Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [rg ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (rg = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (rg = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (rgs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.

Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa.

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness1, affecting 0.9-4% of women and 0.3% of men2-4, with twin-based heritability estimates of 50-60%5. Mortality rates are higher than those in other psychiatric disorders6, and outcomes are unacceptably poor7. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)8,9 and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.

Network analysis of specific psychopathology and psychiatric symptoms in patients with eating disorders.

BACKGROUND: Network analysis of psychiatric symptoms describes reciprocal relationships of individual symptoms, beyond categorical diagnoses. Those with eating disorders (EDs) frequently have complex patterns of comorbid symptoms and the transdiagnostic theory includes shared common core features across diagnoses. We aim to test whether general psychiatric symptoms comprise components of these transdiagnostic features. METHODS: Network analysis was applied on 2068 patients with EDs (955 anorexia nervosa [AN], 813 bulimia nervosa [BN], and 300 binge-eating disorder [BED]). All patients underwent clinical interviews and some self-reported questionnaires, such as the Symptom Check-List 90 (SCL-90) to measure psychiatric symptoms, the Eating Disorder Inventory (EDI) to measure ED-specific symptoms, and the Tridimensional Personality Questionnaire (TPQ) for personality traits. RESULTS: Across EDs and within each ED, SCL-90 scores of depression, anxiety and interpersonal sensitivity, EDI ineffectiveness, interoceptive awareness, interpersonal distrust, and drive for thinness had high centrality. Notably, body mass index (BMI) and EDI bulimia played a central role when considering the whole group, whereas they did not in individual EDs. DISCUSSION: The shared centrality of identified nodes in both individual and merged groups supported the transdiagnostic theory of EDs (diagnoses share core ED features), with a central role of BMI. Moreover, the most central nodes were general psychiatric symptoms, interpersonal domain, and self-efficacy. These findings suggest that-in addition to ED-core symptoms and BMI-depressive and anxiety symptoms, interpersonal sensitivity and ineffectiveness may be important targets to provide effective treatments across AN, BN, and BED.

Decision-making impairment in anorexia nervosa: New insights into the role of age and decision-making style.

OBJECTIVE: Patients with anorexia nervosa (AN) often report difficulties in decision making, which may interfere with treatment. The aim of this study was to investigate decision making in a large sample of adolescent and adult patients with AN, by using the Iowa gambling task. METHOD: Participants were 611 female individuals (310 patients and 301 controls) who underwent neuropsychological and clinical assessment. RESULTS: Significantly poorer decision-making performance was observed in adult patients, whereas no difference emerged between affected and nonaffected adolescents. Both adolescent and adult patients were characterized by trends for higher levels of attention to losses in comparison with healthy controls. Although healthy adult women exhibited better decision-making performance than healthy adolescents, in AN, there was no improvement of decision making with age. A cluster analysis identified 2 different styles of decision making in both patients and controls: a conservative style and an impulsive style. DISCUSSION: Our study provides evidence of dysfunctional decision making in adult patients with AN and reveals an association between poor decision making and excessive punishment sensitivity in AN. The clinical and scientific implications of these findings merit further exploration.

The impact of weight suppression and weight loss speed on baseline clinical characteristics and response to treatment.

OBJECTIVE: Growing evidence suggests an impact of weight suppression (WS) on severity and course of symptoms in patients with eating disorders (ED), but no study explored also the role of the weight loss speed (WLS) together with WS on the same clinical variables, which is the aim of the present work. METHOD: A mixed cross-sectional and longitudinal cohort study was employed. Four hundred and fourteen patients with anorexia nervosa (AN = 208) or bulimia nervosa (BN = 206) according to DSM-5 criteria were recruited and assessed at referral by means of clinical interviews and self-reported questionnaires. Body mass index and diagnostic status were re-evaluated at the end of treatment. RESULTS: WS was positively correlated with body dissatisfaction in patients with AN (p = .005), but negatively correlated in BN (p = .022). In contrast, WLS was significantly inversely correlated with age and duration of illness in all ED (p < .001), and positively correlated with drive for thinness in BN (p = .007). After treatment, WS at intake predicted higher BMI increase in both AN and BN (p < .03), while higher WLS was significantly associated with a lower drop-out rate in patients with BN (p = .02), and predicted BMI increase only in restricting AN patients (p = .02). In the whole group, WLS significantly predicted remission status (p = .039). DISCUSSION: In our study, both WS and WLS were associated with baseline "core" clinical variables and provided complementary abilities to predict weight gain and remission at the end of treatment. If replicated, our data suggest the importance of considering both WS and WLS as useful clinical variables in the baseline assessment of ED.

Functional connectivity correlates of response inhibition impairment in anorexia nervosa.

Anorexia nervosa (AN) is a disorder characterized by high levels of cognitive control and behavioral perseveration. The present study aims at exploring inhibitory control abilities and their functional connectivity correlates in patients with AN. Inhibitory control - an executive function that allows the realization of adaptive behavior according to environmental contingencies - has been assessed by means of the Stop-Signal paradigm. The study involved 155 patients with lifetime AN and 102 healthy women. A subsample underwent resting-state functional magnetic resonance imaging and was genotyped for COMT and 5-HTTLPR polymorphisms. AN patients showed an impaired response inhibition and a disruption of the functional connectivity of the ventral attention circuit, a neural network implicated in behavioral response when a stimulus occurs unexpected. The 5-HTTLPR genotype appears to significantly interact with the functional connectivity of ventral attention network in explaining task performance in both patients and controls, suggesting a role of the serotoninergic system in mechanisms of response selection. The disruption of the ventral attention network in patients with AN suggests lower efficiency of bottom-up signal filtering, which might be involved in difficulties to adapt behavioral responses to environmental needs. Our findings deserve further research to confirm their scientific and therapeutic implications.

Clinical and genetic correlates of decision making in anorexia nervosa.

INTRODUCTION: Decision-making (DM) abilities have been found to be impaired in anorexia nervosa (AN), but few data are available about the characteristics and correlates of this cognitive function. The aim of the present study was to provide data on DM functioning in AN using both veridical and adaptive paradigms. While in veridical DM tasks, the individual's ability to predict a true/false response is measured, adaptive DM is the ability to consider both internal and external demands in order to make a good choice, in the absence of a single true "correct" answer. METHOD: The participants were 189 women, of whom 91 were eating-disordered patients with a lifetime diagnosis of anorexia nervosa, and 98 were healthy women. All the participants underwent clinical, neuropsychological, and genetic assessment. The cognitive evaluation included a set of neuropsychological tasks and two decision-making tests: The Iowa Gambling Task and the Cognitive Bias Task. RESULTS: Anorexia nervosa patients showed significantly poorer performances on both decision-making tasks than healthy women. The Cognitive Bias Task revealed that anorexia nervosa patients employed significantly more context-independent decision-making strategies, which were independent from diagnostic subtype, handedness, education, and psychopathology. In the whole sample (patients and controls), Cognitive Bias Task performance was independently predicted by lifetime anorexia nervosa diagnosis, body mass index at assessment, and 5-HTTLPR genotype. CONCLUSIONS: Patients displayed poor decision-making functioning in both veridical and adaptive situations. The difficulties detected in anorexia nervosa individuals may affect not only the ability to consider the future outcomes of their actions (leading to "myopia for the future"), but also the capacity to update and review one's own mindset according to new environmental stimuli.

Executive Functioning and Visuospatial Abilities in Bulimia Nervosa with or without a Previous History of Anorexia Nervosa.

OBJECTIVE: The aim of the present study was to investigate executive functioning and visuospatial abilities in patients with bulimia nervosa (BN), with a particular interest in exploring the impact of a previous diagnosis of anorexia nervosa (AN). METHOD: Several neuropsychological tasks were administered to 89 BN patients (52 with a previous history of AN and 37 without previous AN) and 160 healthy women. RESULTS: A poorer performance on set-shifting measures (Wisconsin Card Sorting Test) was found only in BN patients with a previous history of AN. Decision-making abilities (Iowa Gambling Task) were significantly impaired in the whole sample of BN patients, but difficulties were more pronounced in the subgroup with previous AN. Finally, we did not find any differences in response inhibition and visuospatial abilities between the two samples of BN patients and healthy women. DISCUSSION: Our findings support the idea that cognitive abilities in patients with BN are more impaired in the presence of a prior history of AN. The clinical and treatment implications of our findings should be explored in future studies.

Gyrification brain abnormalities as predictors of outcome in anorexia nervosa.

Gyrification brain abnormalities are considered a marker of early deviations from normal developmental trajectories and a putative predictor of poor outcome in psychiatric disorders. The aim of this study was to explore cortical folding morphology in patients with anorexia nervosa (AN). A MRI brain study was conducted on 38 patients with AN, 20 fully recovered patients, and 38 healthy women. Local gyrification was measured with procedures implemented in FreeSurfer. Vertex-wise comparisons were carried out to compare: (1) AN patients and healthy women; (2) patients with a full remission at a 3-year longitudinal follow-up assessment and patients who did not recover. AN patients exhibited significantly lower gyrification when compared with healthy controls. Patients with a poor 3-year outcome had significantly lower baseline gyrification when compared to both healthy women and patients with full recovery at follow-up, even after controlling for the effects of duration of illness and gray matter volume. No significant correlation has been found between gyrification, body mass index, amount of weight loss, onset age, and duration of illness. Brain gyrification significantly predicted outcome at follow-up even after controlling for the effects of duration of illness and other clinical prognostic factors. Although the role of starvation in determining our findings cannot be excluded, our study showed that brain gyrification might be a predictor of outcome in AN. Further studies are needed to understand if brain gyrification abnormalities are indices of early neurodevelopmental alterations, the consequence of starvation, or the interaction between both factors.

Stressful life events and binge eating disorder.

Although there is evidence about the role played by stressful life events (SE) in the pathogenesis of eating disorders, few studies to date have explored this problem in binge eating disorder (BED). The aim of the present study was to examine SE preceding the onset of BED. A retrospective interview-based design was used to compare 107 patients with BED and 107 patients with bulimia nervosa (BN), matched for duration of illness. Compared with patients with BN, those with BED reported a greater number of traumatic events in the 6 months preceding onset, revealing more often three types of events: bereavement, separation from a family member and accidents. The presence of SE before onset showed a dose-response relationship with the severity of psychopathology at the time of referral for treatment. Study of SE in patients with BED may be important for better understanding of the pathogenetic pathway to this disorder and to provide adequate treatment.

Effects of obstetric complications on volume and functional connectivity of striatum in anorexia nervosa patients.

OBJECTIVE: To investigate the volume and functional connectivity of dorsal and ventral striatal nuclei in anorexia nervosa (AN) and their relationship with early exposure to obstetric complications. METHOD: Fifty-one patients with lifetime AN (35 acute, 16 recovered) and 34 healthy controls underwent high-resolution and resting-state functional magnetic resonance imaging. RESULTS: The AN group showed reduced functional connectivity of the putamen compared with healthy women, and this reduction was more evident in patients with lifetime binge eating/purging. Both acute and recovered AN groups showed a larger left accumbens area compared with that of healthy women. The functional connectivity of bilateral nucleus accumbens and putamen showed significant negative correlations with number of obstetric complications in the AN group. DISCUSSION: This study supports the hypothesis that AN is associated with structural and functional alterations of striatal networks, and reveals the possible role of obstetric complications in the pathogenesis of striatal dysfunction.

Neural signatures of the interaction between the 5-HTTLPR genotype and stressful life events in healthy women.

A change in neural connectivity of brain structures implicated in the memory of negative life events has been hypothesized to explain the enhancement of memory encoding during the processing of negative stimuli in depressed patients. Here, we investigated the effects of the interaction between negative life events and the 5-HTTLPR genotype - a polymorphism of the serotonin transporter gene - on the functional and structural connectivity of the hippocampal area in 34 healthy women. All participants were genotyped for the presence of the 5-HTTLPR short variant and for the A/G single-nucleotide polymorphism; they underwent clinical assessment including structured diagnostic interviews to exclude the presence of psychiatric disorders and to assess the presence of stressful life events. Resting state functional magnetic resonance imaging and diffusion tensor imaging scans were performed. We found significant interactions between stressful events and the 5-HTTLPR genotype in both the functional connectivity of the parahippocampus with the posterior cingulate cortex and the structural connectivity between the hippocampus and both the amygdala and the putamen. In addition, we found several genotype-related differences in the relationship between functional/structural connectivity of the hippocampal area and the ability to update expectations or stress-related phenotypes, such as anxiety symptoms. If confirmed by future studies, these mechanisms may clarify the role of the 5HTTLPR genotype as a risk factor for depression, in interaction with negative events.

Childhood obsessive-compulsive traits in anorexia nervosa patients, their unaffected sisters and healthy controls: a retrospective study.

Although there is evidence that childhood perfectionistic traits predate the onset of eating disorders, few studies to date have examined the prevalence and clinical correlates of these traits in patients with anorexia nervosa (AN) and their unaffected sisters. The aim of this work was to study the prevalence of childhood obsessive-compulsive traits in patients with lifetime AN, their unaffected sisters and healthy women. A total of 116 AN patients, 32 healthy sisters and 119 controls were assessed by the EATATE Interview to assess traits such as perfectionism, inflexibility, rule-bound traits, drive for order and symmetry, and excessive doubt and cautiousness. Both self-report and maternal reports were collected. AN patients reported more childhood obsessive-compulsive traits than their healthy sisters and controls. In contrast, no differences between healthy controls and unaffected sisters emerged. In patients with AN, a dose-response relationship was found between the number of childhood obsessive-compulsive traits and psychopathology, including body image distortion, thus indicating that these traits are an important feature to be considered in assessing and treating eating disorders.

Catechol-O-methyltransferase genotype modifies executive functioning and prefrontal functional connectivity in women with anorexia nervosa.

BACKGROUND: Anorexia nervosa is characterized by high levels of perseveration and inflexibility, which interfere with successful treatments. Dopamine (DA) signalling seems to play a key role in modulating the prefrontal cortex, since both DA deficiency and excess nega tively influence the efficiency of cognitive functions. The present study explores the effect of a functional polymorphism (Val158Met) in the catechol-O-methyltransferase (COMT) gene on the set-shifting abilities and prefrontal functional connectivity of patients with anorexia nervosa. METHODS: All participants performed the Wisconsin Card Sorting Task, and a subsample underwent resting-state functional magnetic resonance imaging. RESULTS: We included 166 patients with DSM-IV lifetime anorexia nervosa and 140 healthy women in our study. Both underweight and weight-recovered patients with anorexia nervosa showed high levels of perseveration, but only in the underweight group did the Val158Met polymorphism affect cognitive performance, showing the U-shaped curve characteristic of increased DA signalling in the prefrontal cortex. Underweight patients with anorexia nervosa who are Met homozygotes had significantly higher levels of perseveration and increased prefrontal functional connectivity than underweight patients in the other genotype groups, indicating abnormal regional cortical processing. LIMITATIONS: Although our data show that grey matter reduction in starving patients with anorexia nervosa did not explain our findings, the cross-sectional design of the present study did not allow us to distinguish between the effects of starvation and those of low estrogen levels. CONCLUSION: Starvation affects DA release in the prefrontal cortex of patients with anorexia nervosa with different effects on executive functioning and prefrontal functional connectivity according to the COMT genotype. This observation has several therapeutic implications that need to be addressed by future studies.

Clinical and temperamental correlates of body image disturbance in eating disorders.

OBJECTIVE: Although body image disturbance (BID) is considered a core symptom in anorexia nervosa (AN) and bulimia nervosa (BN), little is known about its psychopathological correlates. The present study aimed at analysing the correlation of aspects of BID with psychopathological and temperamental characteristics. METHOD: A sample of 1288 patients (538 AN and 750 BN) were assessed through a structured diagnostic interview, the Eating Disorders Inventory and Tridimensional Personality Questionnaire. Cognition of body image distortion, weight checking, fear of weight gain and body dissatisfaction were assessed by specific questions during the interview. RESULTS: Various aspects of BID formed similar, but not identical, dimensions in AN and BN. In both groups, anticipatory anxiety and interoceptive awareness were significantly and independently associated with body image distortion, whereas ineffectiveness was associated with weight checking. DISCUSSION: Body image disturbance is a multidimensional characteristic linked to psychological features, such as anticipatory anxiety, ineffectiveness and interoceptive awareness. These findings have scientific and treatment implications, and should be considered by clinicians in adopting successful treatment strategies.

Perinatal complications in unaffected sisters of anorexia nervosa patients: testing a covariation model between genetic and environmental factors.

Although perinatal complications are hypothesized to be risk factors for the development of anorexia nervosa (AN), no study to date explored this issue using a discordant sibling design. This type of design allows to explore whether the risk for obstetric complications is itself a consequence of the genetic vulnerability for AN (covariation model) or whether obstetric complications increase the risk of AN independently of (additive model), or in interaction with (interaction model), the disorder's genetic liability. The presence of perinatal complications was assessed through review of the obstetric records of 60 AN subjects, 60 unaffected sisters, and 70 healthy subjects. Unaffected sisters and healthy controls were compared in relation to perinatal characteristics and complications. There was no evidence for an elevated rate of complications in unaffected siblings of AN patients. Mothers with a positive psychiatric history tended to have more perinatal complications. Perinatal complications seem to be independent risk factors that may interact with, but are not caused by, familial risk factors for AN. In terms of prevention, a particular attention should be paid to mothers with a lifetime history of psychiatric disorders.

Set-shifting abilities, central coherence, and handedness in anorexia nervosa patients, their unaffected siblings and healthy controls: exploring putative endophenotypes.

OBJECTIVE: There is consistent evidence that anorexia nervosa (AN) is associated with an impairment of set-shifting abilities and central coherence. No study to date investigated handedness in AN. Our aim was to study set-shifting abilities, central coherence, and handedness in subjects with lifetime AN, in a sample of unaffected sisters and in healthy controls, in order to explore their suitability as endophenotypes of AN. METHODS: The Edinburgh Handedness Inventory and several neuropsychological tasks (Wisconsin Card Sorting Test, Trail Making Test, Rey-Osterrieth Complex Figure Test, Overlapping Figures Test, Object Assembly and Block Design) were administered to 153 subjects with lifetime AN, 28 unaffected sisters and 120 healthy controls. RESULTS: AN subjects and their healthy sisters showed poorer performances on most tasks investigating set-shifting and central coherence. In addition, we did not find any differences between long-term recovered subjects, weight-restored AN patients and those in an acute phase of their illness. AN subjects were significantly more likely to be left-handed than healthy controls (OR=2.8, 95% C.I. 1.1-7.2). CONCLUSIONS: Set-shifting and central coherence seem to be promising cognitive endophenotypes that might help in the understanding of the pathogenetic processes involved in AN. Further studies on larger samples are needed to explore the generalizability and implications of our findings concerning handedness.

Typical and atypical restrictive anorexia nervosa: weight history, body image, psychiatric symptoms, and response to outpatient treatment.

OBJECTIVE: Few studies have examined the characteristics of atypical restrictive anorexia nervosa (AN) with a well-powered design. The study aims to explore this issue, with particular attention paid to psychopathology and response to outpatient treatment. METHOD: The sample consists of 365 participants with restrictive AN and 204 with atypical AN. Three types of atypical AN were included: subthreshold (all the criteria except weight); partial (AN without amenorrhea); and participants with AN without fear of gaining weight. RESULTS: Participants with AN without fear of weight gain reported the lowest lifetime BMI and subthreshold AN the highest. Participant with partial AN reported the highest levels of psychiatric symptoms and novelty seeking. All types of atypical AN showed high rates of dropout, whereas participants with subthreshold AN showed the highest level of full remission after treatment. DISCUSSION: Before considering a revision of the diagnostic criteria of AN, further studies on adequately large samples are needed.

Association between low height and eating disorders: cause or effect?

OBJECTIVE: Few studies have explored the relationship between stature and eating disorders (ED). We aimed to investigate the connection between height and risk for ED in a cohort of female subjects. METHOD: The sample was composed of 1,031 subjects with ED and 832 controls. All participants belonged to the same birth cohort and were living in the same geographical area. RESULTS: ED subjects were, on average, shorter than control subjects, independently from the age of onset. In early-onset anorexia nervosa only, age of onset and lowest body mass index were significant predictors of height. In the whole sample, a lower height was associated with an increased risk of having an ED, even after controlling for possible confounding variables. CONCLUSION: The association between EDs and low stature is statistically significant. Further studies are necessary to understand which genetic and/or environmental factors might explain this association.

The relationship between temperament and impulsive behaviors in eating disordered subjects.

To date, few studies have examined the personality characteristics and clinical predictors of impulsive behaviors in eating disorders (ED). The aim of this work was to study the prevalence of a wide range of impulsive behaviors in a sample of 554 ED subjects and to examine the predictors of these behaviors. Subjects were diagnosed according to DSM-IV criteria as having anorexia nervosa restricting type (ANR; n = 183), anorexia nervosa binge eating/purging type (ANBP; n = 65), bulimia nervosa purging type (BNP; n = 244), and bulimia nervosa nonpurging type (BNNP; n = 62). Nine different types of impulsive behaviors were assessed in these groups. About 55% of the whole sample reported at least one type of impulsive behavior, 35% more than one, and about 13% more than three. According to findings, impulsive and multi-impulsive subjects are characterized by the presence of purging behavior and by specific temperamental features such as high levels of novelty seeking and low persistence. The prediction of impulsive behavior is further improved by considering the presence of a history of childhood abuse, maternal psychiatric morbidity, and some specific psychological symptoms such as maturity fears, perfectionism, depression, and obsessive-compulsive symptoms. The presence of impulsive behavior appears to be associated with overall higher levels of psychiatric symptomatology and eating psychopathology, thus indicating that they are an important feature to be considered in the assessment and treatment of ED.