Genetic Risk Factors in Eating Disorders

Eating disorders such as anorexia nervosa and bulimia nervosa involve complex and interacting mechanisms. Formal genetic studies suggest that there is a substantial genetic influence for these disorders. Animal models of eating disorders are scarce. Candidate gene studies have initially focused on the serotonergic and other central neurotransmitter systems and on genes involved in body weight regulation. Most of the studies, including meta-analysis, have yielded negative results; only a single positive finding has been replicated independently. Recently, systematic genome-wide scans based on families with two or more individuals with an eating disorder (anorexia nervosa or bulimia nervosa) revealed initial linkage regions on chromosomes 1, 3, and 4 (anorexia nervosa) and 10p (bulimia nervosa). Fine mapping of one of these regions led to the identification of genes where an association with anorexia nervosa was detected. Currently treatment of patients with eating disorders can not rely on results of molecular genetic studies.     

Candidate genes in eating disorders

Environmental influences, as well as biological and genetic factors influence risk for eating disorders. Family and twin studies have shown that eating disorders are familial and suggest the influence of genetic factors on their etiology. Positive associations have been observed for some candidate genes that have been studied (such as 5HT2A receptor gene); however, the field has been plagued by nonreplications. In this paper we review the extant association studies of eating disorders.     

Candidate gene polymorphisms in eating disorders

Anorexia nervosa and bulimia nervosa are complex disorders characterized by disordered eating behaviour. Attitudes towards weight and shape as well as the perception of body shape are disturbed. A substantial genetic influence on these disorders has been suggested by formal genetic studies. Obsessive-compulsive behaviour, perfectionism and anxious personality traits seem to occur premorbidly in several patients. Disturbances of neurotransmitter, neuropeptide and neuroendocrine systems have been reported in acutely ill and followed-up patients. Hence, these systems might be involved in the etiology of these eating disorders.

Genetic studies on candidate genes have mainly focussed on the serotonergic system and on genes involved in body weight regulation. Up to now, polymorphisms and variations in various genes (e.g. genes for 5-HT receptors, leptin gene, melanocortin MC₄ receptor gene) have been assessed for association and transmission disequilibrium pertaining to anorexia nervosa and/or bulimia nervosa. Most of the studies yielded negative results. Four studies of a polymorphism (−1438 G/A) within the promoter of the 5-HT_2A gene (5-HT_2A) revealed an association of the A-allele to anorexia nervosa. However, three studies could not confirm this result. Furthermore, a meta-analysis did not support the positive association. Currently, combined efforts within the European Union will answer the question of whether or not the A-allele is involved in the predisposition to anorexia nervosa. A transmission disequilibrium test is being performed in about 300 trios consisting of a patient with anorexia nervosa and both parents. As candidate gene approaches did not unequivocally identify susceptibility genes (alleles) for anorexia nervosa or bulimia nervosa, systematic model-free genome-wide screenings should also be performed in order to identify currently unknown genes involved in eating disorders. This kind of approach has already been initiated for anorexia nervosa. Genetic research on eating disorders will hopefully lead to new pharmacological treatment strategies.     

Eating disorders: an overview of treatment responses and the potential impact of vulnerability genes and endophenotypes

Anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED) are the three main eating disorders. Antidepressants, antipsychotics, anticonvulsants, prokinetic agents, opiate antagonists, appetite suppressants, tetrahydrocannabinol, cyproheptadine, zinc and ondansetron have been tested, and are frequently associated with psychological treatment. Selective serotonin reuptake inhibitors have a proven efficacy in BN and binge eating disorder. Other treatments, such as atypical antipsychotics in AN, anticonvulsants in BN and BED, and naltrexone and ondansetron in BN, may be promising, but lack the appropriate trials. The development of genetic researches in eating disorders may help the clinician to choose the most appropriate treatment in forthcoming years, using genetic polymorphisms of vulnerability genes, those linked to endophenotypes, or genes implicated in the metabolism of the drug treatment.     

Eating disorders: an overview of treatment responses and the potential impact of vulnerability genes and endophenotypes

Anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED) are the three main eating disorders. Antidepressants, antipsychotics, anticonvulsants, prokinetic agents, opiate antagonists, appetite suppressants, tetrahydrocannabinol, cyproheptadine, zinc and ondansetron have been tested, and are frequently associated with psychological treatment. Selective serotonin reuptake inhibitors have a proven efficacy in BN and binge eating disorder. Other treatments, such as atypical antipsychotics in AN, anticonvulsants in BN and BED, and naltrexone and ondansetron in BN, may be promising, but lack the appropriate trials. The development of genetic researches in eating disorders may help the clinician to choose the most appropriate treatment in forthcoming years, using genetic polymorphisms of vulnerability genes, those linked to endophenotypes, or genes implicated in the metabolism of the drug treatment.     

Refinement of behavioural traits in animals for the genetic dissection of eating disorders

Both twin and family studies have revealed the involvement of genetic factors in disorders that affect the regulation of body weight, such as obesity and anorexia nervosa. However, pinpointing the genes that contribute to these human disorders has not yet been very successful. In contrast, genetic studies in animals have been basic for the identification of many genes involved in the regulation of various physiological processes of energy metabolism. We thus plan to review here ways in which findings from animal studies and what is known about behavioural diversity in the human population with eating disorders can be combined. This would probably optimise phenotype-based candidate gene analysis in humans.     

Genes and/or jeans?: Genetic and socio-cultural contributions to risk for eating disorders

Eating disorders are prevalent among young adult females and pose serious psychological and medical risks. Notwithstanding important advances, efforts to develop effective means of preventing and treating eating disorders have been limited by an incomplete understanding of their multifactorial etiology. Whereas epidemiologic data strongly suggest the influence of socio-cultural context in moderating risk, many hypotheses about how these effects are exerted have remained empirically unevaluated. Specifically, experimental and observational data suggest that social transition (e.g., transnational migration, urbanization, modernization), Western media exposure, and certain peer environments (involving social comparison and teasing) may all contribute to risk. With respect to genetic influences on etiology, family and twin studies have supported a genetic diathesis to eating disorders. Whereas, molecular genetic studies have generated interesting leads- with the most promising findings emerging for genes related to the function of serotonin-they have yet to identify well-replicated susceptibility loci. This paper reviews the data supporting both socio-cultural and genetic contributions for eating disorders and suggests productive future strategies for continuing to unravel their likely multiple and complex interactions.     

Candidate gene analysis of the Price Foundation anorexia nervosa affected relative pair dataset

The eating disorders are severe psychiatric illnesses with significant morbidity and mortality that exhibit statistically significant familial risk and heritability, providing support for a molecular genetic approach toward defining etiological factors. An emerging candidate gene literature has concentrated on serotinergic and dopaminergic candidates. With the financial support of the Price Foundation, a group of investigators initiated an international multi-center collaboration (Price Foundation Collaborative Group) in 1995 to study the genetics of anorexia and bulimia nervosa by collecting and analyzing phenotypes and genotypes of individuals and their relatives affected with eating disorders. The first sample of families collected by this collaborative group, known as the Price Foundation Anorexia Nervosa Affected Relative Pair (AN-ARP) dataset, was ascertained on an proband affected with Anorexia Nervosa (AN), with relative pairs affected with the eating disorders AN, Bulimia Nervosa or Eating Disorders Not Otherwise Specified [1]. Biognosis U.S., Inc. was founded to identify and characterize candidate susceptibility genes for anorexia and bulimia nervosa phenotypes in the Price Foundation eating disorder datasets. During 2000-2001, Biognosis U.S., Inc. developed and implemented a research program with a focus on the analysis of candidate genes nominated by neurochemical characteristics of eating disorder patients [2], serotonergic and dopaminergic candidate gene polymorphisms [3], neuroendocrine regulation of appetite [4], and by a positional hypothesis from a linkage analysis of the AN-ARP dataset [5]. This report reviews the anorexia nervosa candidate gene literature through 2001, the candidate gene research program implemented at Biognosis U.S., Inc. and selected candidate gene findings in the AN-ARP dataset derived from that research program.     

Anorexia nervosa and bulimia nervosa: An appraisal

Anorexia nervosa (AN) and bulimia nervosa (BN) are eating disorders characterized by an aberrant pattern of eating behavior, relentless pursuit of thinness, an intense fear about weight gain and an altered perception of body shape. The pathobiology of eating disorders is complex. Several social, psychological and developmental phenomena are proposed to contribute to the etiology of eating disorders. The role of neuropeptide Y, corticotropin releasing hormone and leptin has also been investigated to understand the pathogenesis of eating disorders. However, most of the neuropeptide alterations noted in eating disorders are secondary to starvation. Several nonpharmacological approaches such as cognitive and behavior-based therapy and interpersonal therapy have been developed to assist weight gain and to modify the behavioral impairment associated with eating disorders. Pharmacotherapy serves as an adjunct in AN, whereas it plays a more significant role in the management of BN. Antidepressants are effective in a limited number of AN patients with comorbid depression. On the other hand, the efficacy of fluoxetine in BN patients in reducing the frequency of binge eating and in the severity of behavioral abnormalities is quite impressive. Several adjunct therapies such as prokinetics and anxiolytics have also been used in AN and BN to assist eating behavior. An insight into genetic and neurochemical abnormalities occurring in eating disorders will help to find better therapeutic agents for these disorders. (c) 2001 Prous Science. All rights reserved.     

Academy of eating disorders international conference

New information is being acquired and disseminated about eating disorders, particularly in terms of integrating the roles of genes and environment, and new treatment approaches. Although evidence indicates that genes are not more important in the aetiology of anorexia nervosa (AN) than bulimia nervosa, Western culture does appear to be more important in the aetiology of bulimia nervosa than AN. Pathological fear conditioning offers a very useful and experimentally testable theory of the aetiology of AN. New evidence suggests that an enhanced, 'transdiagnostic' form of cognitive behavioural therapy is highly effective in eating disorder patients suitable for out-patient treatment. Patients who are homozygotic for the short (s) allele of the 5-hydroxytryptamine transporter gene promoter region appear to be more resistant to multimodal treatment.     

Academy of Eating Disorders International Conference

New information is being acquired and disseminated about eating disorders, particularly in terms of integrating the roles of genes and environment, and new treatment approaches. Although evidence indicates that genes are not more important in the aetiology of anorexia nervosa (AN) than bulimia nervosa, Western culture does appear to be more important in the aetiology of bulimia nervosa than AN. Pathological fear conditioning offers a very useful and experimentally testable theory of the aetiology of AN. New evidence suggests that an enhanced, ‘transdiagnostic’ form of cognitive behavioural therapy is highly effective in eating disorder patients suitable for out-patient treatment. Patients who are homozygotic for the short (s) allele of the 5-hydroxytryptamine transporter gene promoter region appear to be more resistant to multimodal treatment.     

A comparison of purging and non-purging eating disorder patients in comorbid personality disorders and psychopathology

OBJECTIVE: We evaluated the significance of purging behavior in the diagnosis of eating disorders through an objective assessment of eating disorder psychopathology including personality disorders. METHODS: Subjects were 42 consecutive outpatients with eating disorders who visited the Outpatient Psychiatric Clinic at Tokai University Hospital (Kanagawa, Japan). Diagnosis of eating and personality disorders was established using the modified Structured Clinical Interviews for DSM-III-R and DSM-III-R-Axis II. Eating disorder symptoms and psychopathology were assessed with the Eating Disorder Examination, Eating Disorder Inventory 2, Beck Depression Inventory, and Leyton Obsessional Inventory Results were compared between purgers and non-purgers. RESULTS: Purgers had severe borderline or avoidant personality disorder, mixed personality disorder, eating attitude, depressive symptoms, and obsessive symptoms. CONCLUSION: Purging behavior in eating disorder patients is associated with personality disorders, depression, and obsessive symptoms. Assessment of this behavior is critical in the diagnosis and treatment of eating disorders.     

Co-occurrence of Substance Use and Eating Disorders: An Approach to the Adolescent Patient in the Context of Family Centered Care. A Literature Review

In this review article, the co-occurrence of substance use and eating disorders will be discussed with a specific emphasis on the approach to the adolescent patient in the context of family centered care. The evidence to date suggests that the associations between eating and substance use disorders are multifactorial. Balancing between confidential health care for substance use and family centered health care for eating disorders is a real challenge in the management of adolescent patients with co-occurring eating and substance use disorders. Reconciling confidential health care with parental involvement should be considered with individually determined limits of confidentiality.     

Approaches to anorexia in rodents: focus on the anx/anx mouse

Eating disorders constitute major medical health problems in the western world. Even though little is known about the mechanisms behind abnormal eating behavior, it has become clear that the central nervous system (CNS), particularly the hypothalamus, plays a significant role. The anorexic anx/anx mouse is a unique model for studying food intake and energy expenditure. The anx mutation is linked to marked alterations in hypothalamic distributions of signal substances known to have potent regulatory roles in the control of food intake. We have identified a mutation in anx/anx mice that is likely to cause the anorectic phenotype. Using RNA profiling, we have found 29 genes with differential expression in the anx/anx mouse brain. The anx gene, its protein product or molecules in the anx pathway may thus be interesting targets for development of new pharmaceuticals for the treatment of eating disorders. Based on the histochemical alterations found in the anx/anx mouse, we hypothesised and showed that many sera from anorectic/bulimic patients contain antibodies that bind specifically to the hypothalamic food intake regulatory system in rat. This finding represents a novel research avenue that may lead to a better understanding of eating disorders. It also suggests that targeted immunological approaches may be used in therapy.     

Redefining success in eating disorders

Currently our definitions of treatment success for obesity and eating disorders are too simplistic and narrow in scope. More varied treatment outcome targets include bodyrelated measures, medical health variables, exercise and eating habits, psychological health factors, body image, and quality of life measures. A new system of redefining success is offered based on the need for a uniform model of eating disorders, the need for an emphasis on progress not perfection, the need to view eating disorders as chronic conditions, and the need to match treatment modules to patient needs.     

Psychopharmacotherapy in eating disorders: a systematic analysis

The most common and serious eating disorders, which are particularly prevalent in young women, are anorexia nervosa (AN), bulimia nervosa (BN), and binge-eating disorders (BED). Further, the prevalence of unspecific hyperphagous eating disorders frequently causing obesity is substantially increasing. All of these eating disorders tend to be chronic and comorbid to psychiatric diagnoses. Because of the multifactorial etiology, these disorders require a multimodal treatment. Among different treatment options, symptomatic psychopharmacotherapy has been an important component, and especially in recent decades, it has been subject to many trials. This article gives an overview of the current literature, summarizing diagnostic criteria, epidemiology, and critically discussing psychopharmacotherapy of those eating disorders. Based on the literature and our clinical experience, the psychopharmacological recommendations for patients with AN, BN, and BED are suggested.     

Eating Disorders: Current Concepts

Objective:To review for the community pharmacist common eating disorders and suggest strategies for pharmacist-directed patient education.Data Source:Current literature.Data Synthesis:Women are much more likely than men to develop eating disorders, and Western culture's emphasis on thinness contributes to the prevalence of eating disorders in the United States. Regardless of the type, all eating disorders are rooted in emotions, often traced to problems during adolescence. Anorexia nervosa patients continually set and strive to obtain lower goal weights to the point that their general well-being is compromised. Bulimia nervosa is characterized by excessive eating followed by purging that is an apparent attempt to relieve the tension and guilt associated with the initial overeating. Rather than directly dealing with tension and anger, a patient suffering from binge eating overindulges in food. Most overeaters are aware that excess weight is detrimental to their health, but they cannot control their overeating behavior.Conclusion:In treating eating disorders, it is important to address patients' emotional and psychological needs as well as physical symptoms. Patients often need encouragement to seek and continue treatment, and pharmacists are in an ideal position to provide that support.     

Animal model of eating disorders]

Patients with eating disorders are increasing in number. Some neurocircuits concerned with feeding behavior might be dysfunctional in these patients with repeated expression of disorganized eating behavior like long-lasting dieting. These neuronal, or endocrinological dysfunctions might even be enhanced by psychological stress. To understand the biological bases of eating disorders is necessary to establish effective treatment. According to the clinical features of the patients, we have conducted some rat studies. We have found that space restriction stress enhances rebound hyperphagia induced by time-restricted scheduled feeding, and propose the phenomenon as a possible rat model of binge eating. We can speculate some part of the biological bases of human eating disorders, and effective prevention and treatment through such animal models.     

Eating Disorders, Serotonin Transporter Polymorphisms and Potential Treatment Response

Anorexia nervosa, bulimia nervosa, and binge eating disorder are eating disorders with common clinical and psychological features, potentially shared mechanisms, significant morbidity and, at least for anorexia nervosa, a high mortality rate. Among the numerous risk factors involved, the importance of a genetic vulnerability has been demonstrated, and the heritability, in the broad sense, has being estimated to be between 50 and 70%. Studies have thus focused on different candidate genes. Serotonin transmission and regulation has been extensively studied with regard to its role in core mechanisms such as feeding and fasting, but also in different clinical characteristics of eating disorders. The serotonin transporter (5-HTT), encoded by the SLC6A4 gene, may also have an important role in eating disorders, as its availability is decreased in patients with bulimia nervosa and binge eating disorder. The promoter region contains a functional insertion/deletion polymorphism with two common alleles that have been designated the short (*S) and long (*L) alleles. The frequency of the SLC6A4*S allele has been assessed in four independent samples of patients with anorexia nervosa, but gave discrepant results. A meta-analysis was performed, which showed that the *S allele could represent a moderate but significant risk factor that increases the risk of anorexia nervosa (odds ratio [OR] = 1.38, 95% confidence interval [CI] 1.16-1.72). Eating disorders are treated using different types of psychotherapy and pharmacotherapy with antidepressants; serotonin reuptake inhibitors being the most frequently prescribed. High doses of selective serotonin reuptake inhibitors (SSRIs) are usually prescribed in eating disorders. The prevalence of non-responders (roughly one out of two), and the presence of a functional genetic polymorphism in the promotor region of SLC6A4, emphasizes the potential utility of psychopharmacogenetics in prescribing SSRIs in the treatment of patients with weight-restored anorexia nervosa. Information about genetic variations of cytochrome P450 could also facilitate pharmacotherapy by preventing the administration of high doses in poor metabolizers and identify rapid metabolizes who may require higher doses for efficacy. SLC6A4 genotyping would allow physicians to individualize selective serotonin reuptake therapy for their patients.     

Anorexia nervosa: towards a neurobiologically based therapy

Eating disorders, i.e. anorexia and bulimia nervosa, are disorders of eating behavior and body weight regulation. Most likely because there are few, if any, effective treatments, eating disorders are considered to be chronic disorders interrupted only by intermittent periods of short-lived remission. The neurobiology of eating, most of which explores hypothalamic mechanisms, has had no influence on the treatment of eating disorders, with the exception of psychopharmacology. However, while most patients are treated with psychoactive drugs, there is no evidence that these are effective. This may be because pharmacological attempts so far have targeted the wrong symptoms. We review the symptomatology of anorexia and bulimia and the outcome of presently used interventions. Everybody agrees that outcome must improve and to attack this clinical problem, we suggest a neurobiologically plausible framework for how the disorders develop and how they are maintained and outline a method of treatment and its results.