Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.publishedVersio

Common Genetic Variation And Age at Onset Of Anorexia Nervosa

Background Genetics and biology may influence the age at onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to AN age at onset and to investigate the genetic associations between age at onset of AN and age at menarche. Methods A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed which included 9,335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age at onset, early-onset AN (< 13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses. Results Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (SNP-h2) were 0.01-0.04 for age at onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age at onset and early-onset AN estimated from independent GWASs significantly predicted age at onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN. Conclusions Our results provide evidence consistent with a common variant genetic basis for age at onset and implicate biological pathways regulating menarche and reproduction.Peer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

The Fitter I Am, the Larger I Feel&mdash;The Vicious Circle of Physical Exercise in Anorexia Nervosa

Introduction: Body image distortion is a core symptom of anorexia nervosa (AN), embodying dissatisfaction and overvaluation of body appearance and weight. Body image distortion is an important factor in the maintenance of weight loss behaviours such as compulsive physical exercise. Conversely, physical exercise seems to have an aggravating effect on body image in patients with AN, but the evidence is still poor. The aim of this study was to examine the relationship between body image distortion and physical exercise in AN in order to understand whether physical exercise may play a specific role in body image distortion beyond psychopathological severity. Methods: Forty patients with AN and 21 healthy controls were tested for body image distortion and different proxies of physical exercise. Univariate correlations tested the relationship between body image distortion and physical exercise in AN and control groups. Then, to experimentally assess the effect of exercise on body image distortion, participants were invited to rate their body image before and after a standardised effort test. Results: In the AN group, a correlation was found between physical activity and body image distortion (p &lt; 0.01), which was still significant after controlling for psychopathological severity. No correlation was found in healthy controls. After a standardised effort, patients with AN had higher increases in body image distortion than healthy controls (almost 4 kg/m2 vs. 0.8 kg/m2) (p &lt; 0.01). Discussion: Physical exercise may contribute to the distortion of body image in anorexia nervosa and explain the paradoxical augmentation of unhealthy exercise despite ongoing weight loss

Clinical insight in anorexia nervosa: Associated and predictive factors

International audienceClinical and cognitive factors associated with clinical insight regarding both baseline level and its time-related changes, in outpatients treated for anorexia nervosa. The 193 participants were recruited at 13 French centers specializing in eating disorders (FFAB network) and assessed for insight (SAI-ED), body mass index (BMI), eating disorder severity, symptoms of depression and anxiety, emotional state, silhouette, and functionality; two cognitive tests were also administered. The 137 patients were then re-assessed 18 weeks later. Minimum and ideal subjective BMI and premorbid intelligence were associated with poor baseline insight. Contrary to nearly all other clinical factors, the level of insight revealed no improvement after four months of care. Only the higher value of the minimum lifetime BMI was significantly predictive of increased insight. More positive emotions (PANAS), less symptoms of depression and anxiety (HADS scores), and fewer syndromes (HADS above threshold) were the only factors that covaried with the changes in the level of insight. In conclusion, poor insight has little time variability, contrary to nearly all clinical and cognitive factors. As increased insight is mainly accompanied by improvements in the emotional domain, the latter could represent potential targets for patients with lack of awareness about their eating disorder

Risk of non-fatal self-harm and premature mortality in the three years following hospitalization in adolescents and young adults with an eating disorder: A nationwide population-based study

International audienceIntroduction: Eating disorders (ED) are associated with high rates of suicide attempts and premature mortality. However, data in large samples of adolescents and young adults are limited. This study aims to assess the risk of self-harm and premature mortality in young people hospitalized with an ED. Methods: Individuals aged 12 to 25 years old hospitalized in 2013–2014 in France with anorexia nervosa and/or bulimia nervosa as a primary or associated diagnosis were identified from French national health records. They were compared to two control groups with no mental disorders, and with any other mental disorder than ED. The main outcomes were any hospitalization for deliberate self-harm and mortality in the 3 years following hospitalization. Logistic regression models were used. Results: This study included 5, 452 patients hospitalized with an ED, 14,967 controls with no mental disorder, and 14,242 controls with a mental disorder other than an ED. During the three-year follow-up, 13.0% were hospitalized for deliberate self-harm (vs. 0.2 and 22.0%, respectively) and 0.8% died (vs. 0.03 and 0.4%). After adjustment, hospitalization with an ED was associated with more self-harm hospitalizations (hazard ratio [HR] = 46.0, 95% confidence interval [32.3–65.3]) and higher all-cause mortality (HR = 12.6 [4.3–37.3]) relative to youths without any mental disorder; less self-harm hospitalizations (HR = 0.5 [0.5–0.6]) but higher mortality (HR = 1.6 [1.0–2.4]) when compared to youths with any other mental disorder. Conclusion: Young patients hospitalized with an ED are at high risk of self-harm and premature mortality. It is urgent to evaluate and implement the best strategies for post-discharge care and follow-up. Public significance: We found that the risk of being hospitalized for a suicide attempt is 46 times higher and mortality 13 times higher than the general population in adolescents and young adults during the 3 years following hospitalization with an eating disorder. Eating disorders are also associated with a 1.5 higher risk of premature mortality relative to other mental disorders. This risk is particularly high in the 6 months following hospitalization. It is therefore crucial to implement careful post-discharge follow-up in patients hospitalized for eating disorders

Increased cognitive flexibility mediates the improvement of eating disorders symptoms, depressive symptoms and level of daily life functioning in patients with anorexia nervosa treated in specialised centres

International audienceObjective: Poor cognitive flexibility has been highlighted in patients with anorexia nervosa (AN), contributing to the development and maintenance of symptoms. The aim of the present study is to investigate how enhanced cognitive flexibility is involved in treatment outcomes in patients with AN.Method: One hundred thirty female out-patients treated for AN have been assessed at baseline and after 4 months of treatment. Path analyses were used to investigate the mediating role of cognitive flexibility, measured through the Brixton test, on a wide range of outcomes: body mass index, eating disorder symptoms, daily life functioning, anxiety, depression, emotions, self-rated silhouette.Results: Cognitive flexibility was improved during treatment, and enhanced cognitive flexibility explains a significant part of level of the improvement in daily life functioning (26%), reduction of eating disorder symptoms (18%) and reduction of depressive symptoms (17%). Others outcomes were also improved, but these improvements were not mediated by cognitive flexibility.Conclusions: Results suggest that enhancing cognitive flexibility could help reduce rigid cognitive and behavioural patterns involved in AN, thus improving everyday functioning and clinical severity. Further studies combining different types of cognitive flexibility evaluation as well as neuroimaging may be necessary to better establish which of its aspects are involved in patients' improvement

Physical exercise-related endophenotypes in anorexia nervosa

International audienceBackground: The persistence of physical exercise in anorexia nervosa (AN) despite underweight and its maintaining factors are poorly understood. The aim of this study was to explore the attitudes toward physical exercise and its effects on emotions, cognitive functioning, and body image perception in patients with AN, and to search for exercise-related endophenotypes of the pathology.Methods: Physical exercise dependence, quantity, and dysregulation were assessed by the Exercise Dependence Scale (EDS), the Godin Leisure Time Exercise Questionnaire (GLTEQ) and a standardized effort test in 88 patients with AN, 30 unaffected relatives and 89 healthy controls. Changes in positive and negative affect, cognitive rigidity, and body image distortion were measured before and after the effort test in the three groups.Results: Patients with AN had higher scores on the EDS and the GLTEQ and used more effort in the standardized effort test. These three measures of physical exercise correlated with negative emotions at baseline. After the effort test, patients with AN had marked emotional improvement, a moderate increase in body image distortion and a small increase in cognitive rigidity compared to HC. Unaffected relatives also had a significant postexercise increase of positive emotion.Discussion: The mood-related drive for physical exercise has the characteristics of an endophenotype of the disorder. Excessive and driven physical exercise may be state-associated features of AN, driven by the positive effect on emotional wellbeing