Supported by National Institute of Mental Health (NIMH), this 12-site international collaboration seeks to identify genetic variants that affect risk for anorexia nervosa (AN).
Four hundred families will be ascertained with two or more individuals affected with AN. The assessment battery produces a rich set of phenotypes comprising eating disorder diagnoses and psychological and personality features known to be associated with vulnerability to eating disorders.
We report attributes of the first 200 families, comprising 200 probands and 232 affected relatives.
These results provide context for the genotyping of the first 200 families by the Center for Inherited Disease Research. We will analyze our first 200 families for linkage, complete recruitment of roughly 400 families, and then perform final linkage analyses on the complete cohort. DNA, genotypes, and phenotypes will form a national eating disorder repository maintained by NIMH and available to qualified investigators.
anorexia nervosa; eating disorders; bulimia nervosa; psychiatric disorders; genetics; linkage analysis; genomics
Follow-up studies of eating disorders (EDs) suggest outcomes ranging from recovery to chronic illness or death, but predictors of outcome have not been consistently identified. We tested 5151 single-nucleotide polymorphisms (SNPs) in approximately 350 candidate genes for association with recovery from ED in 1878 women. Initial analyses focused on a strictly defined discovery cohort of women who were over age 25 years, carried a lifetime diagnosis of an ED, and for whom data were available regarding the presence (n=361 ongoing symptoms in the past year, ie, ‘ill') or absence (n=115 no symptoms in the past year, ie, ‘recovered') of ED symptoms. An intronic SNP (rs17536211) in GABRG1 showed the strongest statistical evidence of association (p=4.63 × 10−6, false discovery rate (FDR)=0.021, odds ratio (OR)=0.46). We replicated these findings in a more liberally defined cohort of women age 25 years or younger (n=464 ill, n=107 recovered; p=0.0336, OR=0.68; combined sample p=4.57 × 10−6, FDR=0.0049, OR=0.55). Enrichment analyses revealed that GABA (γ-aminobutyric acid) SNPs were over-represented among SNPs associated at p<0.05 in both the discovery (Z=3.64, p=0.0003) and combined cohorts (Z=2.07, p=0.0388). In follow-up phenomic association analyses with a third independent cohort (n=154 ED cases, n=677 controls), rs17536211 was associated with trait anxiety (p=0.049), suggesting a possible mechanism through which this variant may influence ED outcome. These findings could provide new insights into the development of more effective interventions for the most treatment-resistant patients.
GABA; anorexia nervosa; recovery from eating disorders; genetic association; single nucleotide polymorphisms; eating/metabolic disorders; GABA; eating/metabolic disorders; neurogenetics; biological psychiatry; genetic association; anorexia nervosa; recovery from eating disorders; single-nucleotide polymorphisms; phenomic association
To describe sexual functioning in women with eating disorders.
We assessed physical intimacy, libido, sexual anxiety, partner and sexual relationships in 242 women from the International Price Foundation Genetic Studies relative to normative data.
Intercourse (55.3%), having a partner (52.7%), decreased sexual desire (66.9%), and increased sexual anxiety (59.2%) were common. Women with restricting and purging anorexia nervosa had a higher prevalence of loss of libido than women with bulimia nervosa and eating disorder not otherwise specified (75%, 74.6%, 39% and 45.4%, respectively). Absence of sexual relationships was associated with lower minimum lifetime body mass index (BMI) and earlier age of onset; loss of libido with lower lifetime BMI, higher interoceptive awareness and trait anxiety; and sexual anxiety with lower lifetime BMI, higher harm avoidance and ineffectiveness. Sexual dysfunction in eating disorders was higher than in the normative sample.
Sexual dysfunction is common across eating disorders subtypes. Low BMI is associated with loss of libido, sexual anxiety, and avoidance of sexual relationships.
anorexia nervosa; eating disorders; sexual behavior; sexual dysfunction
Extremely low body mass index (BMI) values are associated with increased risk for death and poor long-term prognosis in individuals with AN. The present study explores childhood personality characteristics that could be associated with the ability to attain an extremely low BMI.
Participants were 326 women from the Genetics of Anorexia Nervosa (GAN) Study who completed the Structured Interview for Anorexia Nervosa and Bulimic Syndromes and whose mother completed the Child Behavioral Check List and/or Revised Dimensions of Temperament Survey.
Children who were described as having greater fear or anxiety by their mothers attained lower BMIs during AN (p <0.02). Path analysis in the GAN and a validation sample, Price Foundation Anorexia Nervosa Trios Study, confirmed the relation between early childhood anxiety, caloric restriction, qualitative food item restriction, excessive exercise, and low BMI. Path analysis also confirmed a relation between childhood anxiety and caloric restriction, which mediated the relation between childhood anxiety and low BMI in the GAN sample only.
Fearful or anxious behavior as a child was associated with the attainment of low BMI in AN and childhood anxiety was associated with caloric restriction. Measures of anxiety and factors associated with anxiety-proneness in childhood may index children at risk for restrictive behaviors and extremely low BMIs in AN.
Anorexia Nervosa; Anxiety; Body Mass Index
To increase the likelihood of finding genetic variation conferring liability to eating disorders, we measured over 100 attributes thought to be related to liability to eating disorders on affected individuals from multiplex families and two cohorts: one recruited through a proband with anorexia nervosa (AN; AN cohort); the other recruited through a proband with bulimia nervosa (BN; BN cohort). By a multilayer decision process based on expert evaluation and statistical analysis, six traits were selected for linkage analysis (1): obsessionality (OBS), age at menarche (MENAR) and anxiety (ANX) for quantitative trait locus (QTL) linkage analysis; and lifetime minimum Body Mass Index (BMI), concern over mistakes (CM) and food-related obsessions (OBF) for covariate-based linkage analysis. The BN cohort produced the largest linkage signals: for QTL linkage analysis, four suggestive signals: (for MENAR, at 10p13; for ANX, at 1q31.1, 4q35.2, and 8q13.1); for covariate-based linkage analyses, both significant and suggestive linkages (for BMI, one significant [4q21.1] and three suggestive [3p23, 10p13, 5p15.3]; for CM, two significant [16p13.3, 14q21.1] and three suggestive [4p15.33, 8q11.23, 10p11.21]; and for OBF, one significant [14q21.1] and five suggestive [4p16.1, 10p13.1, 8q11.23, 16p13.3, 18p11.31]). Results from the AN cohort were far less compelling: for QTL linkage analysis, two suggestive signals (for OBS at 6q21 and for ANX at 9p21.3); for covariate-based linkage analysis, five suggestive signals (for BMI at 4q13.1, for CM at 11p11.2 and 17q25.1, and for OBF at 17q25.1 and 15q26.2). Overlap between the two cohorts was minimal for substantial linkage signals.
Complex disease; endophenotype; liability; mixture model; regression
Vulnerability to anorexia nervosa (AN) and bulimia nervosa (BN) arise from the interplay of genetic and environmental factors. To explore the genetic contribution, we measured over 100 psychiatric, personality and temperament phenotypes of individuals with eating disorders from 154 multiplex families accessed through an AN proband (AN cohort) and 244 multiplex families accessed through a BN proband (BN cohort). To select a parsimonious subset of these attributes for linkage analysis, we subjected the variables to a multilayer decision process based on expert evaluation and statistical analysis. Criteria for trait choice included relevance to eating disorders pathology, published evidence for heritability, and results from our data. Based on these criteria, we chose six traits to analyze for linkage. Obsessionality, Age-at-Menarche, and a composite Anxiety measure displayed features of heritable quantitative traits, such as normal distribution and familial correlation, and thus appeared ideal for quantitative trait locus (QTL) linkage analysis. By contrast, some families showed highly concordant and extreme values for three variables — lifetime minimum Body Mass Index (lowest BMI attained during the course of illness), concern over mistakes, and food-related obsessions — whereas others did not. These distributions are consistent with a mixture of populations, and thus the variables were matched with covariate linkage analysis. Linkage results appear in a subsequent report. Our report lays out a systematic roadmap for utilizing a rich set of phenotypes for genetic analyses, including the selection of linkage methods paired to those phenotypes.
Complex disease; endophenotype; liability; clinical judgment; covariate selection; mixture model; regression
Previous studies of prognostic factors of anorexia nervosa (AN) course and recovery have followed clinical populations after treatment discharge. This retrospective study examined the association between prognostic factors—eating disorder features, personality traits, and psychiatric comorbidity—and likelihood of recovery in a large sample of women with AN participating in a multi-site genetic study. The study included 680 women with AN. Recovery was defined as the offset of AN symptoms if the participant experienced at least one year without any eating disorder symptoms of low weight, dieting, binge eating, and inappropriate compensatory behaviors. Participants completed a structured interview about eating disorders features, psychiatric comorbidity, and self-report measures of personality. Survival analysis was applied to model time to recovery from AN. Cox regression models were used to fit associations between predictors and the probability of recovery. In the final model, likelihood of recovery was significantly predicted by the following prognostic factors: vomiting, impulsivity, and trait anxiety. Self-induced vomiting and greater trait anxiety were negative prognostic factors and predicted lower likelihood of recovery. Greater impulsivity was a positive prognostic factor and predicted greater likelihood of recovery. There was a significant interaction between impulsivity and time; the association between impulsivity and likelihood of recovery decreased as duration of AN increased. The anxiolytic function of some AN behaviors may impede recovery for individuals with greater trait anxiety.
Eating disorders; anorexia nervosa; recovery; prognostic factors; personality; comorbidity
Women with eating disorders have a significantly higher prevalence of substance use disorders than the general population. The goal of the current study was to assess the temporal pattern of comorbid anorexia nervosa (AN) and alcohol use disorder (AUD) and the impact this ordering has on symptomatology and associated features. Women were placed into one of three groups based on the presence or absence of comorbid AUD and the order of AN and AUD onset in those with both disorders: (1) AN Only, (2) AN First, and (3) AUD First. The groups were compared on psychological symptoms and personality characteristics often associated with AN, AUD, or both using general linear models. Twenty-one percent of women (n = 161) with AN reported a history of AUD with 115 reporting AN onset first and 35 reporting AUD onset first. Women with binge-eating and/or purging type AN were significantly more likely to have AUD. In general, differences were found only between women with AN Only and women with AN and AUD regardless of order of emergence. Women with AN and AUD had higher impulsivity scores and higher prevalence of depression and borderline personality disorder than women with AN Only. Women with AN First scored higher on traits commonly associated with AN, whereas women with comorbid AN and AUD displayed elevations in traits more commonly associated with AUD. Results do not indicate a distinct pattern of symptomatology in comorbid AN and AUD based on the temporal sequence of the disorders.
anorexia nervosa; alcohol use disorder; comorbidity; age of onset
To examine childhood perfectionism in anorexia nervosa (AN) restricting (RAN), purging (PAN), and binge eating with or without purging (BAN) subtypes.
The EATATE, a retrospective assessment of childhood perfectionism, and the Eating Disorder Inventory (EDI-2) were administered to 728 AN participants.
EATATE responses revealed General Childhood Perfectionism, 22.3% of 333 with RAN, 29.2% of 220 with PAN, and 24.8% of 116 with BAN; School Work Perfectionism, 31.2% with RAN, 30.4% with PAN, and 24.8% with BAN; Childhood Order and Symmetry, 18.7% with RAN, 21.7% with PAN, and 17.8% with BAN; and Global Childhood Rigidity, 42.6% with RAN, 48.3% with PAN and 48.1% with BAN. Perfectionism preceded the onset of AN in all subtypes. Significant associations between EDI-2 Drive for Thinness and Body Dissatisfaction were present with four EATATE subscales.
Global Childhood Rigidity was the predominate feature that preceded all AN subtypes. This may be a risk factor for AN.
We studied the relation between intrusive and repetitive hair-pulling, the defining feature of trichotillomania, and compulsive and impulsive features in 1453 individuals with anorexia nervosa and bulimia nervosa. We conducted a series of regression models examining the relative influence of compulsive features associated with obsessive compulsive disorder; compulsive features associated with eating disorders; trait features related to harm avoidance, perfectionism and novelty seeking; and self harm. A final model with a reduced sample (n=928) examined the additional contribution of impulsive attributes. One out of 20 individuals endorsed hair-pulling. Evidence of a positive association with endorsement of compulsive behavior of the obsessive compulsive spectrum emerged. Hair-pulling may be more consonant with ritualistic compulsions than impulsive urges in those with eating disorders.
eating disorders; trichotillomania; hair-pulling; anorexia nervosa; bulimia nervosa; impulsivity; compulsivity
To further refine our understanding of impulsivity, obsessions, and compulsions in anorexia nervosa (AN) by isolating which behaviors—binge eating, purging, or both—are associated with these features.
We conducted regression analyses with binge eating, purging, and the interaction of binge eating with purging as individual predictors of scores for impulsivity, obsessions, and compulsions in two samples of women with AN (n = 1373).
Purging, but not binge eating, was associated with higher scores of impulsivity, obsessions and compulsions. Purging was also associated with worst eating rituals and with worst eating preoccupations.
Our results suggest that purging, compared with binge eating, may be a stronger correlate of impulsivity, obsessions, and compulsions in AN.
anorexia nervosa; impulsivity; compulsivity; binge eating; purging
This exploratory study assessed whether maternal recall of childhood feeding and eating practices differed across anorexia nervosa (AN) subtypes. Participants were 325 women from the Genetics of Anorexia Nervosa study whose mothers completed a childhood feeding and eating questionnaire. Multinomial logistic regression analyses were used to predict AN subtype from measures related to childhood eating: (a) infant feeding (breastfed, feeding schedule, age of solid food introduction), (b) childhood picky eating (picky eating before age one and between ages one and five), and (c) infant gastrointestinal problems (vomiting and colic). Results revealed no significant differences in retrospective maternal report of childhood feeding and eating practices among AN subtypes.
Anorexia Nervosa; Anorexia Nervosa Subtype; Feeding; Maternal Report; Infancy
Comorbidity among eating disorders, traumatic events, and post traumatic stress disorder (PTSD) has been reported in several studies. The main objectives of this study were to describe the nature of traumatic events experienced and to explore the relation between PTSD and anorexia nervosa (AN) in a sample of women.
Eight hundred twenty-four participants from the National Institutes of Health funded Genetics of Anorexia Nervosa Collaborative Study were assessed for eating disorders, PTSD, and personality characteristics.
From a final sample of 753 women with AN, 13.7% (n=103) met DSM-IV criteria for PTSD. The sample mean age was 29.5 years (SD=11.1). In pairwise comparisons across AN subtypes, the odds of having a PTSD diagnosis were significantly lower in individuals with restricting AN (RAN) than individuals with purging AN without binge eating (PAN) (OR=0.49, 95% CI=0.30, 0.80). The majority of participants with PTSD reported the first traumatic event before the onset of AN (64.1%, n=66). The most common traumatic events reported by those with a PTSD diagnosis were sexual related traumas during childhood (40.8%) and during adulthood (35.0%).
AN and PTSD do co-occur and traumatic events tend to occur prior to the onset of AN. Clinically, these results underscore the importance of assessing trauma history and PTSD in individuals with AN and raise the question of whether specific modifications or augmentations to standard treatment for AN should be considered in a subgroup to address PTSD-related psychopathology.
PTSD; anorexia nervosa; trauma; prevalence; comorbid; epigenetic
This analysis is a follow-up to an earlier investigation of 182 genes selected as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN). As those initial case-control results revealed no statistically significant differences in single nucleotide polymorphisms, herein we investigate alternative phenotypes associated with AN. In 1762 females using regression analyses we examined: (1) lowest illness-related attained body mass index; (2) age at menarche; (3) drive for thinness; (4) body dissatisfaction; (5) trait anxiety; (6) concern over mistakes; and (7) the anticipatory worry and pessimism vs. uninhibited optimism subscale of the harm avoidance scale. After controlling for multiple comparisons, no statistically significant results emerged. Although results must be viewed in the context of limitations of statistical power, the approach illustrates a means of potentially identifying genetic variants conferring susceptibility to AN because less complex phenotypes associated with AN are more proximal to the genotype and may be influenced by fewer genes.
covariates; eating disorders; association studies; personality; genetic
Extensive population-based genome-wide association studies have identified an association between the FTO gene and BMI; however, the mechanism of action is still unknown. To determine whether FTO may influence weight regulation through psychological and behavioral factors, seven single nucleotide polymorphisms (SNPs) of the FTO gene were genotyped in 1085 individuals with anorexia nervosa (AN) and 677 healthy weight controls from the international Price Foundation Genetic Studies of Eating Disorders. Each SNP was tested in association with eating disorder phenotypes and measures that have previously been associated with eating behavior pathology: trait anxiety, harm-avoidance, novelty seeking, impulsivity, obsessionality, compulsivity, and concern over mistakes. After appropriate correction for multiple comparisons, no significant associations between individual FTO gene SNPs and eating disorder phenotypes or related eating behavior pathology were identified in cases or controls. Thus, this study found no evidence that FTO gene variants associated with weight regulation in the general population are associated with eating disorder phenotypes in AN participants or matched controls.
We investigated sociodemographic characteristics in women with and without lifetime eating disorders.
Participants were from a multi-site international study of eating disorders (N = 2096). Education level, relationship status, and reproductive status were examined across eating disorder subtypes and compared with a healthy control group.
Overall, women with eating disorders were less educated than controls, and duration of illness and age of onset were associated with educational attainment. Menstrual status was associated with both relationship and reproductive status, but eating disorder subtypes did not differ significantly from each other or from healthy controls on these dimensions.
Differences in educational attainment, relationships, and reproduction do exist in individuals with eating disorders and are differentially associated with various eating disorder symptoms and characteristics. These data could assist with educating patients and family members about long-term consequences of eating disorders.
Children; relationship; education; anorexia nervosa; bulimia nervosa; amenorrhea
We examined prevalence of substance use disorders (SUD) in women with: (1) anorexia nervosa (AN) restricting type (RAN); (2) AN with purging only (PAN); (3) AN with binge eating only (BAN); and (4) lifetime AN and bulimia nervosa (ANBN). Secondary analyses examined SUD related to lifetime purging behavior and lifetime binge eating.
Participants (N = 731) were drawn from the International Price Foundation Genetic Studies.
The prevalence of SUD differed across AN subtypes, with more in the ANBN group reporting SUD than those in the RAN and PAN groups. Individuals who purged were more likely to report substance use than those who did not purge. Prevalence of SUD differed across lifetime binge eating status.
SUD are common in AN and are associated with bulimic symptomatology. Results underscore the heterogeneity in AN, highlighting the importance of screening for SUD across AN subtypes.
eating disorders; anorexia nervosa; bulimia nervosa; drug use; alcohol related disorders; cannabis
We performed association studies with 5,151 SNPs that were judged as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN) based on location under reported linkage peaks, previous results in the literature (182 candidate genes), brain expression, biological plausibility, and estrogen responsivity. We employed a case–control design that tested each SNP individually as well as haplotypes derived from these SNPs in 1,085 case individuals with AN diagnoses and 677 control individuals. We also performed separate association analyses using three increasingly restrictive case definitions for AN: all individuals with any subtype of AN (All AN: n = 1,085); individuals with AN with no binge eating behavior (AN with No Binge Eating: n = 687); and individuals with the restricting subtype of AN (Restricting AN: n = 421). After accounting for multiple comparisons, there were no statistically significant associations for any individual SNP or haplotype block with any definition of illness. These results underscore the importance of large samples to yield appropriate power to detect genotypic differences in individuals with AN and also motivate complementary approaches involving Genome-Wide Association (GWA) studies, Copy Number Variation (CNV) analyses, sequencing-based rare variant discovery assays, and pathway-based analysis in order to make up for deficiencies in traditional candidate gene approaches to AN.
single nucleotide polymorphisms; probands; anorexia nervosa; bulimia nervosa
We investigated the relation between diet pill use and eating disorder subtype, purging and other compensatory behaviors, body mass index (BMI), tobacco and caffeine use, alcohol abuse or dependence, personality characteristics, and Axis I and Axis II disorders in 1,345 participants from the multisite Price Foundation Genetics Studies. Diet pill use was significantly less common in women with restricting type of AN than in women with other eating disorder subtypes. In addition, diet pill use was associated with the use of multiple weight control behaviors, higher BMI, higher novelty seeking, and the presence of anxiety disorders, alcohol abuse or dependence, and borderline personality disorder. Findings suggest that certain clinical and personality variables distinguish individuals with eating disorders who use diet pills from those who do not. In the eating disorder population, vigilant screening for diet pill use should be routine clinical practice.
Eating disorders; diet pills; weight control behaviors; novelty seeking