Evidence for the role of EPHX2 gene variants in anorexia nervosa.

Anorexia nervosa (AN) and related eating disorders are complex, multifactorial neuropsychiatric conditions with likely rare and common genetic and environmental determinants. To identify genetic variants associated with AN, we pursued a series of sequencing and genotyping studies focusing on the coding regions and upstream sequence of 152 candidate genes in a total of 1205 AN cases and 1948 controls. We identified individual variant associations in the Estrogen Receptor-ß (ESR2) gene, as well as a set of rare and common variants in the Epoxide Hydrolase 2 (EPHX2) gene, in an initial sequencing study of 261 early-onset severe AN cases and 73 controls (P=0.0004). The association of EPHX2 variants was further delineated in: (1) a pooling-based replication study involving an additional 500 AN patients and 500 controls (replication set P=0.00000016); (2) single-locus studies in a cohort of 386 previously genotyped broadly defined AN cases and 295 female population controls from the Bogalusa Heart Study (BHS) and a cohort of 58 individuals with self-reported eating disturbances and 851 controls (combined smallest single locus P<0.01). As EPHX2 is known to influence cholesterol metabolism, and AN is often associated with elevated cholesterol levels, we also investigated the association of EPHX2 variants and longitudinal body mass index (BMI) and cholesterol in BHS female and male subjects (N=229) and found evidence for a modifying effect of a subset of variants on the relationship between cholesterol and BMI (P<0.01). These findings suggest a novel association of gene variants within EPHX2 to susceptibility to AN and provide a foundation for future study of this important yet poorly understood condition.

Anorexia nervosa trios: behavioral profiles of individuals with anorexia nervosa and their parents.

BACKGROUND: Anorexia nervosa (AN) is associated with behavioral traits that predate the onset of AN and persist after recovery. We identified patterns of behavioral traits in AN trios (proband plus two biological parents). METHOD: A total of 433 complete trios were collected in the Price Foundation Genetic Study of AN using standardized instruments for eating disorder (ED) symptoms, anxiety, perfectionism, and temperament. We used latent profile analysis and ANOVA to identify and validate patterns of behavioral traits. RESULTS: We distinguished three classes with medium to large effect sizes by mothers' and probands' drive for thinness, body dissatisfaction, perfectionism, neuroticism, trait anxiety, and harm avoidance. Fathers did not differ significantly across classes. Classes were distinguished by degree of symptomatology rather than qualitative differences. Class 1 (approximately 33%) comprised low symptom probands and mothers with scores in the healthy range. Class 2 ( approximately 43%) included probands with marked elevations in drive for thinness, body dissatisfaction, neuroticism, trait anxiety, and harm avoidance and mothers with mild anxious/perfectionistic traits. Class 3 (approximately 24%) included probands and mothers with elevations on ED and anxious/perfectionistic traits. Mother-daughter symptom severity was related in classes 1 and 3 only. Trio profiles did not differ significantly by proband clinical status or subtype. CONCLUSIONS: A key finding is the importance of mother and daughter traits in the identification of temperament and personality patterns in families affected by AN. Mother-daughter pairs with severe ED and anxious/perfectionistic traits may represent a more homogeneous and familial variant of AN that could be of value in genetic studies.

Relapse in anorexia nervosa: a survival analysis.

BACKGROUND: Knowledge about factors that predict relapse in anorexia nervosa (AN) is needed for the development of effective relapse prevention treatments and may also advance understanding of the psychopathology of AN. The aim of the present study was to examine the rate, timing and prediction of relapse in AN following weight restoration in a specialized in-patient treatment programme. METHOD: Fifty-one consecutive first-admission AN patients who were weight-restored following in-patient treatment participated in the study. Follow-up assessments were conducted a median of 15 months post-discharge. Relapse of AN was defined as a body mass index <17.5 for 3 consecutive months. Data were analysed using Kaplan-Meier survival analysis and Cox regression. RESULTS: The overall rate of relapse was 35% and the mean survival time was 18 months. The highest risk period was from 6 to 17 months after discharge. Several significant predictors of relapse were identified: a history of suicide attempt; previous specialized treatment for an eating disorder; severity of obsessive-compulsive symptoms at presentation; excessive exercise immediately after discharge; and residual concern about shape and weight at discharge. CONCLUSIONS: There continues to be a significant risk of relapse among AN patients who remain well for the first year post-discharge. Several variables were shown to be associated with an elevated risk of relapse. These findings have implications for the development of initial treatments and relapse prevention strategies for AN.

Evidence for a susceptibility gene for anorexia nervosa on chromosome 1.

Eating disorders, such as anorexia nervosa (AN), have a significant genetic component. In the current study, a genomewide linkage analysis of 192 families with at least one affected relative pair with AN and related eating disorders, including bulimia nervosa, was performed, resulting in only modest evidence for linkage, with the highest nonparametric linkage (NPL) score, 1.80, at marker D4S2367 on chromosome 4. Since the reduction of sample heterogeneity would increase power to detect linkage, we performed linkage analysis in a subset (n=37) of families in which at least two affected relatives had diagnoses of restricting AN, a clinically defined subtype of AN characterized by severe limitation of food intake without the presence of binge-eating or purging behavior. When we limited the linkage analysis to this clinically more homogeneous subgroup, the highest multipoint NPL score observed was 3.03, at marker D1S3721 on chromosome 1p. The genotyping of additional markers in this region led to a peak multipoint NPL score of 3.45, thereby providing suggestive evidence for the presence of an AN-susceptibility locus on chromosome 1p.

Polymorphism of the serotonin 5-HT1B receptor gene (HTR1B) associated with minimum lifetime body mass index in women with bulimia nervosa.

BACKGROUND: Preclinical research has shown that the serotonin-1B receptor has important modulatory effects on feeding behavior and thus body weight. In the current study, we examined whether genetic variation of the serotonin-1B receptor was associated with minimum and maximum lifetime body mass indices (BMIs) in a sample of women with bulimia nervosa (BN). METHODS: Ninety-eight women with BN were genotyped based on the G861C polymorphism of the serotonin-1B receptor gene (HTR1B). Minimum and maximum lifetime BMIs were compared across the three genotypic groups using analysis of variance. RESULTS: There was a highly significant difference in minimum lifetime BMI across the three genotypic groups (p =.001). Both the G/C and C/C genotypes were associated with significantly lower minimum lifetime BMIs than was the G/G genotype. Maximum lifetime BMI was not significantly different across groups. These results were not attributable to different lifetime rates of anorexia nervosa across the three genotypic groups. CONCLUSIONS: These preliminary findings suggest a possible association between HTR1B genetic polymorphism and minimum lifetime BMI in women with BN. These findings may shed light on why, in response to dieting, some BN patients achieve lower BMIs, whereas others have a natural limitation to their weight loss. Pending replication in a larger sample, these findings point to a possible genetic factor of fundamental importance to the BN population.

Pretreatment motivational enhancement therapy for eating disorders: a pilot study.

UNLABELLED: Eating disorder patients are notoriously ambivalent about treatment and often lack motivation to change. These characteristics may decrease the number of patients entering treatment and increase the number of patients dropping out of treatment prematurely. OBJECTIVE: The aim of this pilot study was to develop and evaluate a motivational enhancement therapy (MET) group program for eating disorder patients. The goal of the MET intervention was to increase participants' motivation to change, which might be expected to increase the success of future treatment of patients with eating disorders. METHOD: Nineteen individuals who were referred for specialized treatment took part in the study. The intervention was based on existing literature in the field of addictions and modified for eating disorders. RESULTS: The motivational measures suggested that the participants' motivation to change increased following the intervention. A decrease in depressive symptoms and an increase in self-esteem were also found. DISCUSSION: The results of this study suggest that MET could be valuable for the treatment of eating disorder patients and provide a rationale to conduct further research in this area.

Comparisons of men with full or partial eating disorders, men without eating disorders, and women with eating disorders in the community.

OBJECTIVE: The authors compared 62 men who met all or most of the DSM-III-R criteria for eating disorders with 212 women who had similar eating disorders and 3,769 men who had no eating disorders on a wide variety of clinical and historical variables. METHOD: The groups of subjects were derived from a community epidemiologic survey performed in the province of Ontario that used the World Health Organization's Composite International Diagnostic Interview. RESULTS: Men with eating disorders were very similar to women with eating disorders on most variables. Men with eating disorders showed higher rates of psychiatric comorbidity and more psychosocial morbidity than men without eating disorders. CONCLUSIONS: These results confirm the clinical similarities between men with eating disorders and women with eating disorders. They also reveal that both groups suffer similar psychosocial morbidity. Men with eating disorders show a wide range of differences from men without eating disorders; the extent to which these differences are effects of the illness or possible risk factors for the occurrence of these illnesses in men is not clear.

Marriage in eating disorders comparisons between patients and spouses and changes over the course of treatment.

OBJECTIVES: This study examines one aspect of the marital satisfaction, intimacy, of couples where one member has an eating disorder (ED), before and after intensive day hospital treatment for ED. METHODS: Subjects were consecutive patients (n=22) attending a day hospital program for EDs and their spouses. The Waring Intimacy Questionnaire (WIQ) was administered to the couples at admission to and discharge from the treatment program. RESULTS: Patients showed less favorable ratings of the marriage at admission and discharge, compared to spouses, but patient's ratings improved significantly over the course of treatment. Patients generally improved in terms of their ED symptoms during the treatment. Spousal ratings showed satisfactory ratings of intimacy at the start of treatment and did not change over the course of treatment. CONCLUSION: The self-reported marital dissatisfaction of patients with an ED is at least partially alleviated after symptomatic treatment of the ED. Treatment of the ED in one member does not diminish marital satisfaction in the other member of the couple. The long-term prognosis for these couples remains unknown.

Perfectionism in anorexia nervosa: variation by clinical subtype, obsessionality, and pathological eating behavior.

OBJECTIVE: The purpose of this study was to examine the role of perfectionism as a phenotypic trait in anorexia nervosa and its relevance across clinical subtypes of this illness. METHOD: The Multidimensional Perfectionism Scale and the perfectionism subscale of the Eating Disorder Inventory were administered to 322 women with a history of anorexia nervosa who were participating in an international, multicenter genetic study of anorexia nervosa. All participants were additionally interviewed with the Yale-Brown Obsessive Compulsive Scale and the Yale-Brown-Cornell Eating Disorder Scale. Mean differences on dependent measures among women with anorexia nervosa and comparison subjects were examined by using generalized estimating equations. RESULTS: Persons who had had anorexia nervosa had significantly higher total scores on the Multidimensional Perfectionism Scale than did the healthy comparison subjects. In addition, scores of the anorexia subjects on the Eating Disorder Inventory-2 perfectionism subscale exceeded Eating Disorder Inventory-2 normative data. For the anorexia nervosa participants, the total score on the Multidimensional Perfectionism Scale and the Eating Disorder Inventory-2 perfectionism subscale score were highly correlated. Total score on the Multidimensional Perfectionism Scale was also significantly related to the total score and the motivation-for-change subscale score of the Yale-Brown-Cornell Eating Disorder Scale. CONCLUSIONS: These data show that perfectionism is a robust, discriminating characteristic of anorexia nervosa. Perfectionism is likely to be one of a cluster of phenotypic trait variables associated with a genetic diathesis for anorexia nervosa.

Temperament and character in women with anorexia nervosa.

The present study examined temperament differences among anorexia nervosa (AN) subtypes and community controls, as well as the effect of body weight on personality traits in women with AN. Temperament and Character Inventory (TCI) scores were compared between 146 women with restrictor-type AN (RAN), 117 women with purging-type AN (PAN), 60 women with binge/purge-type AN (BAN), and 827 community control women (CW) obtained from an archival normative database. Women with AN scored significantly higher on harm avoidance and significantly lower on cooperativeness than CW. Subtype analyses revealed that women with RAN and PAN reported the lowest novelty seeking, RAN women the highest persistence and self-directedness, and PAN women the highest harm avoidance. Body mass index had a nominal effect on subgroup differences, suggesting that personality disturbances are independent of body weight. Findings suggest that certain facets of temperament differ markedly between women with AN, regardless of diagnostic subtype, and controls. More subtle temperament and character differences that were independent of body weight emerged that distinguish among subtypes of AN.

A search for susceptibility loci for anorexia nervosa: methods and sample description.

BACKGROUND: Eating disorders have not traditionally been viewed as heritable illnesses; however, recent family and twin studies lend credence to the potential role of genetic transmission. The Price Foundation funded an international, multisite study to identify genetic factors contributing to the pathogenesis of anorexia nervosa (AN) by recruiting affective relative pairs. This article is an overview of study methods and the clinical characteristics of the sample. METHODS: All probands met modified DSM-IV criteria for AN; all affected first, second, and third degree relatives met DSM-IV criteria for AN, bulimia nervosa (BN), or eating disorder not otherwise specified (NOS). Probands and affected relatives were assessed diagnostically with the Structured Interview for Anorexia and Bulimia. DNA was collected from probands, affected relatives and a subset of their biological parents. RESULTS: Assessments were obtained from 196 probands and 237 affected relatives, over 98% of whom are of Caucasian ancestry. Overall, there were 229 relative pairs who were informative for linkage analysis. Of the proband-relative pairs, 63% were AN-AN, 20% were AN-BN, and 16% were AN-NOS. For family-based association analyses, DNA has been collected from both biological parents of 159 eating-disordered subjects. Few significant differences in demographic characteristics were found between proband and relative groups. CONCLUSIONS: The present study represents the first large-scale molecular genetic investigation of AN. Our successful recruitment of over 500 subjects, consisting of affected probands, affected relatives, and their biological parents, will provide the basis to investigate genetic transmission of eating disorders via a genome scan and assessment of candidate genes.

Laxative withdrawal in eating disorders: treatment protocol and 3 to 20-month follow-up.

OBJECTIVE: This article describes a treatment protocol for laxative withdrawal and presents some preliminary information about response to treatment at 3 to 20-month follow-up. METHOD: Patients were contacted 3 to 20 months after admission and evaluated with a shortened form of the Eating Disorders Examination (EDE). RESULTS: Fifty-seven percent of patients were abstinent from laxatives at follow-up and there were significant reductions in laxative-related symptom variables. Abstinence from laxatives was not accompanied by any other changes in eating behavior and was not associated with any pretreatment variables that were assessed. DISCUSSION: It appears to be feasible to withdraw patients from laxatives as an isolated intervention with a reasonably high rate of success.

Specificity of eating disorders diagnoses in families of probands with anorexia nervosa and bulimia nervosa.

This study examines the prevalence of anorexia nervosa and bulimia nervosa in relatives of probands, and examines the probandwise specificity of any familial clustering. Data were collected from probands using the family history method. Probands were recruited in a sequential cohort fashion. Information collected from probands was rated semiblindly by two of the authors, and a diagnostic hierarchy applied to arrive at a diagnosis for each of the relatives assessed. Data are reported on 2,125 family members, collected from 93 probands. Diagnostic agreement between raters was high, with serious disagreement present in three of 167 possible cases of an eating disorder. Rates of anorexia nervosa, bulimia nervosa, major depression, and substance abuse declined from first- to third-degree relatives, which is consistent with genetic clustering, and there was evidence of a cohort effect operating for anorexia nervosa and bulimia nervosa. The rates of anorexia nervosa and bulimia nervosa in all family members were 5.1%, and 4.3% respectively. An analysis of maternal and paternal descent showed no evidence for X-linked dominant transmission in these families. Preliminary analysis of the clustering of diagnoses in relatives showed a tendency (chi 2 = 14.47, P = .006) for family members to be affected by the same diagnosis as was the proband. This trend was strongest for anorexia nervosa, but there was overlap when the proband had a lifetime diagnosis of bulimia nervosa, with or without anorexia nervosa. These results are compatible with the existence of genetic factors influencing predisposition to eating disorders, but do not prove such.

Obsessionality in anorexia nervosa: the moderating influence of exercise.

OBJECTIVE: Research has confirmed substantial links between OCD and AN. Not only are there psychopathological similarities between the two syndromes, but a marked neurochemical correspondence. Extensive exercising is a common feature of AN and also has relevance in its links with OCD. There is evidence from the exercise-induced weight-loss syndrome in animals that exercise and caloric restriction, in combination, tend to increase serotonergic activity in a synergistic manner. This syndrome has been proposed as a valid model of OCD as well as for AN. To date, little research has directly tested this theory in the human condition. METHOD: Fifty-three AN patients were categorized as high-level exercisers (N = 22) or moderate/nonexercisers (N = 31) based on the frequency of their physical activity over the year before assessment. RESULTS: Exercisers scored significantly higher on a measure of OC personality characteristics, OC symptomatology, and perfectionism--a personality factor associated with the development of Obsessive-Compulsive Personality Disorder. On the other hand, there were no group differences on other salient eating disorder characteristics such as body esteem, self-esteem, or weight preoccupation. There were also no differences in degree of emaciation as indicated by Body Mass Index. CONCLUSIONS: Findings suggest that among AN patients obsessional personality characteristics are linked to high-level exercising, and that exercising is associated with a greater degree of OC symptomatology. Results are discussed in the context of current theories of AN, OCD, and some biological mechanisms.

The prevalence of high-level exercise in the eating disorders: etiological implications.

There is increasing evidence both from animal experimentation and from clinical field studies that physical activity can play a central role in the pathogenesis of some eating disorders. However, few studies have addressed the issue of prevalence or whether there are different rates of occurrence across diagnostic categories, and the estimates that do exist are not entirely satisfactory. The present study was designed to conduct a detailed examination of the physical activity history in patients with anorexia nervosa (AN) and bulimia nervosa (BN) both during and prior to the onset of their disorder. A sample of adult patients and a second sample of adolescent AN patients took part in the study. A series of chi-square analyses compared diagnostic groups on a number of variables related to sport/exercise behaviors both premorbidly and comorbidly. Data were obtained by means of a detailed structured interview with each patient. We found that a large proportion of eating disorder patients were exercising excessively during an acute phase of the disorder, overexercising is significantly more frequent among those with AN versus BN, and premorbid activity levels significantly predict excessive exercise comorbidity. These findings underscore the centrality of physical activity in the development and maintenance of some eating disorders. They also have important clinical implications in light of the large proportion of individuals who combine dieting and exercise in an attempt to lose weight, and the increasing recognition of the adverse effects of strenuous physical activity in malnourished individuals.

Purging and nonpurging forms of bulimia nervosa in a community sample.

OBJECTIVE: Recent consensus on the subclassification of the eating disorder bulimia nervosa into purging and nonpurging forms is examined in the context of a large psychiatric epidemiological survey in Ontario, Canada. METHOD: Among a sample of 8,116 individuals, 62 met criteria for bulimia nervosa. Of these, the 17 who were of the purging subtype could be distinguished from the nonpurging group on a variety of parameters of comorbidity, family history, and childhood environment. RESULTS: The purging subtype was distinguishable on the basis of early age of onset, and high rates of affective disorders and anxiety and alcoholism, sexual abuse, and parental discord. DISCUSSION: The data support the taxonomy and point to the need for better understanding of the meaning of purging behavior.

Long-term follow-up of patient-reported family functioning in eating disorders after intensive day hospital treatment.

This study examines eating disorder outcome and self-report ratings of family functioning by patients at admission to, discharge from, and 2-year follow-up after an intensive treatment program for eating disorders. The authors assess whether previously observed improvements in patient ratings of family functioning over the course of treatment persist throughout the follow-up period, and whether poorer eating disorder outcome is associated with less favorable patient ratings of family functioning at any of the measurement periods. Fifty-seven subjects were administered two scales of the Family Assessment Measure at admission to, discharge from, and 2 year after an intensive day hospital program for eating disorders. Structured interview determined eating disorder clinical outcome at each time. Patient assignment to clinical outcome group was determined by status at discharge, and group membership was maintained for the purposes of all analyses. Previously observed improvements in subject rating of family functioning were confirmed. Subjects with good clinical outcome at discharge showed continued improvement in some ratings of their family's functioning from discharge to follow-up by which point their ratings were significantly more favorable on the Self-Rating Scale than ratings by subjects with poor clinical outcome at discharge. Ratings by subjects with poor clinical outcome at discharge were not significantly changed during the 2-year follow-up period. We conclude that subject self-report ratings of family functioning appear to be associated with the presence of actively disordered eating, improve during treatment, and are maintained over the course of 2-year posttreatment. Individuals with a good clinical outcome at the end of treatment show further improvements on some ratings of family functioning between discharge and 2-year follow-up.

Should amenorrhoea be necessary for the diagnosis of anorexia nervosa? Evidence from a Canadian community sample.

BACKGROUND: This study compares the characteristics of women with anorexia nervosa with those of women who have all the diagnostic features of that disorder except amenorrhoea. METHOD: The study uses data from a large community epidemiological survey of the mental health status of household residents in Ontario, Canada. A multi-stage stratified sampling design generated a sample of 4285 females aged 15-64. DSM-III-R diagnoses were made using the Composite International Diagnostic interview. RESULTS: Eighty-four out of 4285 female respondents met full or partial-syndrome criteria for anorexia nervosa. Comparison of these two groups revealed few statistically significant differences in terms of demographics, psychiatric comorbidity, family history or early experiences. CONCLUSIONS: Amenorrhoea did not discriminate between women with anorexia nervosa and women with all the features except amenorrhoea across a number of relevant variables. The authors question the utility of amenorrhoea as a diagnostic criterion.

Family functioning in anxiety and eating disorders--a comparative study.

This study examines ratings of family functioning in families of origin and current (marital) families by patients with anxiety disorders (ADs) and compares them with known population means and with similar ratings by patients with eating disorders. Subjects were drawn from the Anxiety Disorders and Eating Disorders clinics of The Toronto Hospital, each group consisting of a consecutive sample. Family functioning was assessed using the general and self-rating scales of the Family Assessment Measure (FAM). Patients with ADs rated their families of origin less favorably than established population norms (general and self-rating scales, P < .001). Ratings by patients with ADs did not differ from comparable ratings by patients with eating disorders. AD patients' less favorable ratings of family of origin suggest a perception of significant family dysfunction. However, the similarity in ratings between AD and bulimia nervosa (BN) subjects suggests that this is unlikely to be specific to having an AD.

Bulimia nervosa in a Canadian community sample: prevalence and comparison of subgroups.

OBJECTIVE: Previous epidemiological studies of bulimia nervosa have generated differing estimates of the incidence and prevalence of the disorder. These differences are attributable, in part, to varying definitions of the illness and a range of methodologies. The authors sought to define the prevalence of bulimia nervosa in a nonclinical community sample, examine the clinical significance of DSM-III-R threshold criteria, and examine comorbidity. METHOD: Subjects across Ontario (N = 8,116) were assessed with a structured interview, the World Health Organization Composite International Diagnostic Interview, with specific questions added for bulimia nervosa. Subjects who met DSM-III-R criteria for bulimia nervosa were compared with those who were missing only the frequency criterion (two or more binge-eating episodes per week for 3 months). RESULTS: In this sample, the lifetime prevalence of bulimia nervosa was 1.1% for female subjects and 0.1% for male subjects. The subjects with full- and partial-syndrome bulimia nervosa showed significant vulnerability for mood and anxiety disorders. Lifetime rates of alcohol dependence were high in the full-syndrome group. Rates of parental psychopathologies were high in both bulimic groups but tended to be higher in the subjects with full-syndrome bulimia nervosa. Both bulimic groups were significantly more likely to experience childhood sexual abuse than a normal female comparison group. CONCLUSIONS: This study confirms other prevalence estimates of bulimia nervosa and its comorbid diagnoses from studies that were based on sound methodologies. It also points to the arbitrary aspects of the frequency of binge eating as a diagnostic threshold criterion for the disorder.