A genome-wide association study of anorexia nervosa suggests a risk locus implicated in dysregulated leptin signaling.
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ABSTRACT:
SUBMITTER: Li D
PROVIDER: S-EPMC5476671 | biostudies-literature | 2017 Jun
REPOSITORIES: biostudies-literature
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A genome-wide association study of anorexia nervosa suggests a risk locus implicated in dysregulated leptin signaling.
Li Dong D Chang Xiao X Connolly John J JJ Tian Lifeng L Liu Yichuan Y Bhoj Elizabeth J EJ Robinson Nora N Abrams Debra D Li Yun R YR Bradfield Jonathan P JP Kim Cecilia E CE Li Jin J Wang Fengxiang F Snyder James J Lemma Maria M Hou Cuiping C Wei Zhi Z Guo Yiran Y Qiu Haijun H Mentch Frank D FD Thomas Kelly A KA Chiavacci Rosetta M RM Cone Roger R Li Bingshan B Sleiman Patrick A PA Hakonarson Hakon H
Scientific reports 20170619 1
We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P = 2.04 × 10<sup>-7</sup>; OR = 0.7; 95% confidence interval (CI) = 0.61-0.8) with independent replication (P = 0.04), suggesting a variant-mediated dysregulation of leptin signaling may play a role in AN ...[more]
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Project description:OBJECTIVE:The authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. METHOD:Following uniform quality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anorexia nervosa cases and 10,982 controls, the authors performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based heritability [h2SNP]), partitioned heritability, and genetic correlations (rg) between anorexia nervosa and 159 other phenotypes. RESULTS:Results were obtained for 10,641,224 SNPs and insertion-deletion variants with minor allele frequencies >1% and imputation quality scores >0.6. The h2SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. The authors identified one genome-wide significant locus on chromosome 12 (rs4622308) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high-density lipoprotein cholesterol, and significant negative genetic correlations were observed between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes. CONCLUSIONS:Anorexia nervosa is a complex heritable phenotype for which this study has uncovered the first genome-wide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. The study results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology.
| S-EPMC5581217 | biostudies-literature
Project description:ObjectiveRelapse after weight restoration in anorexia nervosa (AN) is a critical problem. Higher body fat percentage after weight gain has been shown to predict better weight maintenance outcome. Leptin, a fat-derived hormone, has been associated with progress during weight gain, but its association with weight maintenance is unknown. This study aims to determine whether leptin levels after weight restoration in AN are associated with weight maintenance.MethodParticipants were 41 women with AN hospitalized for inpatient treatment. Participants were evaluated 2-4 weeks after weight restoration to body mass index (BMI) ≥ 19.5 kg/m2 for plasma leptin and body composition. Weight maintenance outcome was defined by whether a participant maintained a BMI of at least 18.5 kg/m2 at the end of 1 year following hospital discharge.ResultsTwenty (48.8%) out of 41 patients maintained their weight at 1 year. Percent body fat and leptin were significantly higher in the group who maintained weight (body fat, p = .004, Hedges' g = 0.944; log-leptin, p = .010, Hedges' g = 0.821), but there were no differences in predischarge BMI, duration of illness, and duration of amenorrhea. Using regression modeling, only higher log-leptin (pWald = .021) and percent body fat (pWald = .010), as well as fat-adjusted leptin (pWald = .029), independently predicted weight maintenance at 1 year.DiscussionsOur findings suggest that for acutely-weight restored women with AN, higher predischarge leptin measurements are associated with better outcome in the year following treatment. Prospective studies examining leptin as well as other parameters of metabolic health could offer insights into biomarkers that may improve clinical outcomes.
| S-EPMC9851598 | biostudies-literature
Project description:Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14?860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21?080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.
| S-EPMC4325090 | biostudies-literature
Project description:Epigenetic alterations are increasingly implicated in the pathophysiology of anorexia nervosa (AN) but are as yet poorly understood. We investigated possible associations between the leptin gene (LEP) and the leptin receptor gene (LEPR) DNA promoter methylation and (1) a diagnosis of AN and (2) outcome after a 10 months psychotherapeutic outpatient treatment. 129 (LEPR: n = 135) patients with AN were investigated during the large scale psychotherapeutic Anorexia Nervosa Treatment Outpatient Study (ANTOP) trial, compared to 117 (LEPR: n = 119) age and height matched, normal-weight healthy controls. Blood samples were taken at baseline, the end of therapy (40 weeks) and the 12-months follow-up and compared to controls. Methylation was measured in whole blood via bisulfite sequencing. Within the promoter region 32 (LEP) and 39 CpG sites (LEPR) were analyzed. Two key findings were observed. First, LEP and LEPR methylation at baseline were lower in patients compared to controls (LEP: [%] AN: 30.94 ± 13.2 vs. controls: 34.53 ± 14.6); LEPR ([%] AN: 3.73 ± 5.4 vs. controls: 5.22 ± 8.3, mixed linear models: both P < 0.001). Second, lower DNA methylation of the LEP promoter, with a dynamic upregulation during treatment, was associated with a full recovery in AN patients (% change from baseline to follow-up in full recovery patients: +35.13% (SD: 47.56); mixed linear model: P < 0.0001). To test for potential predictive properties of mean LEP DNA methylation a LEP DNA methylation cut-off (31.25% DNA methylation) was calculated, which significantly discriminated full recovery vs. full syndrome AN patients. This cut-off was then tested in a group of previously unclassified patients (missing follow-up data of the Structured Interview for Anorexic and Bulimic disorders; n = 33). Patients below the cut-off (31.25% LEP DNA methylation) showed an increase in BMI over time, while those above the cut-off had a decrease in BMI (ANOVA at the 12-months follow-up: P = 0.0142). To our knowledge, this is the first study investigating epigenetic alterations in AN over time. Our findings indicate that LEP DNA methylation might be involved in the disease course of AN.
| S-EPMC6470249 | biostudies-literature
Project description:LEAP-2 is a ghrelin antagonist with an anorexigenic drive. This study investigates the evolution of plasma ghrelin and LEAP-2 concentrations in 29 patients with anorexia nervosa (AN) before and after refeeding and compares it to physiological adaptations during fasting in healthy controls or to mouse model of chronic food restriction and refeeding. Acute and chronic food restriction decrease LEAP-2 and increase ghrelin concentrations in both humans and mice, while patients with AN displayed higher ghrelin and LEAP-2 concentrations before than after refeeding (p = 0.043). After 6 months follow-up, patients with unstable weight gain (n = 17) had significantly decreased LEAP-2 concentrations after refeeding (p = 0.044), in contrast to patients with stable weight gain (n = 12). We provide evidence that the ghrelin/LEAP-2 system is not regulated according to the nutritional status in AN, in contrast to what is physiologically expected when coping with food restriction.
| S-EPMC10587521 | biostudies-literature
Project description:In anorexia nervosa (AN), hyperactivity is observed in about 80% of patients and has been associated with low leptin levels in the acute stage of AN and in anorexia animal models. To further understand the importance of this correlation in AN, we investigated the relationship between hypoleptinaemia and hyperactivity in AN patients longitudinally and assessed their predictive value for recovery. Body weight, activity levels, and serum leptin levels were assessed in adolescents and adult AN patient groups at the start and during treatment, up to a year. In the adolescent group, initial leptin and activity levels were correlated. This negative correlation changes over time into a positive correlation with physiological recovery. Treatment outcome in both groups could be predicted by initial BMI and leptin levels but not by activity levels. No major relationship of activity with the course of recovery was detected, suggesting that in contrast to the acute stage of the disease, leptin and activity levels during the recovery process are dissociated.
| S-EPMC2798977 | biostudies-other
Project description:ImportancePeople with anorexia nervosa often experience difficulties regulating their emotions. There is no longitudinal evidence as to whether these differences are already present in childhood or when they begin to emerge.ObjectiveTo investigate the association between emotion regulation trajectories from 3 to 7 years of age and symptoms of anorexia nervosa and atypical anorexia nervosa in adolescence.Design, setting, and participantsThis cohort study included all children with complete exposure data in the Millennium Cohort Study, a UK general population birth cohort. Data were acquired from June 2001 to March 2016 and analyzed from June to November 2020.ExposuresMothers reported on their children's emotion regulation skills at 3, 5, and 7 years of age using the Children's Social Behavior Questionnaire. Multilevel models were used to derive early childhood emotion regulation scores (ie, predicted intercept) and within-child changes in emotion regulation scores from 3 to 7 years of age (ie, predicted slope).Main outcome and measuresSymptoms consistent with a DSM-5 diagnosis of anorexia nervosa or atypical anorexia nervosa at 14 years of age, defined using a range of questions relative to body image, weight perception, and dieting behaviors (hereinafter referred to as broad anorexia nervosa). Univariable and multivariable logistic regression models tested the association between exposures and outcome. Regression models were adjusted for child and family sociodemographic and socioeconomic characteristics and mental health difficulties, prenatal and perinatal factors, child's cognitive development, and maternal attachment.ResultsA total of 15 896 participants (85.7% of total sample; 51.0% boys; 84.5% White individuals) had complete data on the exposure and were included in the main analyses. Among those with complete exposure and outcome data (9912 of the analytical sample [62.4%]), 97 participants (1.0%; 86 [88.7%] girls and 85 [87.6%] White individuals) had symptoms consistent with a diagnosis of broad anorexia nervosa at 14 years of age. No evidence suggested that children with lower emotion regulation ability at 3 years of age had greater odds of later reporting symptoms of broad anorexia nervosa (odds ratio [OR], 1.21; 95% CI, 0.91-1.63). However, children whose emotion regulation skills did not improve over childhood and who had greater problems regulating emotions at 7 years of age had higher odds of having broad anorexia nervosa at 14 years of age (OR, 1.45; 95% CI, 1.16-1.83).Conclusions and relevanceThese findings suggest that difficulties in developing age-appropriate emotion regulation skills in childhood are associated with experiencing broad anorexia nervosa in adolescence. Interventions to support the development of emotion regulation skills across childhood may help reduce the incidence of anorexia nervosa.
| S-EPMC8264752 | biostudies-literature
Project description:Up until now, no study has looked specifically at epigenomic landscapes throughout twin samples, discordant for Anorexia nervosa (AN). Our goal was to find evidence to confirm the hypothesis that epigenetic variations play a key role in the aetiology of AN. In this study, we quantified genome-wide patterns of DNA methylation using the Infinium Human DNA Methylation EPIC BeadChip array (850K) in DNA samples isolated from whole blood collected from a group of 7 monozygotic twin pairs discordant for AN. Results were then validated performing a genome-wide DNA methylation profiling using DNA extracted from whole blood of a group of non-family related AN patients and a group of healthy controls. Our first analysis using the twin sample revealed 9 CpGs associated to a gene. The validation analysis showed two statistically significant CpGs with the rank regression method related to two genes associated to metabolic traits, PPP2R2C and CHST1. When doing beta regression, 6 of them showed statistically significant differences, including 3 CpGs associated to genes JAM3, UBAP2L and SYNJ2.Finally, the overall pattern of results shows genetic links to phenotypes which the literature has constantly related to AN, including metabolic and psychological traits. The genes PPP2R2C and CHST1 have both been linked to the metabolic traits type 2 diabetes through GWAS studies. The genes UBAP2L and SYNJ2 have been related to other psychiatric comorbidity.
2022-01-31 | GSE186766 | GEO
Project description:Anorexia nervosa (AN) is a psychiatric disorder with an estimated heritability of around 70%. Although the largest genome-wide association study meta-analysis on AN identified independent loci-conferring risk to the disorder, the molecular mechanisms underlying the genetic basis of AN remains to be elucidated. To explore AN, we ran a transcriptome profiling in peripheral blood mononuclear cells of 15 AN subjects and 15 healthy controls. We validated our mean results in a mouse model of chronic food restriction mimicking several aspects of AN. Through this exploratory study we identified 673 significantly differentially expressed genes in AN. Among these genes, we identified the Vanin-1 (Vnn1) gene that appears to play a major role in the regulation of multiple metabolic pathways. We confirmed an underexpression of Vnn1, especially in the liver, in a mouse model of chronic food restriction. These results indicate that quantitative food restriction affects Vnn1 expression, suggesting that this gene may contribute to the anorexic phenotype in the chronic food restriction mouse model as well as in patients affected by AN. We believe that this report highlights promising candidate genes and gene pathways for AN and reveals Vnn1 as a biomarker that may be used as molecular targets to predict and/or to understand AN.
2023-10-31 | GSE245978 | GEO
Project description:ObjectiveAlthough low weight is a key factor contributing to the high mortality in anorexia nervosa (AN), it is unclear how AN patients sustain low weight compared with bulimia nervosa (BN) patients with similar psychopathology. Studies of genes involved in appetite and weight regulation in eating disorders have yielded variable findings, in part due to small sample size and clinical heterogeneity. This study: (1) assessed the role of leptin, melanocortin, and neurotrophin genetic variants in conferring risk for AN and BN; and (2) explored the involvement of these genes in body mass index (BMI) variations within AN and BN.MethodOur sample consisted of 745 individuals with AN without a history of BN, 245 individuals with BN without a history of AN, and 321 controls. We genotyped 20 markers with known or putative function among genes selected from leptin, melanocortin, and neurotrophin systems.ResultsThere were no significant differences in allele frequencies among individuals with AN, BN, and controls. AGRP rs13338499 polymorphism was associated with lowest illness-related BMI in those with AN (p = 0.0013), and NTRK2 rs1042571 was associated with highest BMI in those with BN (p = 0.0018).DiscussionTo our knowledge, this is the first study to address the issue of clinical heterogeneity in eating disorder genetic research and to explore the role of known or putatively functional markers in genes regulating appetite and weight in individuals with AN and BN. If replicated, our results may serve as an important first step toward gaining a better understanding of weight regulation in eating disorders.
| S-EPMC4191922 | biostudies-literature