ABSTRACT
Cholinergic striatal interneurons (ChIs) express the vesicular glutamate transporter 3 (VGLUT3) which allows them to regulate the striatal network with glutamate and acetylcholine (ACh). In addition, VGLUT3-dependent glutamate increases ACh vesicular stores through vesicular synergy. A missense polymorphism, VGLUT3-p.T8I, was identified in patients with substance use disorders (SUDs) and eating disorders (EDs). A mouse line was generated to understand the neurochemical and behavioral impact of the p.T8I variant. In VGLUT3T8I/T8I male mice, glutamate signaling was unchanged but vesicular synergy and ACh release were blunted. Mutant male mice exhibited a reduced DA release in the dorsomedial striatum but not in the dorsolateral striatum, facilitating habit formation and exacerbating maladaptive use of drug or food. Increasing ACh tone with donepezil reversed the self-starvation phenotype observed in VGLUT3T8I/T8I male mice. Our study suggests that unbalanced dopaminergic transmission in the dorsal striatum could be a common mechanism between SUDs and EDs.
Subject(s)
Corpus Striatum , Dopamine , Animals , Male , Dopamine/metabolism , Mice , Corpus Striatum/metabolism , Humans , Acetylcholine/metabolism , Substance-Related Disorders/metabolism , Substance-Related Disorders/genetics , Signal Transduction/drug effects , Glutamic Acid/metabolism , Interneurons/metabolism , Interneurons/drug effects , Feeding and Eating Disorders/metabolism , Feeding and Eating Disorders/genetics , Feeding and Eating Disorders/physiopathology , Mice, Inbred C57BL , Amino Acid Transport Systems, Acidic/metabolism , Amino Acid Transport Systems, Acidic/genetics , Mutation , Mutation, Missense , Vesicular Acetylcholine Transport ProteinsABSTRACT
Eating disorders are a group of severe and potentially enduring psychiatric disorders associated with increased mortality. Compared to other severe mental illnesses, they have received relatively limited research attention. Epidemiological studies often only report relative measures despite these being difficult to interpret having limited practical use. The aims of this study were to evaluate the incidence and prevalence of diagnosed anorexia nervosa (AN), bulimia nervosa, and eating disorder not otherwise specified recorded in Danish hospital registers and estimate both relative and absolute measures of subsequent mortality - both all-cause and cause-specific in a general nationwide population of 1,667,374 individuals. In a smaller, genetically informed case-cohort sample, the prediction of polygenic scores for AN, body fat percentage, and body mass index on AN prevalence and severity was estimated. Despite males being less likely to be diagnosed with an eating disorder, those that do have significantly increased rates of mortality. AN prevalence was highest for individuals with high AN and low body fat percentage/body mass index polygenic scores.
Subject(s)
Feeding and Eating Disorders , Multifactorial Inheritance , Registries , Humans , Denmark/epidemiology , Male , Female , Feeding and Eating Disorders/epidemiology , Feeding and Eating Disorders/mortality , Feeding and Eating Disorders/genetics , Adult , Prevalence , Incidence , Adolescent , Young Adult , Middle Aged , Body Mass Index , Anorexia Nervosa/epidemiology , Anorexia Nervosa/mortality , Anorexia Nervosa/geneticsABSTRACT
Feeding and eating disorders (FEDs) are heterogenous and characterized by varying patterns of dysregulated eating and weight. Genome-wide association studies (GWASs) are clarifying their underlying biology and their genetic relationship to other psychiatric and metabolic/anthropometric traits. Genetic research on anorexia nervosa (AN) has identified eight significant loci and uncovered genetic correlations implicating both psychiatric and metabolic/anthropometric risk factors. Careful explication of these metabolic contributors may be key to developing effective and enduring treatments for devastating, life-altering, and frequently lethal illnesses. We discuss clinical phenomenology, genomics, phenomics, intestinal microbiota, and functional genomics and propose a path that translates variants to genes, genes to pathways, and pathways to metabolic outcomes to advance the science and eventually treatment of FEDs.
Subject(s)
Anorexia Nervosa , Feeding and Eating Disorders , Humans , Genome-Wide Association Study , Feeding and Eating Disorders/genetics , Anorexia Nervosa/genetics , Phenotype , BiologyABSTRACT
OBJECTIVE: Reward-based eating drives are putative mechanisms of uncontrolled eating implicated in obesity and disordered eating (e.g., binge eating). Uncovering the genetic and environmental contributions to reward-related eating, and their genetic correlation with BMI, could shed light on key mechanisms underlying eating and weight-related disorders. METHOD: We conducted a classical twin study to examine how much variance in uncontrolled eating phenotypes and body mass index (BMI) was explained by genetic factors, and the extent that these phenotypes shared common genetic factors. 353 monozygotic twins and 128 dizygotic twins completed the Reward-based Eating Drive 13 scale, which measures three distinct uncontrolled eating phenotypes (loss of control over eating, preoccupation with thoughts about food, and lack of satiety), and a demographic questionnaire which included height and weight for BMI calculation. We estimated additive genetic (A), common environmental (C), and unique environmental (E) factors for each phenotype, as well as their genetic correlations, with a multivariate ACE model. A common pathway model also estimated whether genetic variance in the uncontrolled eating phenotypes was better explained by a common latent uncontrolled eating factor. RESULTS: There were moderate genetic correlations between uncontrolled eating phenotypes and BMI (.26-.41). Variance from the uncontrolled eating phenotypes was also best explained by a common latent uncontrolled eating factor that was explained by additive genetic factors (52%). DISCUSSION: These results suggest that uncontrolled eating phenotypes are heritable traits that also share genetic variance with BMI. This has implications for understanding the cognitive mechanisms that underpin obesity and disordered eating. PUBLIC SIGNIFICANCE: Our study clarifies the degree to which uncontrolled eating phenotypes and BMI are influenced by shared genetics and shows that vulnerability to uncontrolled eating traits is impacted by common genetic factors.
Subject(s)
Body Mass Index , Phenotype , Humans , Female , Male , Adult , Feeding Behavior , Twins, Monozygotic/genetics , Feeding and Eating Disorders/genetics , Twins, Dizygotic/genetics , Reward , Middle Aged , Surveys and Questionnaires , Obesity/geneticsABSTRACT
INTRODUCTION: The role of catechol-O-methyltransferase (COMT) in catecholamine neurotransmitter metabolism has led to the investigation of variants of the corresponding gene in the etiology of different psychiatric disorders, but the results are inconclusive. METHODS: We have examined the relationship between COMT Val158Met single nucleotide polymorphism (rs4680) and the occurrence of psychiatric disorders in a highly representative birth cohort sample of young adults in the Estonian Children Personality Behaviour and Health Study (original n = 1,238). The lifetime occurrence of psychiatric disorders at the age of 25 years was assessed with the Mini-International Neuropsychiatric Interview. RESULTS: Both Val- and Met-alleles of the COMT Val158Met were associated with specific psychiatric disorders. Met-allele carriers had a significantly higher occurrence of agoraphobia (3.2% vs. 0.5%; χ2 = 4.10; p < 0.05) compared to Val/Val homozygotes. Also, the occurrence of panic disorder was significantly higher in female Met-allele carriers than in Val/Val homozygote females (10.2% vs. 3.6%; χ2 = 4.62 p = 0.03). In contrast, the occurrence of generalized anxiety disorder was higher in Val/Val females when compared to Met-allele carriers (12.7% vs. 6.8%; χ2 = 4.16; p = 0.04). Also, female Val/Val homozygotes (15.5%) had a higher occurrence of eating disorders than Met-allele carriers (6.1%) of the COMT Val158Met polymorphism (χ2 = 10.39; p = 0.002). In the whole sample, Met-allele homozygotes had a higher occurrence of alcohol use and substance use disorders than Val-allele carriers (χ2 = 3.62 and 3.68, respectively; p < 0.05). CONCLUSION: In a regional highly birth cohort representative sample, either COMT rs4680 variant was observed in association with specific psychiatric disorders.
Subject(s)
Feeding and Eating Disorders , Substance-Related Disorders , Adult , Female , Humans , Alleles , Anxiety/genetics , Anxiety Disorders/epidemiology , Anxiety Disorders/genetics , Birth Cohort , Catechol O-Methyltransferase/genetics , Fear , Feeding and Eating Disorders/epidemiology , Feeding and Eating Disorders/genetics , Genotype , Polymorphism, Single NucleotideABSTRACT
BACKGROUND: Some preliminary research suggests higher rates of gastrointestinal disease in individuals with eating disorders (EDs). However, research is limited, and it remains unknown what etiologic factors account for observed associations. This was the first study to examine how EDs and dimensional ED symptoms (e.g. body dissatisfaction, binge eating) are phenotypically and etiologically associated with gastrointestinal disease in a large, population-based twin sample. METHODS: Adult female (N = 2980) and male (N = 2903) twins from the Michigan State University Twin Registry reported whether they had a lifetime ED (anorexia nervosa, bulimia nervosa, or binge-eating disorder) and completed a measure of dimensional ED symptoms. We coded the presence/absence of lifetime gastrointestinal disease (e.g. inflammatory bowel disease) based on responses to questions regarding chronic illnesses and medications. We first examined whether twins with gastrointestinal disease had higher rates of EDs and ED symptoms, then used correlated factors twin models to investigate genetic and environmental contributions to the overlap between disorders. RESULTS: Twins with gastrointestinal disease had significantly greater dimensional ED symptoms (ß = 0.21, p < 0.001) and odds of a lifetime ED (OR 2.90, p = 0.001), regardless of sex. Shared genetic factors fully accounted for the overlap between disorders, with no significant sex differences in etiologic associations. CONCLUSIONS: Comorbidity between EDs and gastrointestinal disease may be explained by overlap in genetic influences, potentially including inflammatory genes implicated in both types of disorders. Screening for gastrointestinal disease in people with EDs, and EDs in those with gastrointestinal disease, is warranted.
Subject(s)
Anorexia Nervosa , Binge-Eating Disorder , Bulimia Nervosa , Feeding and Eating Disorders , Gastrointestinal Diseases , Adult , Humans , Female , Male , Feeding and Eating Disorders/epidemiology , Feeding and Eating Disorders/genetics , Bulimia Nervosa/epidemiology , Bulimia Nervosa/genetics , Bulimia Nervosa/diagnosis , Anorexia Nervosa/genetics , Binge-Eating Disorder/genetics , Gastrointestinal Diseases/epidemiology , Gastrointestinal Diseases/geneticsABSTRACT
OBJECTIVE: Circulating cell-free DNA (cfDNA) holds promise as a rapid and convenient biomarker for identifying individuals with eating disorders. To investigate this hypothesis, we measured plasma cfDNA in patients with different eating disorders. METHODS: In this study, 110 participants (98 patients with eating disorders divided into 30 patients with bulimia nervosa, 33 patients with anorexia nervosa (AN) Restricting subtype, 35 patients with AN Binge-eating/purging subtype and 12 controls) were enrolled. We measured both cell-free nuclear DNA (cf-nDNA) and cell-free mitochondrial DNA (cf-mtDNA) from plasma using two specific droplet digital PCR assays each, referring to two amplicon sizes. RESULTS: Levels of plasma cf-nDNA and cf-mtDNA showed no significant differences between control participants and those with eating disorders. However, we observed a higher proportion of long cf-nDNA fragments in patients with eating disorders, suggesting its potential as a biomarker for eating disorders. CONCLUSION: This is the first study of cfDNA in patients with eating disorders. Our findings highlight the potential for qualitative exploration of cfDNA, although not of quantitative interest. Full characterization of cfDNA may serve as a valuable biomarker for eating disorders and provide some insights into the hidden mechanisms underlying the chronic development of these conditions. Future studies are needed to confirm or refute this hypothesis.
Subject(s)
Anorexia Nervosa , Cell-Free Nucleic Acids , Feeding and Eating Disorders , Humans , Feeding and Eating Disorders/diagnosis , Feeding and Eating Disorders/genetics , Anorexia Nervosa/diagnosis , Anorexia Nervosa/genetics , Biomarkers , DNA, Mitochondrial/geneticsABSTRACT
A growing body of literature recognizes associations between eating disorders (EDs) and schizophrenia and suggests that familial liability to schizophrenia in individuals with anorexia nervosa (AN) reveals distinct patterns of clinical outcomes. To further investigate the influence of schizophrenia genetic liability among individuals with EDs, we evaluated the associations between schizophrenia polygenic risk scores (PRS) and clinical presentations of individuals with EDs including their overall health condition and ED-related symptoms. Using data from two previous studies of the genetics of EDs comprising 3,573 Anorexia Nervosa Genetics Initiative (ANGI) cases and 696 Binge Eating Genetics Initiative (BEGIN) cases born after 1973 and linked to the Swedish National Patient Register, we examined the association of schizophrenia PRS on ED clinical features, psychiatric comorbidities, and somatic and mental health burden. Among ANGI cases, higher schizophrenia PRS was statistically significantly associated with higher risk of major depressive disorder (MDD) measured by hazard ratio (HR) with 95% confidence interval (CI) (HR [95% CI]: 1.07 [1.02, 1.13]) and substance abuse disorder (SUD) (HR [95% CI]: 1.14 [1.03, 1.25]) after applying multiple testing correction. Additionally, higher schizophrenia PRS was associated with decreased clinical impairment assessment scores (-0.56, 95% CI: [-1.04, -0.08]) at the conventional significance level (p < 0.05). Further, in BEGIN cases, higher schizophrenia PRS was statistically significantly associated with earlier age at first ED symptom (-0.35 year, 95% CI: [-0.64, -0.06]), higher ED symptom scores (0.16, 95% CI: [0.04, 0.29]), higher risk of MDD (HR [95% CI]: 1.18 [1.04, 1.34]) and SUD (HR [95% CI]: 1.36 [1.07, 1.73]). Similar, but attenuated, patterns held in the subgroup of exclusively AN vs other eating disorder (OED) cases. These results suggest a similar pattern of influence of schizophrenia PRS for AN and OED cases in terms of psychiatric comorbidities, but a different pattern in terms of ED-related clinical features. The disparity of the effect of schizophrenia PRS on AN vs OED merits further investigation.
Subject(s)
Anorexia Nervosa , Depressive Disorder, Major , Feeding and Eating Disorders , Schizophrenia , Substance-Related Disorders , Humans , Depressive Disorder, Major/diagnosis , Depressive Disorder, Major/epidemiology , Depressive Disorder, Major/genetics , Schizophrenia/diagnosis , Schizophrenia/epidemiology , Schizophrenia/genetics , Feeding and Eating Disorders/epidemiology , Feeding and Eating Disorders/genetics , Risk Factors , Anorexia Nervosa/epidemiology , Anorexia Nervosa/genetics , Multifactorial InheritanceABSTRACT
Mental disorders are strongly connected with several psychiatric conditions including depression, bipolar disorder, schizophrenia, eating disorder, and suicides. There are many biological conditions and pathways that define these complicated illnesses. For example, eating disorders are complex mental health conditions that require the intervention of geneticists, psychiatrists, and medical experts in order to alleviate their symptoms. A patient with suicidal ideation should first be identified and consequently monitored by a similar team of specialists. Both genetics and epigenetics can shed light on eating disorders and suicides as they are found in the main core of such investigations. In the present study, an analysis has been performed on two specific members of the GPCR family toward drawing conclusions regarding their functionality and implementation in mental disorders. Specifically, evolutionary and structural studies on the adrenoceptor alpha 2b (ADRA2B) and the 5-hydroxytryptamine receptor 1A (HTR1A) have been carried out. Both receptors are classified in the biogenic amine receptors sub-cluster of the GPCRs and have been connected in many studies with mental diseases and malnutrition conditions. The major goal of this study is the investigation of conserved motifs among biogenic amine receptors that play an important role in this family signaling pathway, through an updated evolutionary analysis and the correlation of this information with the structural features of the HTR1A and ADRA2B. Furthermore, the structural comparison of ADRA2B, HTR1A, and other members of GPCRs related to mental disorders is performed.
Subject(s)
Mental Disorders , Receptor, Serotonin, 5-HT1A , Receptors, Biogenic Amine , Humans , Mental Disorders/genetics , Mental Disorders/metabolism , Receptor, Serotonin, 5-HT1A/genetics , Receptors, Adrenergic, alpha-2 , Receptors, Biogenic Amine/genetics , Receptors, Biogenic Amine/metabolism , Serotonin , Feeding and Eating Disorders/genetics , Suicidal IdeationABSTRACT
Importance: Endometriosis is a common chronic gynecologic pathology with a large negative impact on women's health. Beyond severe physical symptoms, endometriosis is also associated with several psychiatric comorbidities, including depression and anxiety. Objective: To investigate whether pleiotropy contributes to the association of endometriosis with depression, anxiety, and eating disorders. Design, Setting, and Participants: This genetic association study was performed between September 13, 2021, and June 24, 2022, in 202â¯276 unrelated female participants. Genotypic and phenotypic information from the UK Biobank was combined with genome-wide association statistics available from the Psychiatric Genomics Consortium (11 countries), the Million Veteran Program (US), the FinnGen study (Finland), and the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium (5 countries). Main Outcomes and Measures: The main outcomes were the phenotypic and genetic associations of endometriosis with anxiety, depression, and eating disorders. Results: A total of 8276 women with endometriosis (mean [SD] age, 53.1 [7.9] years) and 194â¯000 female controls (mean [SD] age, 56.7 [7.9] years) were included in the study. In a multivariate regression analysis accounting for age, body mass index, socioeconomic status, chronic pain-related phenotypes, irritable bowel syndrome, and psychiatric comorbidities, endometriosis was associated with increased odds of depression (odds ratio [OR], 3.61; 95% CI, 3.32-3.92), eating disorders (OR, 2.94; 95% CI, 1.96-4.41), and anxiety (OR, 2.61; 95% CI, 2.30-2.97). These associations were supported by consistent genetic correlations (rg) (depression rg, 0.36, P = 1.5 × 10-9; anxiety rg, 0.33, P = 1.17 × 10-5; and eating disorders rg, 0.61, P = .02). With the application of a 1-sample mendelian randomization, the genetic liabilities to depression and anxiety were associated with increased odds of endometriosis (depression: OR, 1.09; 95% CI, 1.08-1.11; anxiety: OR, 1.39; 95% CI, 1.13-1.65). A genome-wide analysis of pleiotropic associations shared between endometriosis and psychiatric disorders identified 1 locus, DGKB rs12666606, with evidence of pleiotropy between endometriosis and depression after multiple testing correction (z = -9.46 for endometriosis, z = 8.10 for depression, P = 5.56 × 10-8; false discovery rate q = 4.95 × 10-4). Conclusions and Relevance: These findings highlight that endometriosis is associated with women's mental health through pleiotropic mechanisms. To our knowledge, this is the first large-scale study to provide genetic and phenotypic evidence of the processes underlying the psychiatric comorbidities of endometriosis.
Subject(s)
Endometriosis , Feeding and Eating Disorders , Humans , Female , Endometriosis/epidemiology , Endometriosis/genetics , Depression/epidemiology , Depression/genetics , Depression/psychology , Genome-Wide Association Study , Anxiety/epidemiology , Anxiety/genetics , Anxiety/psychology , Feeding and Eating Disorders/epidemiology , Feeding and Eating Disorders/geneticsABSTRACT
Background: The incidence of eating disorders (EDs), serious mental and physical conditions characterized by a disturbance in eating or eating-related behaviors, has increased steadily. The present study aims to develop insights into the pathophysiology of EDs, spanning over biochemical, epigenetic, psychopathological, and clinical data. In particular, we focused our attention on the relationship between (i) DNA methylation profiles at promoter-associated CpG sites of the SCL6A4 gene, (ii) serum kynurenine/tryptophan levels and ratio (Kyn/Trp), and (iii) psychopathological traits in a cohort of ED patients. Among these, 45 patients were affected by restricting anorexia nervosa (AN0), 21 by purging AN (AN1), 21 by bulimia (BN), 31 by binge eating disorders (BED), 23 by unspecified feeding or eating disorders (UFED), and finally 14 by other specified eating disorders (OSFED) were compared to 34 healthy controls (CTRs). Results: Kyn level was higher in BED, UFED, and OSFED compared to CTRs (p ≤ 0.001). On the other hand, AN0, AN1, and BN patients showed significatively lower Kyn levels compared to the other three ED groups but were closed to CTRs. Trp was significantly higher in AN0, AN1, and BN in comparison to other ED groups. Moreover, AN1 and BN showed more relevant Trp levels than CTRs (p <0.001). BED patients showed a lower Trp as compared with CTRs (p ≤ 0.001). In addition, Kyn/Trp ratio was lower in the AN1 subtype but higher in BED, UFED, and OSFED patients than in CTRs (p ≤ 0.001). SCL6A4 DNA methylation level at CpG5 was lower in AN0 compared to BED (p = 0.021), and the CpG6 methylation was also significantly lower in AN0 in comparison to CTRs (p = 0.025). The mean methylation levels of the six CpGs analyzed were lower only in the AN0 subgroup compared to CTRs (p = 0.008). Relevant psychological trait EDI-3 subscales were correlated with biochemical and epigenetic data. Conclusions: These findings underline the complexity of psychological and pathophysiological components of EDs.
Subject(s)
Anorexia Nervosa , Binge-Eating Disorder , Bulimia Nervosa , Feeding and Eating Disorders , Humans , Tryptophan , Kynurenine , DNA Methylation , Feeding and Eating Disorders/genetics , Bulimia Nervosa/epidemiology , Binge-Eating Disorder/psychology , Anorexia Nervosa/psychology , Serotonin Plasma Membrane Transport ProteinsABSTRACT
OBJECTIVE: To close the chasm between theory about families containing a parent with an eating disorders (EDs) history and lack of selective or indicated prevention programming for such families with an older child or adolescent who is, genetically, at high risk. METHOD: A search of four major databases for January 2000 through September 2022 yielded no publications that (a) identified genetically high-risk families with offspring ages 10 through 18; (b) devised a prevention program for the family; and (c) evaluated program effects on risk/protective factors. To rectify this gap, research on three lines of family-based prevention is reviewed: (1) programs for adolescents at genetic risk for depression or anxiety; (2) the Stanford-Dresden project for adolescents at high risk for anorexia nervosa; and (3) Sadeh-Sharvit et al.'s work concerning the Parent-Based Prevention program for mothers with an EDs history and a child under age 5. RESULTS: The significant challenges for innovative prevention programming should be addressed by experts in effective EDs, depression, and anxiety prevention, and in family-based treatment (FBT) for EDs, collaborating with people from genetically vulnerable families. Innovative programming should focus on robust risk factors for EDs, adaptive expression of non-specific risk factors (e.g., temperament), and strengthening family functioning. DISCUSSION: The field is overdue for development of prevention programs designed for older children or adolescents who are at risk because a parent has an ED. Evidence-based prevention programs for EDs and for depression and anxiety, as well as parent-based prevention informed by FBT, provide a springboard for addressing this gap. PUBLIC SIGNIFICANCE: The foundation of theory and research is available for stakeholders to develop prevention programming that closes the huge gap between theory and research about families that are genetically vulnerable for eating disorders versus the complete lack of prevention programming for such families that have an older child or adolescent at high risk.
Subject(s)
Anorexia Nervosa , Feeding and Eating Disorders , Child , Adolescent , Humans , Child, Preschool , Feeding and Eating Disorders/genetics , Feeding and Eating Disorders/prevention & control , Anxiety Disorders , AnxietyABSTRACT
Although bivariate associations between attention-deficit/hyperactivity disorder (ADHD) and eating disorders in adolescent girls and boys have been previously identified, the mechanistic link underlying the symptom-level associations remains unclear. We evaluated shared genetic and environmental influences on ADHD symptoms and disordered eating in 819 female and 756 male twins from the Swedish TCHAD cohort using bivariate models. Common additive genetic and unique environmental effects accounted for majority of ADHD and disordered eating associations in a differential manner. For girls, the strongest genetic correlation was observed for cognitive/inattention problems-bulimia (0.54), with genetic factors accounting for 67% of the phenotypic correlation. For boys, the strongest genetic correlations were observed for conduct problems-bulimia and hyperactivity-bulimia (~ 0.54), accounting for 83% and 95% of the phenotypic correlation, respectively. As per our findings, the risk of comorbidity and shared genetics highlights the need for preventative measures and specialized treatment for ADHD and disordered eating in both sexes.
Subject(s)
Attention Deficit Disorder with Hyperactivity , Bulimia , Feeding and Eating Disorders , Humans , Male , Adolescent , Female , Attention Deficit Disorder with Hyperactivity/genetics , Bulimia/complications , Bulimia/genetics , Twins/genetics , Feeding and Eating Disorders/genetics , Feeding and Eating Disorders/complications , ComorbidityABSTRACT
OBJECTIVES: Recent studies have reported altered methylation levels at disorder-relevant DNA sites in people who are ill with Anorexia Nervosa (AN) compared to findings in people with no eating disorder (ED) or in whom AN has remitted. The preceding implies state-related influences upon gene expression in people with AN. This study further examined this notion. METHODS: We measured genome-wide DNA methylation in 145 women with active AN, 49 showing stable one-year remission of AN, and 64 with no ED. RESULTS: Comparisons revealed 205 differentially methylated sites between active and no ED groups, and 162 differentially methylated sites between active and remitted groups (Q < 0.01). Probes tended to map onto genes relevant to psychiatric, metabolic and immune functions. Notably, several of the genes identified here as being differentially methylated in people with AN (e.g. SYNJ2, PRKAG2, STAT3, CSGALNACT1, NEGR1, NR1H3) have figured in previous studies on AN. Effects also associated illness chronicity and lower BMI with more pronounced DNA methylation alterations, and remission of AN with normalisation of DNA methylation. CONCLUSIONS: Findings corroborate earlier results suggesting reversible DNA methylation alterations in AN, and point to particular genes at which epigenetic mechanisms may act to shape AN phenomenology.
Subject(s)
Anorexia Nervosa , Feeding and Eating Disorders , Female , Humans , Anorexia Nervosa/genetics , Anorexia Nervosa/psychology , DNA Methylation , Epigenome , Feeding and Eating Disorders/genetics , Epigenesis, GeneticABSTRACT
BACKGROUND: Translational (genetic) research focuses on the translation of preclinical research into practice. While many genetic studies have been conducted in recent years, the results do not simply translate to the clinic.
AIM: To visualize the steps through which translational genetic research contributes to the unraveling of the biological backgrounds of psychiatric disorders, in particular of eating disorders.
METHOD: Literature review.
RESULTS: Genetic studies have unraveled a mechanism underlying the hunger and satiety system. There is hope that genome-wide studies of eating disorders will lead to identification of neural circuits in which associated genes cluster. New techniques, such as opto- and chemogenetics, provide the opportunity to define the precise role of these circuits in eating disorders.
CONCLUSION: New techniques in molecular neuroscience allow the unravelling of the complexity of how the brain works and some of those techniques (such as chemogenetics) are being further developed for application in humans. However, it will be years before we can definitively translate this into the treatment of psychiatric disorders.
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Subject(s)
Feeding and Eating Disorders , Motivation , Brain , Feeding and Eating Disorders/genetics , Feeding and Eating Disorders/therapy , HumansABSTRACT
Substantial progress has been made in the understanding of anorexia nervosa (AN) and eating disorder (ED) genetics through the efforts of large-scale collaborative consortia, yielding the first genome-wide significant loci, AN-associated genes, and insights into metabo-psychiatric underpinnings of the disorders. However, the translatability, generalizability, and reach of these insights are hampered by an overly narrow focus in our research. In particular, stereotypes, myths, assumptions and misconceptions have resulted in incomplete or incorrect understandings of ED presentations and trajectories, and exclusion of certain patient groups from our studies. In this review, we aim to counteract these historical imbalances. Taking as our starting point the Academy for Eating Disorders (AED) Truth #5 "Eating disorders affect people of all genders, ages, races, ethnicities, body shapes and weights, sexual orientations, and socioeconomic statuses", we discuss what we do and do not know about the genetic underpinnings of EDs among people in each of these groups, and suggest strategies to design more inclusive studies. In the second half of our review, we outline broad strategic goals whereby ED researchers can expand the diversity, insights, and clinical translatability of their studies.
Subject(s)
Anorexia Nervosa , Feeding and Eating Disorders , Female , Humans , Male , Feeding and Eating Disorders/genetics , Anorexia Nervosa/geneticsABSTRACT
AIM: Eating disorders (EDs) are complex, multifactorial psychiatric conditions. Previous studies identified pathogenic copy number variations associated with NDDs (NDD-CNVs) in ED patients. However, no statistical evidence for an association between NDD-CNVs and EDs has been demonstrated. Therefore, we examined whether NDD-CNVs confer risk for EDs. METHODS: Using array comparative genomic hybridization (aCGH), we conducted a high-resolution CNV analysis of 71 severe female ED patients and 1045 female controls. According to the American College of Medical Genetics guidelines, we identified NDD-CNVs or pathogenic/likely pathogenic CNVs in NDD-linked loci. Gene set analysis was performed to examine the involvement of synaptic dysfunction in EDs. Clinical data were retrospectively examined for ED patients with NDD-CNVs. RESULTS: Of the samples analyzed with aCGH, 70 severe ED patients (98.6%) and 1036 controls (99.1%) passed our quality control filtering. We obtained 189 and 2539 rare CNVs from patients and controls, respectively. NDD-CNVs were identified in 10.0% (7/70) of patients and 2.3% (24/1036) of controls. Statistical analysis revealed a significant association between NDD-CNVs and EDs (odds ratio = 4.69, P = 0.0023). NDD-CNVs in ED patients included 45,X and deletions at KATNAL2, DIP2A, PTPRT, RBFOX1, CNTN4, MACROD2, and FAM92B. Four of these genes were related to synaptic function. In gene set analysis, we observed a nominally significant enrichment of rare exonic CNVs in synaptic signaling in ED patients (odds ratio = 2.55, P = 0.0254). CONCLUSION: Our study provides the first preliminary evidence that NDD-CNVs may confer risk for severe EDs. The pathophysiology may involve synaptic dysfunction.
Subject(s)
DNA Copy Number Variations , Feeding and Eating Disorders , Comparative Genomic Hybridization , DNA Copy Number Variations/genetics , Feeding and Eating Disorders/genetics , Female , Humans , Retrospective StudiesABSTRACT
Eating disorders (anorexia nervosa, bulimia nervosa and binge-eating disorder) are a heterogeneous class of complex illnesses marked by weight and appetite dysregulation coupled with distinctive behavioral and psychological features. Our understanding of their genetics and neurobiology is evolving thanks to global cooperation on genome-wide association studies, neuroimaging, and animal models. Until now, however, these approaches have advanced the field in parallel, with inadequate cross-talk. This review covers overlapping advances in these key domains and encourages greater integration of hypotheses and findings to create a more unified science of eating disorders. We highlight ongoing and future work designed to identify implicated biological pathways that will inform staging models based on biology as well as targeted prevention and tailored intervention, and will galvanize interest in the development of pharmacologic agents that target the core biology of the illnesses, for which we currently have few effective pharmacotherapeutics.
Subject(s)
Anorexia Nervosa , Binge-Eating Disorder , Bulimia Nervosa , Feeding and Eating Disorders , Animals , Binge-Eating Disorder/psychology , Bulimia Nervosa/psychology , Feeding and Eating Disorders/genetics , Genome-Wide Association StudyABSTRACT
About 20% of individuals with anorexia nervosa (AN) remain chronically ill. Therefore, early identification of poor outcome could improve care. Genetic research has identified regions of the genome associated with AN. Patients with anorexia nervosa were identified via the Swedish eating disorder quality registers Stepwise and Riksät and invited to participate in the Anorexia Nervosa Genetics Initiative. First, we associated genetic information longitudinally with eating disorder severity indexed by scores on the Clinical Impairment Assessment (CIA) in 2843 patients with lifetime AN with or without diagnostic migration to other forms of eating disorders followed for up to 16 years (mean = 5.3 years). Second, we indexed the development of a severe and enduring eating disorder (SEED) by a high CIA score plus a follow-up time ≥5 years. We associated individual polygenic scores (PGSs) indexing polygenic liability for AN, schizophrenia, and body mass index (BMI) with severity and SEED. After multiple testing correction, only the BMI PGS when calculated with traditional clumping and p value thresholding was robustly associated with disorder severity (ßPGS = 1.30; 95% CI: 0.72, 1.88; p = 1.2 × 10-5) across all p value thresholds at which we generated the PGS. However, using the alternative PGS calculation method PRS-CS yielded inconsistent results for all PGS. The positive association stands in contrast to the negative genetic correlation between BMI and AN. Larger discovery GWASs to calculate PGS will increase power, and it is essential to increase sample sizes of the AN GWASs to generate clinically meaningful PGS as adjunct risk prediction variables. Nevertheless, this study provides the first evidence of potential clinical utility of PGSs for eating disorders.