Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10−7) in SOX2OT and rs17030795 (P=5.84×10−6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10−6) between CUL3 and FAM124B and rs1886797 (P=8.05×10−6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P= 4×10−6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.
anorexia nervosa; eating disorders; GWAS; genome-wide association study; body mass index; metabolic
Introduction: Studies suggest that initial smoking pleasure influences future smoking behavior. We investigated how initial reactions to cigarettes or Swedish smokeless tobacco (snus) were associated with future use among 10,708 adults from the Swedish Twin Registry.
Methods: The Early Smoking Experience questionnaire captured physiologic reactions to initial tobacco use. Binary recursive partitioning (BRP) identified combinations of initial reactions predictive of regular tobacco use. Analyses, stratified by sex, were conducted separately among those who experimented with only cigarettes (EC), only snus (ES), and both products (EC+S).
Results: Among EC, 39.8% of men and 43.7% of women became smokers, while among ES, 78.6% of men and 53.7% of women became snus users. Among EC+S, 31.3% of men and 20.0% of women became dual users. BRP identified different reactions as predictive of future smoking for men (buzz) and women (dizziness, difficulty inhaling). No initial reaction predicted future snus use among men, but pleasant sensations, later age at first use, and relaxation predicted future snus use for women. Among EC+S, future exclusive use of either product was associated with a favorable initial reaction to that product. Dual users experienced higher prevalence of pleasant reactions and lower prevalence of unpleasant reactions in response to both products.
Conclusions: Our findings support that those who progress to regular tobacco use may be sensitive to the rewarding effects of nicotine but suggest that initial reactions differ by tobacco type. A high proportion of men became regular snus users regardless of initial reactions.
Early maturing girls are at increased risk for disordered eating. However, it is unclear if the association between puberty and disordered eating continues throughout pubertal development and if a similar association is exhibited in boys.
Participants included 1340 same- and 624 opposite-sex twins from the Swedish Twin Study of Child and Adolescent Development. Pubertal development was assessed at age 13–14 with the Pubertal Development Scale. General disordered eating, measured with the Eating Disorder Inventory-2 (EDI) was assessed at age 16–17, and dieting and purging behaviors were assessed at both ages 16–17 and 19–20. We applied analysis of variance and logistic regression analyses to determine whether pubertal development in early-to-mid adolescence predicted eating disorder-related behaviors in late adolescence and young adulthood
Pubertal development in early-to-mid adolescence was significantly associated with EDI scores and dieting in late adolescence. No significant association was observed between pubertal development and dieting and purging in young adulthood.
Complex combinations of cultural and biological influences likely converge during pubertal development increasing vulnerability to disordered eating. The impact of pubertal development on disordered eating appears to be limited to the adolescent period.
disordered eating; eating disorder; puberty; pubertal development; development; adolescence
An early age at menarche is associated with disordered eating in women. However, it is unclear whether they share genetic factors. The goal of the current study is to delineate the genetic correlation between age at menarche and disordered eating.
Participants included 427 monozygotic and 329 dizygotic 16-17 year-old female twins from the Swedish Twin Study of Child and Adolescent Development. Disordered eating was assessed with the Eating Disorder Inventory-2. Age at menarche was assessed via self-report. A bivariate correlated factors model was used to delineate the genetic correlation between age at menarche and disordered eating.
The analysis revealed a negative genetic correlation of −.18 in the best-fit model indicating that the genetic factors that influence younger age at menarche are associated with increased liability for disordered eating.
Future research should examine possible causes for this correlation such as the estrogen system and gene-environment interactions.
disordered eating; puberty; adolescence; twin study
NOURISH is a community-based treatment program for parents of overweight and obese children (ages 6–11, BMI ≥ 85th percentile). This study examined the impact of NOURISH on child and parent dietary intake, secondary trial outcomes.
In Virginia from 2008–2009, this randomized controlled pilot was implemented and dietary assessment of parents and children conducted at baseline, post-test, and 6-month follow-up. Parents (85% female, 62% African American, mean BMI=34.1±9.1) were randomized into intervention (n=46) or control (n=50) groups. Children’s (mean age=8.6±1.5) mean BMI percentile was 98.1±2.6. Parents completed 24-hour dietary records for themselves and their child(ren). Repeated measures analyses assessed treatment effects over time. T-tests evaluated within-group changes from baseline to post-test and to follow-up, using a modified intent-to-treat approach.
Both groups reported significant dietary changes, with few treatment effects found. For parents in NOURISH, significant improvements were found in intakes of total kilocalories/day, grams/day of carbohydrates and sugar, and percent calories from protein (p<0.05). Among control group children, significant improvements in total kilocalories/day and grams/day of carbohydrates and sugar were found (p<0.05).
Among parents who self-select into a childhood obesity program, minimal intervention can elicit short-term dietary changes comparable to those of a structured intervention.
parent; diet; pediatric obesity
We examined the association among current self-reported sleep problems, lifetime binge eating, and current obesity in women from the Swedish Twin study of Adults: Genes and Environment study
Logistic regression analyses were used to evaluate these associations in 3,790 women aged 20-47 years.
Binge eating was reported by 244 (6.4%) women and was positively associated with not getting enough sleep (p < .015), sleeping poorly (p < .001), problems falling asleep (p < .001), feeling sleepy during work or free time (p < .001), and disturbed sleep (p < .001). These same sleep variables, as well as napping and being a night person, were also significantly associated with obesity. The associations between binge eating and sleep remained after accounting for obesity.
This investigation offers empirical support for an independent association between sleep problems and binge eating, which is likely due to complex psychological, biological, neuroendocrine, and metabolic factors.
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
We assessed the impact of reducing the binge eating frequency and duration thresholds on the diagnostic criteria for bulimia nervosa (BN) and binge eating disorder (BED).
We estimated the lifetime population prevalence of BN and BED in 13,295 female twins from the Swedish Twin study of Adults: Genes and Environment employing a range of frequency and duration thresholds. External validation (risk to co-twin) was used to investigate empirical evidence for an optimal binge eating frequency threshold.
The lifetime prevalence estimates of BN and BED increased linearly as the frequency criterion decreased. As the required duration increased, the prevalence of BED decreased slightly. Discontinuity in co-twin risk was observed in BN between at least four times per month and at least five times per month. This model could not be fit for BED.
The proposed changes to the DSM-5 binge eating frequency and duration criteria would allow for better detection of binge eating pathology without resulting in a markedly higher lifetime prevalence of BN or BED.
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
Family, twin, and adoption studies of anorexia nervosa (AN), bulimia nervosa (BN), binge-eating disorder (BED), and the proposed purging disorder presentation (PD) have consistently demonstrated that genetic factors contribute to the variance in liability to eating disorders. In addition, endophenotypes and component phenotypes of eating disorders have been evaluated and provide further insight regarding genetic factors influencing eating disorders and eating disorder diagnostic criteria. Many of these phenotypes have demonstrated substantial heritability. This chapter reviews biometrical genetic methods and current findings from family and twin studies that investigate the role of genes and environment in the etiology of eating disorders. We review the methodology used to estimate heritability, the results of these studies, and discuss the implications of this research for the basic conceptualization of eating disorders and the future value of twin modeling in the molecular genetic era.
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
These three studies examined the hypothesis that prenatal exposure to sex hormones influences twins’ risk for eating disorders based on co-twin sex, such that individuals with a female co-twin would be more likely than individuals with a male co-twin to meet diagnostic criteria for an eating disorder.
Male and female twins from the United States (N=2,607), Norway (N=2,796) and Sweden (N=16,458) with known co-twin sex and zygosity were assessed for eating disorders.
In the U.S. and Swedish samples, sex was significantly associated with eating disorder diagnoses, and although co-twin sex was not associated with eating disorders overall, it was associated with broadly defined bulimia nervosa in the Swedish sample. The effects for bulimia were not sustained when monozygotic twins were excluded, suggesting that the effects of prenatal sex hormones play a minor role in influencing eating disorders. Sex and co-twin sex were not associated with eating disorders in the Norwegian sample.
The prenatal sex hormone hypothesis, which proposes that prenatal hormone exposure is associated with later eating disorder symptomatology, was not supported in these three population-based twin samples.
eating disorders; estrogen; opposite sex twin pairs; prenatal hormone exposure; testosterone; twin study
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
We explore comorbidity of anorexia nervosa (AN) and generalized anxiety disorder (GAD) and their relation with body mass index (BMI) and evaluate the presence of fasting and excessive exercise which both have anxiolytic and weight loss effects. All participants were female: 32 with AN only, 607 with GAD only, 22 with AN and GAD (AN+GAD), and 5,424 with no history of AN or GAD (referent) from the Swedish Twin study of Adults: Genes and Environment (STAGE). Lowest adult BMI differed significantly (p < .001) and was lower in those with AN+GAD than those with AN only (p < .029). Those with AN+GAD were most likely to endorse fasting and excessive exercise, followed by women with AN only, women with GAD only, and the referent. Comorbid AN and GAD may be a particularly pernicious presentation influencing both BMI and proclivity to engage in behaviors such as fasting and exercise that serve both weight loss and anxiolytic goals.
Anorexia nervosa; Generalized anxiety disorder; Body mass index; fasting; comorbidity
Practical limitations and sample size considerations often lead to broadening of diagnostic criteria for anorexia nervosa (AN) in research. The current study sought to elucidate the effects of this practice on resultant sample characteristics in terms of eating disorder behaviors, psychiatric comorbidities, temperament and personality characteristics, and heritability point estimates. Three definitions of AN were created: meeting all Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria for AN (AN-DSM-IV), meeting all DSM-IV criteria except criterion D, amenorrhea, (AN-noD), and broadening DSM-IV AN criteria by allowing a higher body mass index value, eliminating criterion D, and allowing less stringent body weight concerns (AN-Broad). Using data from the Swedish Twin Registry, 473 women fit one of the three definitions of AN. Women with AN-DSM-IV reported significantly more eating disorder behaviors than women with AN-Broad. Women with AN-noD reported more comorbid psychiatric disorders than women with AN-DSM-IV and AN-Broad. Temperament and personality characteristics did not differ across the three groups. Heritability point estimates decreased as AN definition broadened. Broadening the diagnostic criteria for AN results in an increased number of individuals available for participation in research studies. However, broader criteria for AN yield a more heterogeneous sample with regard to eating disorder symptoms and psychiatric comorbidity than a sample defined by narrower criteria.
Anorexia Nervosa; Classification; Diagnostic Criteria; Eating Disorder
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
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
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