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.

Alterations in serotonin activity and psychiatric symptoms after recovery from bulimia nervosa.

BACKGROUND: Women with bulimia nervosa (BN) have disturbances of mood and behavior and alterations of monoamine activity when they are bingeing and purging. It is not known whether these alterations are secondary to pathological eating behavior or traits that could contribute to the pathogenesis of BN. METHODS: To avoid the confounding effects of pathological eating behavior, we studied 30 women after long-term recovery (>1 year with no bingeing or purging, normal weight, and regular menstrual cycles) from BN. Subjects were compared with 31 healthy volunteer women. We assessed psychiatric diagnoses and symptoms to determine whether there was any persistent disturbance of behavior after recovery. We measured cerebrospinal fluid (CSF) levels of the major metabolites of serotonin (5-hydroxyindoleacetic acid [5-HIAA]), dopamine (homovanillic acid [HVA]), and norepinephrine (3-methoxy-4-hydroxyphenylglycol [MHPG]) as well as hormonal and behavioral response to m-chlorophenylpiperazine (m-CPP), a serotonin-specific agent. RESULTS: Women who were recovered from BN had mild to moderate negative moods and obsessions with perfectionism and exactness and exaggerated core eating disorder symptoms compared with healthy volunteer women. Recovered BN women had increased levels of CSF 5-HIAA compared with control women (117 +/- 33 vs 73 +/- 15 pmol/mL; P< or =.001) but normal CSF HVA and MHPG concentrations. Recovered BN women had an anxious and disorganized behavioral response to m-CPP but a normal hormonal response. CONCLUSIONS: Persistent serotonergic and behavioral abnormalities after recovery raise the possibility that these psychobiological alterations might be trait-related and contribute to the pathogenesis of BN.

A controlled family study of anorexia nervosa and bulimia nervosa: psychiatric disorders in first-degree relatives and effects of proband comorbidity.

BACKGROUND: We used contemporary family-epidemiological methods to examine patterns of comorbidity and familial aggregation of psychiatric disorders for anorexia and bulimia nervosa. METHODS: Direct interviews and blind best-estimate diagnostic procedures were used with diagnostically "pure" groups of probands with eating disorders and a matched control group. Lifetime prevalence rates of eating disorders, mood disorders, substance use disorders, anxiety disorders, and selected personality disorders were determined in female probands with restricting anorexia nervosa (n=26) or bulimia nervosa (n=47), control women (n=44), and first-degree biological relatives (n=460). RESULTS: Relatives of anorexic and bulimic probands had increased risk of clinically subthreshold forms of an eating disorder, major depressive disorder, and obsessive-compulsive disorder. Familial aggregation of major depressive disorder and obsessive-compulsive disorder was independent of that of anorexia nervosa and bulimia nervosa. These relatives also had increased risk of other anxiety disorders, but the mode of familial transmission was not clear-cut. The risk of substance dependence was elevated among relatives of bulimic probands compared with relatives of anorexic probands, and familial aggregation was independent of that of bulimia nervosa. The risk of obsessive-compulsive personality disorder was elevated only among relatives of anorexic probands, and there was evidence that these 2 disorders may have shared familial risk factors. CONCLUSIONS: There may be a common familial vulnerability for anorexia nervosa and bulimia nervosa. Major depressive disorder, obsessive-compulsive disorder, and substance dependence are not likely to share a common cause with eating disorders. However, obsessional personality traits may be a specific familial risk factor for anorexia nervosa.

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.

Sexual abuse in eating disorder subtypes and control women: the role of comorbid substance dependence in bulimia nervosa.

OBJECTIVE: The relationship between sexual abuse and eating disorders remains uncertain. Recent data have raised the possibility of differential rates of sexual abuse among subtypes of eating disorders. METHODS: We studied women with three subtypes of eating disorders: (1) 26 anorexia nervosa subjects (AN); (2) 20 bulimia nervosa subjects with comorbid substance dependence (BN + SDD); and (3) 27 bulimia nervosa subjects without substance dependence (BN - SDD). We compared women with these eating disorder subtypes to 44 control women (CW). Sexual abuse rates and diagnoses were assessed through direct structured interviews. RESULTS: We found an order effect for sexual abuse which was most common (65%) in BN + SDD subjects, followed by a rate of 37% in BN - SDD subjects and 23% in AN subjects. Subjects of all eating disorder subtypes had significantly higher rates of sexual abuse compared to a rate of 7% in CW subjects. DISCUSSION: Women with BN + SDD had the highest frequency and the most severe history of sexual abuse. However, the causal relationship between eating disorders and sexual abuse remains to be elucidated.

Familial aggregation of eating disorders: results from a controlled family study of bulimia nervosa.

OBJECTIVE: While familial aggregation of bulimia nervosa (BN) is known to occur, the extent to which aggregation of a broader spectrum of eating disorders (ED) occurs in the families of individuals with BN is less certain. METHOD: Direct interviews and blind best-estimate diagnostic procedures were used to assess lifetime histories of EDs among first-degree relatives (n = 177) of probands with BN (n = 47) and first-degree relatives (n = 190) of non-ED control probands (n = 44). RESULTS: Forty-three percent of sisters and 26% of mothers of BN probands had a lifetime ED diagnosis, with eating disorder not otherwise specified (ED-NOS) diagnoses being most common. These rates were significantly higher than among sisters (5%) and mothers (5%) of controls. Few male relatives of either cohort had an ED. CONCLUSIONS: Diagnostic assessment using contemporary family-epidemiology methodology revealed very strong familial aggregation of a broad spectrum of EDs among female relatives of women with BN.

Personality traits among currently eating disordered, recovered and never ill first-degree female relatives of bulimic and control women.

BACKGROUND: A combined family study and recovered study design was utilized to examine several hypothesized relationships between personality and bulimia nervosa (BN). METHODS: We studied 47 women with a lifetime history of DSM-III-R BN (31 currently ill and 16 recovered), 44 matched control women (CW) with no history of an eating disorder (ED), and their first-degree female relatives (N = 89 and N = 100, respectively), some of whom had current or previous EDs. RESULTS: BN probands' relatives with no ED history had significantly elevated levels of perfectionism, ineffectiveness, and interpersonal distrust compared to CW probands' relatives with no ED history. In contrast, diminished interoceptive awareness, heightened stress reactivity and perfectionistic doubting of actions were found among the previously eating disordered relatives of bulimic probands compared to their never ill relatives. Finally, a sense of alienation and emotional responsivity to the environment were elevated among currently ill compared to recovered bulimic probands. CONCLUSIONS: The fact that perfectionism, ineffectiveness and interpersonal distrust are transmitted independently of an ED in relatives suggests that they may be of potential aetiological relevance for BN. In contrast, diminished interoceptive awareness, heightened stress reactivity and perfectionistic doubting of actions are more likely consequent to, or exacerbated by, previously having experienced the illness. Finally, a sense of alienation and emotional responsivity to the environment are more likely to be associated with currently having BN.

Bulimia nervosa and substance dependence: association and family transmission.

Alcohol and drug use disorders are common among women with bulimia nervosa (BN) and their family members. However, it is not known whether there is a familial relationship between BN and substance use disorders. We compared 47 women with BN and 44 non-eating-disordered community control women, and their first-degree relatives (177 and 190, respectively). BN probands were stratified by the presence (43%) or absence (57%) of lifetime alcohol and/or drug dependence. The first-degree relatives of substance-dependent BN probands had significantly higher lifetime rates of alcohol/drug dependence (38%), compared with relatives of nonsubstance-dependent BN probands (10%) or relatives of community controls (18%). These data suggest that BN and substance dependence are transmitted independently in families.

Psychiatric disorders in women with bulimia nervosa and their first-degree relatives: effects of comorbid substance dependence.

OBJECTIVE: Women with bulimia nervosa (BN) and comorbid substance dependence often display impulsive behaviors. We assessed Axis I and II psychiatric diagnoses in their first-degree relatives in order to understand the etiological factors that may contribute to this subtype of BN. METHOD: We used contemporary family-epidemiological methodology to compare the lifetime prevalence of psychiatric disorders among 47 women with BN and 44 non-eating-disordered community control women, and their first-degree relatives (177 and 190, respectively). BN probands were stratified by the presence (n = 20) or absence (n = 27) of a lifetime history of alcohol and/or drug dependence. RESULTS: Social phobia, conduct disorder, and clusters B and C personality disorders were significantly more prevalent among BN probands with substance dependence than among BN probands without substance dependence or control women probands. Substance use disorders, social phobia, panic disorder, and cluster B personality disorders were significantly more prevalent among the relatives of BN probands with substance dependence than the relatives of the other two groups. DISCUSSION: Women with BN and substance dependence have problems with social anxiety, antisocial behavior, and a variety of personality disturbances, and come from families where there are problems with substance use disorders, anxiety, impulsivity, and affective instability. These data raise the possibility that a familial vulnerability for impulsivity and affective instability may contribute to the development of substance dependence in a subgroup of women with BN.

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.