Shared genetic influences between eating disorders and gastrointestinal disease in a large, population-based sample of adult women and men.

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.

Gene variants in eating disorders. Focus on anorexia nervosa, bulimia nervosa, and binge-eating disorder.

Eating disorders such as anorexia nervosa, bulimia nervosa and binge-eating disorder, have a deep social impact, concluding with death in cases of severe disease. Eating disorders affect up to 5% of the population in the industrialized countries, but probably the phenomenon is under-detection and under-diagnosis. Eating disorders are multifactorial disorders, resulting from the interaction between environmental triggers, psychological factors, but there is also a strong genetic component. In fact, genetic factors predispose for approximately 33-84% to anorexia nervosa, 28-83% to bulimia nervosa, and 41-57% to binge eating disorder. Twins and family studies have provided an unassailable proof on the heritability of these disorders. Other types of genetic studies, including genome-wide association studies, whole genome sequencing and linkage analysis, allowed to identify the genes and their variants associated with eating disorders and moreover global collaborative efforts have led to delineate the etiology of these disorders. Next Generation Sequencing technologies can be considered as an ideal diagnostic approach to identify not only the common variants, such as single nucleotide polymorphism, but also rare variants. Here we summarize the present knowledge on the molecular etiology and genetic determinants of eating disorders including serotonergic genes, dopaminergic genes, opioid genes, appetite regulation genes, endocannabinoid genes and vitamin D3.

The Eating Disorders Genetics Initiative (EDGI): study protocol.

BACKGROUND: The Eating Disorders Genetics Initiative (EDGI) is an international investigation exploring the role of genes and environment in anorexia nervosa, bulimia nervosa, and binge-eating disorder. METHODS: A total of 14,500 individuals with eating disorders and 1500 controls will be included from the United States (US), Australia (AU), New Zealand (NZ), and Denmark (DK). In the US, AU, and NZ, participants will complete comprehensive online phenotyping and will submit a saliva sample for genotyping. In DK, individuals with eating disorders will be identified by the National Patient Register, and genotyping will occur using bloodspots archived from birth. A genome-wide association study will be conducted within EDGI and via meta-analysis with other data from the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED). DISCUSSION: EDGI represents the largest genetic study of eating disorders ever to be conducted and is designed to rapidly advance the study of the genetics of the three major eating disorders (anorexia nervosa, bulimia nervosa, and binge-eating disorder). We will explicate the genetic architecture of eating disorders relative to each other and to other psychiatric and metabolic disorders and traits. Our goal is for EDGI to deliver "actionable" findings that can be transformed into clinically meaningful insights. TRIAL REGISTRATION: EDGI is a registered clinical trial: clinicaltrials.gov NCT04378101 .

Association of 5-HTR2A -1438A/G polymorphism with anorexia nervosa and bulimia nervosa: A meta-analysis.

Although a number of studies have been conducted on the association of -1438A/G polymorphism in serotonin 2A receptor (5-HTR2A) gene with anorexia nervosa (AN) and bulimia nervosa (BN), the results remained inconsistent. We thus performed a meta-analysis to clarify the effects of -1438A/G polymorphism on the risk of AN and BN. PubMed, Embase, the Cochrane Library, CNKI, Weipu and Wanfang databases were searched for eligible studies. Pooled odds ratio (OR) and 95 % confidence interval (CI) were calculated to estimate the strength of the association. Subgroup analysis was also performed by ethnicity. In total, 17 studies were included for the meta-analysis, of which 15 studies containing 2028 cases and 2725 controls were used for AN analysis and 7 studies containing 505 cases and 1129 controls for BN analysis. The results showed -1438A/G polymorphism was significantly associated with the risk of AN in four genetic models (allele model, A vs. G: OR = 1.31, 95 % CI = 1.11-1.64, P = 0.003; recessive model, AA vs. GA + GG: OR = 1.69, 95 % CI = 1.28-2.23, P = 0.000; dominant model, AA + GA vs. GG: OR = 1.35, 95 % CI = 1.02-1.79, P = 0.037; co-dominant model, AA vs. GG: OR = 1.94, 95 % CI = 1.29-2.92, P = 0.002) in Caucasians, but not in Asians. We failed to observe a significant association between -1438A/G polymorphism and the risk of BN either in overall or in Caucasian population. The present meta-analysis indicated that A allele and AA genotype of 5-HTR2A -1438A/G polymorphism may contribute to higher risk of AN, especially in Caucasians. However, this polymorphism was not associated with the susceptibility to BN.

One size does not fit all. Genomics differentiates among anorexia nervosa, bulimia nervosa, and binge-eating disorder.

OBJECTIVE: Genome-wide association studies have identified multiple genomic regions associated with anorexia nervosa. No genome-wide studies of other eating disorders, such as bulimia nervosa and binge-eating disorder, have been performed, despite their substantial heritability. Exploratively, we aimed to identify traits that are genetically associated with binge-type eating disorders. METHOD: We calculated genome-wide polygenic scores for 269 trait and disease outcomes using PRSice v2.2 and their association with anorexia nervosa, bulimia nervosa, and binge-eating disorder in up to 640 cases and 17,050 controls from the UK Biobank. Significant associations were tested for replication in the Avon Longitudinal Study of Parents and Children (up to 217 cases and 3,018 controls). RESULTS: Individuals with binge-type eating disorders had higher polygenic scores than controls for other psychiatric disorders, including depression, schizophrenia, and attention deficit hyperactivity disorder, and higher polygenic scores for body mass index. DISCUSSION: Our findings replicate some of the known comorbidities of eating disorders on a genomic level and motivate a deeper investigation of shared and unique genomic factors across the three primary eating disorders.

Genetics of eating disorders in the genome-wide era.

Enabled by advances in high throughput genomic sequencing and an unprecedented level of global data sharing, molecular genetic research is beginning to unlock the biological basis of eating disorders. This invited review provides an overview of genetic discoveries in eating disorders in the genome-wide era. To date, five genome-wide association studies on eating disorders have been conducted - all on anorexia nervosa (AN). For AN, several risk loci have been detected, and ~11-17% of the heritability has been accounted for by common genetic variants. There is extensive genetic overlap between AN and psychological traits, especially obsessive-compulsive disorder, and intriguingly, with metabolic phenotypes even after adjusting for body mass index (BMI) risk variants. Furthermore, genetic risk variants predisposing to lower BMI may be causal risk factors for AN. Causal genes and biological pathways of eating disorders have yet to be elucidated and will require greater sample sizes and statistical power, and functional follow-up studies. Several studies are underway to recruit individuals with bulimia nervosa and binge-eating disorder to enable further genome-wide studies. Data collections and research labs focused on the genetics of eating disorders have joined together in a global effort with the Psychiatric Genomics Consortium. Molecular genetics research in the genome-wide era is improving knowledge about the biology behind the established heritability of eating disorders. This has the potential to offer new hope for understanding eating disorder etiology and for overcoming the therapeutic challenges that confront the eating disorder field.

Genetic variants in dopamine pathways affect personality dimensions displayed by patients with eating disorders.

PURPOSE: We aimed to analyze the association between common polymorphisms in dopamine pathways with personality dimensions frequently present in patients with eating disorders (ED). METHODS: A total of 324 patients [210 with anorexia nervosa (AN), 80 with bulimia nervosa (BN) and 34 with binge-eating disorder (BED)] were diagnosed according to DSM-5 criteria and interviewed using the EDI 2 and SCL-90R questionnaires at the eating disorders unit. Blood samples were drawn and the DNA screened for polymorphisms in dopamine receptor genes (DRD2 A2/A1 and DRD3 Ser9Gly) and in the dopamine transporter DAT1 10R/9R. RESULTS: AN patients who carried the DRD3 Gly9Gly genotype displayed significantly higher EDI-2 total scores than patients with the Ser9 allele (118.09 ± 8.75 vs. 97.23 ± 2.73, p = 0.010). In these patients, Gly9Gly carriers also showed higher scores in all the individuals' EDI-2 scales. Differences were especially relevant for bulimia (p = 0.004), ineffectiveness (p = 0.044), interpersonal distrust (p = 0.037), interoceptive awareness (p = 0.006) and maturity fears (p = 0.038). Epistasis analyses showed a strong effect of the interaction between DRD3 Ser9Gly and DRD2 A2A1 on the bulimia (p < 0.05), ineffectiveness (p < 0.05) and asceticism (p < 0.01) scales, as well as on the EDI-2 total score (p < 0.05). The scores of the SCL-90R inventory were largely unaffected by the presence of the polymorphisms. CONCLUSION: Whilst no associations were found for the BN and BED groups, our results suggest that women with AN carrying the homozygous variant Gly9Gly genotype in the dopamine D3 receptor have significantly worse ED-related symptomatology. LEVEL OF EVIDENCE: Level III (evidence obtained from well-designed cohort or case-control analytic studies).

Genetic and environmental contributions to diagnostic fluctuation in anorexia nervosa and bulimia nervosa.

BACKGROUND: Anorexia nervosa and bulimia nervosa are two severe eating disorders associated with high premature mortality, suicidal risk and serious medical complications. Transition between anorexia nervosa and bulimia nervosa over the illness course and familial co-aggregation of the two eating disorders imply aetiological overlap. However, genetic and environmental liabilities to the overlap are poorly understood. Quantitative genetic research using clinical diagnosis is needed. METHODS: We acquired a clinical diagnosis of anorexia nervosa (prevalence = 0.90%) and bulimia nervosa (prevalence = 0.48%) in a large population-based sample (N = 782 938) of randomly selected full-sisters and maternal half-sisters born in Sweden between 1970 and 2005. Structural equation modelling was applied to quantify heritability of clinically diagnosed anorexia nervosa and bulimia nervosa and the contributions of genetic and environmental effects on their overlap. RESULTS: The heritability of clinically diagnosed anorexia nervosa and bulimia nervosa was estimated at 43% [95% confidence interval (CI) (36-50%)] and 41% (31-52%), respectively, in the study population, with the remaining variance explained by variance in unique environmental effects. We found statistically significant genetic [0.66, 95% CI (0.49-0.82)] and unique environmental correlations [0.55 (0.43-0.66)] between the two clinically diagnosed eating disorders; and their overlap was about equally explained by genetic and unique environmental effects [co-heritability 47% (35-58%)]. CONCLUSIONS: Our study supports shared mechanisms for anorexia nervosa and bulimia nervosa and extends the literature from self-reported behavioural measures to clinical diagnosis. The findings encourage future molecular genetic research on both eating disorders and emphasize clinical vigilance for symptom fluctuation between them.

The Binge Eating Genetics Initiative (BEGIN): study protocol.

BACKGROUND: The Binge Eating Genetics Initiative (BEGIN) is a multipronged investigation examining the interplay of genomic, gut microbiota, and behavioral factors in bulimia nervosa and binge-eating disorder. METHODS: 1000 individuals who meet current diagnostic criteria for bulimia nervosa or binge-eating disorder are being recruited to collect saliva samples for genotyping, fecal sampling for microbiota characterization, and recording of 30 days of passive data and behavioral phenotyping related to eating disorders using the app Recovery Record adapted for the Apple Watch. DISCUSSION: BEGIN examines the interplay of genomic, gut microbiota, and behavioral factors to explore etiology and develop predictors of risk, course of illness, and response to treatment in bulimia nervosa and binge-eating disorder. We will optimize the richness and longitudinal structure of deep passive and active phenotypic data to lay the foundation for a personalized precision medicine approach enabling just-in-time interventions that will allow individuals to disrupt eating disorder behaviors in real time before they occur. TRIAL REGISTRATION: The ClinicalTrials.gov identifier is NCT04162574. November 14, 2019, Retrospectively Registered.

Sequence analysis of five exons of SLC6A4 gene in Mexican patients with anorexia nervosa and bulimia nervosa.

BACKGROUND: Accumulating evidence indicates that alterations in the serotonin system are related to changes in eating behavior. The serotonin transporter is encoded by the SLC6A4 gene and has been an interesting candidate for anorexia nervosa- restrictive type (AN-R) and bulimia nervosa (BN). Interestingly, functional variants have been identified in the coding region that could contribute to understand the role of this gene in eating disorders. The aim was to identify genetic variants in five exons of SLC6A4 gene using Sanger-sequencing in anorexia nervosa-restrictive and bulimia nervosa patients, and a control group. METHOD: The sample consisted of 86 patients and 50 control subjects. We obtained DNA samples from all subjects and performed Sanger-sequence analysis of the 1, 2, 3, 8 and 9 exons. The sequences were compared with the reference sequence of the SLC6A4 gene. RESULTS: The sequence analysis of the five exons of the gene identified several variants. In the AN-R, we observed two novel variants (g.130delA and c.1740G > A), three synonymous variants (rs57172732, rs55908624, rs74478645) and a missense variant (L90F) reporting a probably deleterious and damaging variant. In BN, we identified two novel variants (g.295C > G and c.1725G > A), and the non-synonymous (rs28914832/I425V), reported as benign. Interestingly, we observed the 425V variant in three patients in the BN, variant that previously was reported in patients with a spectrum obsessive-compulsive disorder. CONCLUSION: The results of our study suggest that variants of the SLC6A4 gene are related with a possible damaging or gain-of-function and may be involved in the susceptibility to AN-R and BN patients. However, the present findings should be considered as preliminary until replicated in large samples.

The Role of Puberty and Ovarian Hormones in the Genetic Diathesis of Eating Disorders in Females.

Puberty is a critical risk period for eating disorders (EDs). ED incidence increases across the pubertal period and becomes female predominant, and genetic influences on disordered eating significantly increase. Surges of ovarian hormones, particularly estrogen, may drive this increasing genetic effect for EDs in pubertal girls and contribute to differential phenotypic presentations beyond puberty. In this article, we explain phenotypic associations between puberty and disordered eating and present evidence showing underlying genetic and hormonal influence. Potential benefits of communicating roles of genetic influence to people with or at risk for EDs are also discussed.

Understanding the genetics and epigenetics of bulimia nervosa/bulimia spectrum disorder and comorbid borderline personality disorder (BN/BSD-BPD): a systematic review.

PURPOSE: To evaluate and understand the genetic and epigenetic basis of bulimia nervosa/bulimia spectrum disorder and comorbid borderline personality disorder (BN/BSD-BPD). METHODS: The present systematic review was conducted in accordance to PRISMA guidelines. Advanced systematic searches of Medline, EMBASE, PsychINFO, Web of Science, Scopus, CINHAL plus, and the Cochrane Library were conducted using the search terms 'bulimia nervosa', 'bulimia spectrum disorder', 'borderline personality disorder', 'genes', and 'genetics'. The search strategy garnered seven studies for inclusion in the present review. RESULTS: Women with BN/BSD-BPD had significantly lower serotonin and monoamine oxidise activity compared to women with BN/BSD or healthy controls (HC). As well, women with BN/BSD-BPD displayed elevated methylation of the dopamine receptor gene promoter, brain-derived neurotrophic factor, and changes in the methylation of the glucocorticoid receptor gene promoter (NR3C1) compared to women with BN/BSD and HC. The results also demonstrated that rates of childhood sexual abuse and childhood physical abuse are higher in those with BN/BSD-BPD than those with BN/BSD and HC, and that these types of abuse are often correlated with the methylation differences seen in BN/BSD-BPD women. CONCLUSION: Due to the differences observed between individuals with BN/BSD-BPD and those with BN/BSD and HC a genetic/epigenetic aetiological model of BN/BSD-BPD was developed and is proposed in this review. This evidence-based model visually illustrates the current state of the field and draws attention to the need for subsequent research.

Role of eating disorders-related polymorphisms in obesity pathophysiology.

Human biological system provides innumerable neuroendocrine inputs for food intake control, with effects on appetite's modulation and the satiety signs. Its regulation is very complex, engaging several molecular interactions with many tissues, hormones, and neural circuits. Thus, signaling molecules that control food intake are critical for normal energy homeostasis and a deregulation of these pathways can lead to eating disorders and obesity. In line of this, genetic factors have a significantly influence of the regulation of neural circuits controlling the appetite and satiety pathways, as well as the regulation of brain reward systems. Single Nucleotide Polymorphisms (SNPs) in genes related to hypothalamic appetite and satiety mechanisms, further in multiple neurotransmitter systems may contribute to the development of major Eating Disorders (EDs) related to obesity, among them Binge Eating Disorder (BED) and Bulimia Nervosa (BN), which are discussed in this review.

Genetics of Eating Disorders: What the Clinician Needs to Know.

Anorexia nervosa (AN), bulimia nervosa (BN), and binge-eating disorder (BED) are heritable conditions that are influenced by both genetic and environmental factors. Recent genome-wide association studies (GWAS) of AN have identified specific genetic loci implicated in AN, and genetic correlations have implicated both psychiatric and metabolic factors in its origin. No GWAS have been performed for BN or BED. Genetic counseling is an important tool and can aid families and patients in understanding risk for these illnesses.

Association study of variants in genes FTO, SLC6A4, DRD2, BDNF and GHRL with binge eating disorder (BED) in Portuguese women.

A population based case-control study was conducted in Portuguese women with overweight/obesity to investigate the possible association of variants in genes FTO, SLC6A4, DRD2, BDNF and GHRL with binge eating disorder (BED). The distribution of seven polymorphisms was evaluated in 31 BED patients and 62 controls. No significant associations were found between polymorphisms and BED. Of interest, a markedly lower frequency of the FTO rs9939609 obesity risk A-allele was found in BED patients (0.290) in relation to the control group (0.402). Contrasting with anorexia nervosa and bulimia nervosa, our data suggest that rs9939609 A-allele has no potential role in BED.

Sex Differences in Adolescent Anorexia and Bulimia Nervosa: Beyond the Signs and Symptoms.

PURPOSE OF REVIEW: We review research related to sex differences in eating disorders (EDs) in adolescents. Prior work has explored clinical differences; thus, we examine literature in areas identified as playing an etiological or maintenance role in EDs including: genetics, hormones, neurocognitive inefficiencies, and reward circuitry. RECENT FINDINGS: Sex steroids appear to a play role in the unmasking of genetic risk for development of EDs and puberty may be a heightened period of risk for females. While neurocognitive differences have been well studied in adults with ED, research with adolescents has been less conclusive. Recent work suggests that neural circuitry involved in reward and punishment may play role in development and maintenance of EDs in females. Males are underrepresented in these areas of research. Given known sex differences in healthy adolescents, it is likely there are sex differences in the putative biological etiology/maintenance of EDs. Males should be included in future research.

Epigenetics in eating disorders: a systematic review.

Eating disorders are complex heritable conditions influenced by both genetic and environmental factors. Given the progress of genomic discovery in anorexia nervosa, with the identification of the first genome-wide significant locus, as well as animated discussion of epigenetic mechanisms in linking environmental factors with disease onset, our goal was to conduct a systematic review of the current body of evidence on epigenetic factors in eating disorders to inform future directions in this area. Following PRISMA guidelines, two independent authors conducted a search within PubMed and Web of Science and identified 18 journal articles and conference abstracts addressing anorexia nervosa (n = 13), bulimia nervosa (n = 6), and binge-eating disorder (n = 1), published between January 2003 and October 2017. We reviewed all articles and included a critical discussion of field-specific methodological considerations. The majority of epigenetic analyses of eating disorders investigated methylation at candidate genes (n = 13), focusing on anorexia and bulimia nervosa in very small samples with considerable sample overlap across published studies. Three studies used microarray-based technologies to examine DNA methylation across the genome of anorexia nervosa and binge-eating disorder patients. Overall, results were inconclusive and were primarily exploratory in nature. The field of epigenetics in eating disorders remains in its infancy. We encourage the scientific community to apply methodologically sound approaches using genome-wide designs including epigenome-wide association studies (EWAS), to increase sample sizes, and to broaden the focus to include all eating disorder types.

Rigor and reproducibility in genetic research on eating disorders.

OBJECTIVE: We explored both within-method and between-method rigor and reproducibility in the field of eating disorders genetics. METHOD: We present critical evaluation and commentary on component methods of genetic research (family studies, twin studies, molecular genetic studies) and discuss both successful and unsuccessful efforts in the field. RESULTS: Eating disorders genetics has had a number of robust results that converge across component methodologies. Familial aggregation of eating disorders, twin-based heritability estimates of eating disorders, and genome-wide association studies (GWAS) all point toward a substantial role for genetics in eating disorders etiology and support the premise that genes do not act alone. Candidate gene and linkage studies have been less informative historically. DISCUSSION: The eating disorders field has entered the GWAS era with studies of anorexia nervosa. Continued growth of sample sizes is essential for rigorous discovery of actionable variation. Molecular genetic studies of bulimia nervosa, binge-eating disorder, and other eating disorders are virtually nonexistent and lag seriously behind other major psychiatric disorders. Expanded efforts are necessary to reveal the fundamental biology of eating disorders, inform clinical practice, and deliver new therapeutic targets.

Which Comes First? An Examination of Associations and Shared Risk Factors for Eating Disorders and Suicidality.

PURPOSE OF REVIEW: This narrative review evaluates recent literature on the associations between eating disorders and suicidality and discusses potential shared mechanisms that may account for these relationships. Additionally, the review highlights shortcomings with the literature to date and suggests avenues for future research. RECENT FINDINGS: Individuals with anorexia nervosa, bulimia nervosa, and binge eating disorder experience elevated rates of suicidality compared to the general population. Suicide risk is higher when eating disorders occur with other psychological conditions. Additionally, genetic factors, emotion dysregulation, trauma, stressful life events, and lack of body regard may have roles in the development of both eating disorders and suicidality. Much of the risk for suicidality in eating disorders appears to be driven by comorbid psychopathology and genetic factors. However, the lack of longitudinal research makes it difficult to draw conclusions about the directionality or temporality of these relations; thus, novel methods are needed.

Association of COMT Val158Met Polymorphism with Psychopathological Symptoms in Patients with Eating Disorders.

BACKGROUND: Dopamine physiological functions make dopaminergic genes suitable candidates for association studies in eating disorders (ED). A Val158Met polymorphism in the catechol-O-methyltransferase (COMT) gene, which is involved in dopamine degradation, has been studied in relation to ED. OBJECTIVE: We aimed to analyze the association between this polymorphism and general psychopathological symptoms that are often coupled to these disorders. METHOD: A total of 303 ED patients, diagnosed according to DSM-5 criteria, completed the SCL-90R questionnaire and were genotyped for the Val158Met polymorphism. RESULTS: There were significant differences in the global indices of the SCL-90R inventory between the three ED groups (Anorexia Nervosa (AN), Bulimia Nervosa (BN) and binge-eating disorder; ANOVA-p < 0.05). Females with BN showed the highest scores (worse symptomatology) of all participants. In this group, a gene-dose effect was observed on the psychometric evaluation of the patients, as Val/Val carriers displayed the highest scores for all the SCL-90R scales, followed by Val/Met and then Met/Met carriers. Significant differences between genotypes were observed in the Obsessive- Compulsive (p = 0.018), Paranoid Ideation (p = 0.0005) and Psychoticism (p = 0.039) scales, as well as in the PSDI (p = 0.014) general index. CONCLUSION: The results taken together suggest that COMT genetic variability may contribute to general psychopathological symptoms in patients with BN.