters in their superscripts differ at the p < .05 level orbetter on Tukey’s HSD tests. Variations in ns and dfs reflect isolated missing values.
A Wald test values pertain only to eating-disordered participants, who were included in the latent class analysis.
Table 2Frequencies of diagnoses (AN-spectrum and Restricter), diagnostic history (history of AN) and medication use, as well as means for Age, BMI and Binge Days per Month, and forMonthly Binge, Vomit and Purge Frequencies (including episodes of vomiting, and laxative or diuretic misuse) by LCA-based groups. Chi-Square and F values reflecting inter-group difference are also reported. Values with different letters in their superscripts differ at the p < .05 level or better on Turkey’s HSD tests.
of the highest-function triallelic genotype (i.e., LA/LA) to other statistical trends [v2 = 21.95; df = 15; p = .109, and v2 = 12.25; genotypes, with eating-disordered participants displaying signifi- df = 6; p = .057, respectively]. More importantly, tests of associa- cantly higher rates of the LA/LA genotype.
tion between genotypes (organized to reflect homozygosity or het- To ensure that we had not obscured potential anorexic-bulimic erozygosity for low- and high-function alleles) and groups (see differences, we repeated the set of analyses shown in Table 3, but Table 4e) or between low- and high-function allele frequencies with eating-disordered participants organized into those display- and groups (see Table 4f) both yielded significant results ing anorexia- (i.e., AN/R, AN/BP, EDNOS-AN/R and EDNOS-AN/BP) [v2 = 15.45; df = 6; p = .017 and v2 = 9.67; df = 3; p = .022, respec- or bulimia- (BN and EDNOS/BN) spectrum disorders. These analy- tively]. A main implication is that members of the Inhibited/Com- ses yielded no significant effects for biallelic or triallelic 5HTTLPR pulsive eating-disordered group tended to be more likely than models, and no within-ED subtype differences. Likewise, a parallel were members of other groups to be carriers of one or two copies set of analyses that organized the eating-disordered participants into those displaying ‘‘restrictive” or ‘‘bulimic” ED variants yielded More fine-grained analyses, conducted using individual Chi- no significant effects on the set of genetic indicators.
squared tests to localize differences between groups indicated Suspecting that the difference observed between eating- and the following (always in relation to the triallelic 5HTTLPR): there non-eating-disordered groups may have reflected different load- were significant pairwise group differences as to genotype fre- ings of psychopathological traits within these groups, our next quencies obtained in the Inhibited/Compulsive group versus the data-analytic step explored the correspondence between psycho- Normal Eaters [v2 = 9.57; df = 2; p = .008] and versus the Disso- pathological-trait variations, on the one hand, and genotype- or al- cial/Impulsive patients [v2 = 7.17; df = 2; p = .028]. The highest- lele-frequency variations, on the other. Table 4 shows analyses expressing genotype (LA/LA) appeared to occur significantly more designed to detect differences among frequencies (and percent- frequently in Inhibited/ Compulsive patients than it did in the ages) of 5HTTLPR genotypes and alleles (biallelic and triallelic other two groups noted (see Table 4e for values in question). Odds models) for individuals in each of the LCA, psychopathological-trait ratios indicated Inhibited/ Compulsive patients to be 4 times more defined groups, as well as for the overall Normal-Eater control likely (95% CI: 1.57–10.22) to have the highest-expressing geno- group. The biallelic formulation yielded no significant results in type (LA/LA) than controls. Conversely, Inhibited/Compulsive pa- either (a) a 3 Â 4 chi-squared test of association between groups tients were 3.6 times less likely (95% CI: 1.26–10.33) to have the and genotypes, or (b) a 2 Â 4 chi-squared test of associations be- lowest-expressing genotype (S/S, S/LG or LG/LG) than were Disso- tween groups and allele frequencies (see Table 4a and b). With cial/Impulsive patients. Reflecting the same trend, the absolute fre- the triallelic 5HTTLPR formulation, tests of association between quency of LA alleles carried by Inhibited/Compulsive patients twice discreet genotypes and groups (see Table 3c) and between allele exceeded that carried by Normal Eaters [v2 = 6.95; df = 1; p = .008; (S, LG and LA) frequencies and groups (see Table 4d) both yielded p = .009 on a Fisher’s exact test] and Dissocial/Impulsive patients H. Steiger et al. / Journal of Psychiatric Research 43 (2009) 1086–1094 The main goal of the present study was to explore the associa- Frequencies (and percentages) of 5HTTLPR genotypes and alleles (biallelic and tion of 5HTTLPR variations with presence of an eating disorder, and triallelic models), comparing Eating-Disordered individuals to normal-eater control with trait profiles that characterize eating-disorder sufferers.
Although we found the highest-function 5HTTLPR genotype (LA/LA) to be more common in eating-disorder sufferers than in controls, finer-grained analyses examining associations of genetic variations with variations in psychopathological traits suggested that the association observed was not so much characteristic of our eating-disordered sample (in a wholesale fashion), or of partic- ular diagnostic subgroups (e.g., those with Anorexia-spectrum syn-dromes), as it was of those members of the sample who were markedly Inhibited/Compulsive. In other words, our results associ- ate genetic variations more specifically with trait variations (such as the Inhibited/Compulsive versus Dissocial/Impulsive distinctionwe derived) than with presence or absence of an ED syndrome per se. In this respect, our results corroborate other findings (obtainedin eating- and non-eating-disordered populations) suggesting that 5HTTLPR triallelic model(c) Genotype (S, L heightened inhibition/compulsivity coincides with the gain-of- function (LA) allele (triallelic model) of 5HTTLPR (Hu et al., 2006), and heightened impulsivity and affective instability with the low-function 5HTTLPR alleles (Anguelova et al., 2003; Lesch et al., 1996; Sander et al., 1998; Steiger et al., 2005b, 2007). Our study may, furthermore, take a step beyond the simple corrobora- tion of the association noted, in suggesting a correspondence be- tween the polymorphism of interest and phenotypic variations (or latent classes) that are validated empirically—our hope being that this effort may improve the stability (and hence replicability) of the findings. Members of an empirically derived ‘‘Inhibited/ Compulsive” subgroup (when compared to those of Dissocial/ Impulsive or Low Psychopathology ED subgroups, or members of a normal-eater control group) were significantly more likely to car- ry at least one copy of the triallelic 5HTTLPR gain-of-function LA al- lele, and to be high-function homozygotes (i.e., LA/LA genotype carriers) – which for 5HTTLPR represents the highest-expressing In a similar vein, ‘‘Inhibited/Compulsive” group members were more likely than other LCA-based groups to exhibit AnorexiaNervosa (versus a bulimic ED variant). Important clues as to [v2 = 8.07; df = 1; p = .005; p = .005 on a Fisher’s exact test; odds ra- the interpretation of this finding would seem to lie in the obser- tio of 2.17 (95% CI: 1.21–3.88) and 2.34 (95% CI: 1.29–4.24), respec- vation that the LA allele is, elsewhere, associated with heightened tively] (see Table 4f for values in question).
risk of obsessive–compulsive disorder (Hu et al., 2006), and thatobsessive–compulsive characteristics predominate in anorexic (and particularly restrictive-anorexic) ED variants (Westen andHarnden-Fischer, 2001; Steiger and Bruce, 2007). Together, these Based on comorbid psychopathological traits, this study classi- observations suggest that the 5HTTLPR LA allele, while not a spe- fied treatment-seeking eating-disordered patients, and then exam- cific factor in eating-disorder risk, may exercise a ‘‘pathoplastic” ined the association of resulting empirical classifications with effect—heightening the likelihood of expression of obsessive– variations in the serotonin transporter promoter polymorphism compulsiveness and pronounced dietary restraint in eating- (5HTTLPR). Our results indicated a trio of latent classes, accommo- disordered individuals. In other words, we may be observing a dating progressively smaller proportions of our eating-disordered shaping impact of a genetic factor (in this case, of the 5HTTLPR sample, to which we could fit the descriptors ‘‘Dissocial/ Impul- high-function alleles) upon expression of traits (in the Inhib- sive”, ‘‘Low Psychopathology” and ‘‘Inhibited/ Compulsive”. The ited/Compulsive versus Dissocial/Impulsive spectrum) which, in classes derived closely resemble those obtained in comparable eating-disorder sufferers shapes eating-symptom expression classification efforts–one study in an eating-disordered sample (i.e., anorexic versus bulimic forms). In addition, our results sup- characterizing groups obtained as ‘‘emotionally dysregulated/ port the notion that Anorexia Nervosa may not only resemble undercontrolled”, ‘‘high-functioning/perfectionistic” and ‘‘con- obsessive–compulsive disorder in a phenomenological sense stricted/ overcontrolled” (Westen and Harnden-Fischer, 2001) (bodily obsessions motivating dieting compulsions), but that and another, groups described as ‘‘impulsive”, ‘‘low comorbidity”, these disorders may also have at least one common, molecular- and ‘‘affective/ perfectionistic” (Wonderlich et al., 2005). Evident genetic determinant (i.e., the 5HTTLPR LA allele).
correspondences across these studies suggest that the tendency On the ‘‘opposite side of the same coin”, we note that members for eating-disordered individuals to cluster into impulsive, rela- of our Dissocial/Impulsive subgroup were significantly more likely tively intact, and compulsive sub-groups is quite a replicable one.
than members of the ‘‘Inhibited/Compulsive” group to carry low- Making such correspondences all-the-more striking, the studies function genotypes and alleles. The preceding corroborates parallel in question apply disparate psychopathological indices and statis- findings obtained in eating-disordered (Steiger et al., 2005b, 2007) and non-eating-disordered populations (Lesch et al., 1996; H. Steiger et al. / Journal of Psychiatric Research 43 (2009) 1086–1094 Table 4Frequencies (and percentages) of 5HTTLPR genotypes and alleles (biallelic and triallelic) across LCA-defined eating-disordered groups and normal-eater controls.
5HTTLPR triallelic model(c) Genotype (S, LG, and LA alleles) Anguelova et al., 2003) that link low-function 5HTTLPR alleles with OCPD, and other phenotypes in a putative obsessive–compulsive traits of impulsivity or dysregulation.
spectrum (e.g., Hollander, 2007). Awaiting this clarification, we How should such findings be interpreted? Evidence of lack of note that OCPD traits and syndromic OCD are both common in eat- association of the triallelic 5HTTLPR with PET-determined trans- ing-disordered patients (Westen and Harnden-Fischer, 2001; Stei- porter binding in normal humans has led to the proposal that asso- ciations of 5HTTLPR with clinical phenotypes may depend, notupon direct (momentary) effects on serotonin binding, but effects of 5HTTLPR upon brain development (Parsey et al., 2006). Follow-ing from this idea, we speculate that it is not opportune to inter- Our sample is relatively small for a multivariate exploration, pret 5HTTLPR variants as having any simple or direct connotation and this may limit stability of findings and power to detect certain for ‘‘high” versus ‘‘low” levels of intrasynaptic 5-HT. Rather, pres- effects of potential interest. Furthermore, in this study, we have ence of high- or low-function 5HTTLPR alleles may have implica- not addressed gene–environment interaction effects that may be tions for the ‘‘adaptability”, ‘‘resilience”, or other ‘‘global relevant to the understanding of associations between genetic fac- propensities” of an individual’s 5-HT system—and may therefore tors, on the one hand, and psychopathology-defined classifications, have relevance for the likelihood of specific psychopathological on the other. Suggesting that such effects may be important, our expressions when the adaptive capacities of this system are over- group has recently documented several instances of gene-environ- taxed. Available findings implying that 5HTTLPR variants may ment interaction effects linking 5HTTLPR and childhood abuse to influence psychopathological responses to environmental stressors such traits as novelty seeking (Steiger et al., 2007) or Dissocial in ED patients (see Steiger et al., 2007, 2008) are consistent with Behavior (Steiger et al., 2008). In addition, we reiterate a point made earlier that, due to recruitment factors, our sample cannot A final comment is necessary, concerning the meaning of the be assumed to be representative of the population seeking treat- ‘‘Inhibited/Compulsive” construct we have applied. This higher-or- ment in specialized eating-disorders programs. Nonetheless, our der DAPP factor encompasses lower-order traits of Restricted sample’s heterogeneity allowed for exploration of possible rela- Expression (emotional constriction or guardedness), Compulsivity tionships between genetic variables, on the one hand, and person- (traits such as orderliness, conscientiousness, and hypervigilance), ality and eating-symptom variables, on the other.
and Intimacy Problems (insecure or avoidant attachments). The‘‘inhibited/ compulsive” construct thus appears to more closely represent obsessive–compulsive personality disorder (OCPD) thanit does OCD. That previous work has linked the high-function Our findings provide evidence of association amongst trait- 5HTTLPR allele to OCD, whereas our study suggests a link to a con- based, eating-disorder sub-phenotypes (inhibited/compulsive, dis- struct more closely approximating OCPD, suggests that there may social/impulsive, or low psychopathology) and variations in be a need, in future work, to define the implications of 5HTTLPR 5HTTLPR genotypes- and less so, with categorical ED phenotypes high-function alleles and genotypes for the expression of OCD, (e.g., Anorexia- versus Bulimia-spectrum syndromes). We believe H. Steiger et al. / Journal of Psychiatric Research 43 (2009) 1086–1094 that this pattern of findings may guide the understanding of the sign; in the collection, analysis and interpretation of data; in the relationships between genotypic variations and complex pheno- writing of the report, or in the decision to submit the paper for types, like eating disorders and their subtypes. A ‘‘lesson” to be de- publication. Preliminary results from this study were presented rived from the present findings may be that the correct loci at at the annual meeting of the Eating Disorders Research Society, which to seek correspondences between genotypes and pheno- Montreal, Quebec, Canada, Sept. 26, 2008. Authors are grateful to types may be those linking genetic effects to higher-order, trait- Patricia Groleau, Catherine Villenneuve-Tang and Catherine Sene- based phenotypes (e.g., Inhibited/Compulsive) rather than to syn- cal for their assistance in various aspects of this research.
dromic variations (e.g., Anorexia Nervosa). Findings such as thepresent ones suggest, for example, that 5HTTLPR (and presumably other polymorphisms in the 5-HT system) may influence psycho-pathological and behavioral traits, and in so doing, may indirectly Anguelova M, Benkelfat C, Turecki G. A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin channel vulnerable individuals’ thinness and body-image preoccu- transporter II: suicidal behavior. Molecular Psychiatry 2003;8:646–53.
pations into either restrictive or bulimic expressions. This interpre- Baca-Garcia E, Rodriguez Aalgado B, Dolengvich Segal H, Vaquero Lorenzo C, Navio tation is consistent with general findings on serotonin indices in Acosta M, Arrojo Romero M, et al. A pilot genetic study of the continuumbetween compulsivity and impulsivity in females: the serotonin transporter eating-disordered individuals suggesting that serotonin-system promoter polymorphism. Progress in Neuropsychopharmacology and Biological variations may be more powerful correlates of generalized psycho- pathological-trait variations seen in ED sufferers than they are of Bagge C, Trull T. DAPP-BQ: factor structure and relations to personality disorder eating-symptom variations and severities per se (see Steiger, symptoms in a non-clinical sample. Journal of Personality Disorders2003;17:19–32.
Bengel D, Greenberg BD, Cora-Locatelli G, Altemus M, Heils A, Li Q, et al. Association of the serotonin transporter promoter regulatory regions polymorphism andobsessive–compulsive disorder. Molecular Psychiatry 1999;4:463–6.
Blake DD, Weathers FW, Nagy LM, et al. The development of a clinician- administered PTSD scale. Journal of Traumatic Stress 1995;8:75–90.
Howard Steiger was Principal Investigator (PI) on the grants Bruce KR, Steiger H, Ng Ying Kin NMK, Israel M. Reduced platelet [3H] paroxetine binding in anorexia nervosa: relationship to eating symptoms and personality that supported this research and on the research itself, and over- pathology. Psychiatry Research 2006;142:225–32.
saw all aspects of this work. Jodie Richardson assisted in the Bucholz KK, Robins LN, Shayka JJ, Przybeck TR, Heltzer JE, Goldring E, et al.
study’s conceptualization and design, and conducted main data Performance of two forms of a computer psychiatric screening interview:version 1 of the DISSI. Journal of Psychiatry Research 1991;25:117–29.
analyses. With Steiger, she helped co-write the first draft of this Cloninger CR, Svrakic DM, Przybeck TR. A psychobiological model of temperament manuscript. Norbert Schmitz contributed to statistical aspects of and character. Archives of General Psychiatry 1993;50:975–90.
the report, carried out data analyses, and offered particular guid- Di Bella DD, Catalano M, Cavallini MC, Riboldi C, Bellodi L. Serotonin transporter ance on latent class analyses. Ridha Joober was responsible for ge- linked polymorphic region in anorexia nervosa and bulimia nervosa. MolecularPsychiatry 2000;5:233–41.
netic assays and contributed to the conceptualization and design of Fairburn C, Cooper P. The eating disorders examination. In: Fairburn C, Wilson G, the study. Mimi Israel contributed to the conceptualization and de- editors. Binge eating: nature. Assessment and treatment. New York: Guilford; sign of the study, and supervised clinical assessments and medical First MB, Spitzer RL, Gibbon M, Williams J. Structured Clinical Interview for DSM-IV acts. Kenneth Bruce contributed to conceptualization and design of Axis I Disorders – Patient Edition (SCID-I/P, Version 2.0). New York: Biometrics the study, to data analyses, and to training and supervision of re- Research Department, New York State Psychiatric Institute; 1996.
search assistants. Lise Gauvin contributed to the conceptualization Frank GK, Kaye WH. Positron emission tomography studies in eating disorders: multireceptor brain imaging, correlates with behavior and implications for and design of the study, and to the design and execution of data pharmacotherapy. Nuclear Medicine and Biology 2005;32:755–61.
analyses. Cathy Dandurand and Annelie Anestin contributed to Heinz A, Braus DF, Smolka MN, Wrase J, Puls I, Hermann D, et al. Amygdala- participant recruitment, testing, data entry and management, liter- prefrontal coupling depends on a genetic variation of the serotonintreansporter. Nature Neuroscience 2005;8:20–1.
ature searches, and design and execution of certain data analyses.
Hollander E. Treatment of obsessive–compulsive spectrum disorders with SSRIs.
All authors have contributed to different sections of draft manu- British Journal of Psychiatry 1998;35(Suppl.):7–12.
scripts, and all have approved the final manuscript.
Hollander E. Anxiety and OC spectrum disorders over life cycle. International Journal of Psychiatry in Clinical Practice 2007;11(Suppl.):5–10.
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Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S. Association of anxiety- Funding agencies had no further role in study design; in the col- related traits with a polymorphism in the serotonin transporter gene regulatory lection, analysis and interpretation of data; in the writing of the re- port, or in the decision to submit the paper for publication.
Livesley WJ, Jackson DN, Schroeder ML. Factorial structure of traits delineating personality disorders in clinical and general population samples. Journal of Preliminary results from this study were presented at the annual Abnormal Psychology 1992;101:432–40.
meeting of the Eating Disorders Research Society, Montreal, Que- Matsushita S, Suzuki K, Murayama M, Nishiguchi N, Hishimoto A, Takeda A, et al.
Serotonin transporter regulatory region polymorphism is associated withanorexia nervosa. American Journal of Medical Genetics (NeuropsychiatricGenetics) 2004;128:114–7.
Monteleone P, Santonastaso P, Mauri M, Nellodi L, Erzegovesi S, Fuscino A, et al.
Investigation of the serotonin transporter regulatory region polymorphism inbulimia nervosa: relationships to harm avoidance, nutritional parameters and Dr. Joober has received honoraria for consultations from Janssen psychiatric comorbidity. Psychosomatic Medicine 2006;68:99–103.
Parsey RV, Hastings RS, Oquendo MA, Hu X, Goldman D, Huang Y-y, et al. Effect of a triallelic functional polymorphism of the serotonin-transporter linked promoterregion on expression of serotonin transporter in the human brain. American Journal of Psychiatry 2006;163:48–51.
Patton JH, Stanford MS, Barrat E. Factor structure of the Barrat impulsiveness scale.
This research was supported by grants awarded to Dr. Steiger Journal of Clinical Psychology 1995;51:609–774.
Sander T, Harms H, Dufeu P, Kuhn S, Hoehe M, Lesch KP, et al. Serotonin transporter and colleagues (No. 6313A from the Fonds de la Recherche en Santé gene variants in alcohol-dependent subjects with dissocial personality disorder.
du Québec, and nos. MOP-79490 and MOP-57929 from the Cana- Biological Psychiatry 1998;43:908–12.
dian Institutes for Health Research), and by a doctoral bursary Steiger H. Eating disorders and the serotonin connection: state, trait and developmental effects. Journal of Psychiatry and Neuroscience 2004;29:20–9.
awarded to Jodie Richardson from the Canadian Institutes for Steiger H, Bruce KR. Phenotypes, endophenotypes, and genotypes in bulimia- Health Research. Funding agencies had no further role in study de- spectrum eating disorders. Canadian Journal of Psychiatry 2007;52:220–7.
H. Steiger et al. / Journal of Psychiatric Research 43 (2009) 1086–1094 Steiger H, Gauvin L, Joober R, Israel M, Ng Ying Kin NMK, Bruce KR, et al.
Tauscher J, Pirker W, Willeit M, de Zwaan M, Bailer U, Neumeister A, et al. Beta-CIT Intrafamilial correspondences on platelet [3H-] paroxetine-binding indices in and single photon emission computer tomography reveal reduced brain serotonin transporter availability in bulimia nervosa. Biological Psychiatry Neuropsychopharmacology 2006;31:1785–92.
Steiger H, Joober R, Israël M, Young SN, Ng Ying Kin NMK, Gauvin L, et al. The Vermunt JK, Magidson J. Latent GOLD 2.0 user’s guide. Massachusetts; 2000.
5HTTLPR polymorphism, psychopathological symptoms, and platelet [3H-] Weissman MM, Sholomskas D, Pottenger M, Prusoff BA, Locke BZ. Assessing paroxetine binding in bulimic syndromes. International Journal of Eating depressive symptoms in five psychiatric populations: a validation study.
American Journal of Epidemiology 1977;106:203–14.
Steiger H, Richardson J, Israel M, Ng Ying Kin NMK, Bruce K, Mansour S, et al.
Westen D, Harnden-Fischer J. Personality profiles in eating disorders: rethinking the Reduced density of platelet-binding sites for 3H-paroxetine in remitted bulimic distinction between axis I and axis II. American Journal of Psychiatry women. Neuropsychopharmacology 2005a;30:1028–32.
Steiger H, Richardson J, Joober R, Gauvin L, Israel M, Bruce KR, et al. The 5HTTLPR Wonderlich SA, Crosby RD, Joiner T, Peterson CB, Bardone-Cone A, Klein M, et al.
Personality subtyping and bulimia nervosa: psychopathological and genetic manifestations in women with bulimic syndromes. Journal of Psychiatry and correlates. Psychological Medicine 2005;35:649–57.
Zalsman G, Huang Y-y, Oquendo MA, Burke AK, Hu X-z, Brent DA, et al. Association Steiger H, Richardson J, Joober R, Israel M, Bruce KR, Ng Ying Kin NMK, et al.
of a triallelic serotonin transporter gene promoter region (5-HTTLPR) Dissocial behavior, the 5HTTLPR polymorphism and maltreatment in women polymorphism with stressful life events and severity of depression. American with bulimic syndromes. American Journal of Medical Genetics Part B Journal of Psychiatry 2006;163:1588–93.

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