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Background: Anorexia nervosa (AN) is a severe psychiatric disorder associated with frequent relapses and variability in treatment responses. Previous literature suggested that such variability is influenced by premorbid vulnerabilities such as abnormalities of the reward system. Several factors may indicate these vulnerabilities, such as neurocognitive markers (tendency to favour delayed reward, poor cognitive flexibility, abnormal decision process), genetic and epigenetic markers, biological and hormonal markers, and physiological markers.The present study will aim to identify markers that can predict body mass index (BMI) stability 6 months after discharge. The secondary aim of this study will be focused on characterising the biological, genetic, epigenetic and neurocognitive markers of remission in AN., Methods and Analysis: One hundred and twenty-five (n=125) female adult inpatients diagnosed with AN will be recruited and evaluated at three different times: at the beginning of hospitalisation, when discharged and 6 months later. Depending on the BMI at the third visit, patients will be split into two groups: stable remission (BMI≥18.5 kg/m²) or unstable remission (BMI<18.5 kg/m²). One hundred (n=100) volunteers will be included as healthy controls.Each visit will consist in self-reported inventories (measuring depression, anxiety, suicidal thoughts and feelings, eating disorders symptoms, exercise addiction and the presence of comorbidities), neurocognitive tasks (Delay Discounting Task, Trail-Making Test, Brixton Test and Slip-of-action Task), the collection of blood samples, the repeated collection of blood samples around a standard meal and MRI scans at rest and while resolving a delay discounting task.Analyses will mainly consist in comparing patients stabilised 6 months later and patients who relapsed during these 6 months., Ethics and Dissemination: Investigators will ask all participants to give written informed consent prior to participation, and all data will be recorded anonymously. The study will be conducted according to ethics recommendations from the Helsinki declaration (World Medical Association, 2013). It was registered on clinicaltrials.gov on 25 August 2020 as 'Remission Factors in Anorexia Nervosa (REMANO)', with the identifier NCT04560517 (for more details, see https://clinicaltrials.gov/ct2/show/record/NCT04560517). The present article is based on the latest protocol version from 29 November 2019. The sponsor, Institut National de la Santé Et de la Recherche Médicale (INSERM, https://www.inserm.fr/), is an academic institution responsible for the monitoring of the study, with an audit planned on a yearly basis.The results will be published after final analysis in the form of scientific articles in peer-reviewed journals and may be presented at national and international conferences., Trial Registration Number: clinicaltrials.govNCT04560517., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. Up to now, four genome-wide association studies of AN have been conducted to date and identified only few significant loci. However, both previous studies focused on common variation and on rare exonic variants. Currently, de novo variants are one of the most significant risk factors for neurodevelopmental disorders and psychiatric disorders., Methods: We analyzed by whole exome sequencing a cohort of nine female AN individuals and their parents (mother and father), and focused our analysis on de novo variants., Results: Here, we found seven de novo missense variants in potential genes in nine studied AN patients. Four of these genes (CSMD1, CREB3, PTPRD and GAB1) belong to a same signaling pathway involving neuron differentiation and dopamine pathway., Conclusions: This study provides a list of interesting genes such as CSDM1 and CREB3 that are candidates to be involved in the etiology of anorexia nervosa., Level of Evidence: basic research.

As a polygenic psychiatric disorder, the genetics of anorexia nervosa (AN) remains largely unexplored. Recently a large GWAS meta-analysis identified a significant SNP (rs6589488) as associated with AN. We suggested that rs6589488 might have gotten its association as being in linkage disequilibrium with unknown variants or functional intronic variants. In a selective cohort containing 51 patients diagnosed with restrictive subtype AN, we screened the whole coding region of the CADM1gene by Sanger sequencing and further investigated if these variants are associated with specific outcome. Only 13 single nucleotide polymorphisms, including 2 missense variants, 2 synonymous variants, 2 variants located at 5'-UTR and 7 intronic variants, including rs6589488, were identified in our AN cohort. The 2 missense variants, p.Val5Leu and p.Asp285Glu were not predicted to be deleterious. In conclusion, the intronic initial variant appears to be not associated with causative coding variant in the vicinity. If CADM1 is not the AN predisposition factor, the causative variant probably lies within 1 Mb of CADM1. Interestingly, among the 7 closest genes to CADM1, the nicotinamide N-methyltransferase (NNMT) gene is known to be associated with obesity. We suggest that the intronic variant in CADM1 could be in linkage disequilibrium with other causative variants located in NNMT., Competing Interests: Declaration of Competing Interest PG received during the last 5 years fees for presentations at congresses or participation in scientific boards from Alcediag-Alcen, AstraZeneca, Bristol-Myers-Squibb, GSK, Janssen, Lilly, Lundbeck, Otsuka and Servier, none of them being related to the present study. PG is not employed by a commercial company. All other authors declare no competing interests., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Anorexia nervosa (AN) is a severe debilitating eating disorder. To date, only very few genes that predispose to AN have been identified. An alternative to association studies is to characterize ultra-rare variants in familial forms of AN. Here, we have implemented this approach to identify pathways that contribute to the development of AN through the analysis of a family with three members suffering from AN by exome analysis. We identified three ultra-rare deleterious variants in three genes (DRD4, CCKAR, NMS), already connected to the reward pathway, that co-segregate with AN, suggesting that this pathway might be playing a predisposing role in AN at least in familial forms.

Background: Anorexia nervosa is a complex neuropsychiatric disorder presenting with life-threatening low body weight, and a persistent fear of gaining weight. To date, no whole exome sequencing was performed in male individuals with anorexia nervosa., Aim and Methods: Here, we performed an exome analysis in two independent families with male individuals with anorexia nervosa and found variants in the Neuronatin (NNAT) gene in both probands. To confirm our data, we carried out the screening of the NNAT gene in a cohort of 8 male and 144 female individuals with anorexia nervosa., Results: Exome sequencing revealed a nonsense variant p.Trp33* in NNAT in one patient and a rare variant in the 5'UTR region of NNAT in the other patient. Screening of the NNAT gene in a cohort of 8 male and 144 female individuals with anorexia nervosa allowed to identify 11 other NNAT variants showing that 40.00% and 6.25% of male and female anorexia nervosa individuals carried a NNAT variant, respectively. Moreover, two novel missense variants were identified in female anorexia nervosa patients., Conclusion: Our data suggest that NNAT variants and NNAT expression changes may be associated with susceptibility to eating disorders such as anorexia nervosa.

Anorexia Nervosa (AN) is a chronic psychiatric disorder whose pathophysiology is largely unknown but has a significant genetic component. The objective of this work was to identify rare genetic variants of predisposition for anorexia nervosa. We studied 10 families of 15 affected women, 11 cases of restrictive ANR (ANR) and 4 cases of binge-purging AN, and analyzed in trio by new generation sequencing. The variants were filtered by quality controls (blanket, IGV viewer), segregation in familial forms, deleterious in silico prediction of variants (Cadd> 15), and absence or rarity in unaffected controls and in the databases (Gnomad, "Déjà vu" Paris Descartes) (< 1%). The analysis of the de novo variants did not make it possible to identify deleterious candidate variants (with the exception of p.L206 V, deleterious in the LUMAN/CREB3 gene) and recurrent ones. In index cases of familial forms, potential de novo variants have been identified. Dominant model analysis identified 349 potential variants distributed in 110 genes. Analysis of this list of genes by String, David and GeneOntology has identified several biological pathways that may be altered. Three major KEGG pathways could be identified: "neuroactive ligand-receptor interaction" 9 genes, "cholinergic synapse" 6 genes, and "dopaminergic synapse" 6 genes. In addition, the literature analysis identified 24 variants in genes contributing to neuropsychiatric disorders. We identified specific damaging variant in several genes than can play a role in AN. Targeted analyzes of a large cohort of patients should be conducted to confirm our results. This study was supported by Fondation Maladies Rares (#11632) Program high throughput sequencing and rare diseases. [ABSTRACT FROM AUTHOR]