Exome & precision medicine in eating disorders

Abstract

Introduction Eating disorders (EDs) are complex and multifactorial psychiatric illnesses associated with significant and sustained pathological disruption of food intake. The Diagnostic and Statistical Manual of Mental Illnesses (DSM-5) distinguishes anorexia nervosa (AN), bulimia nervosa (BN) and binge eating disorder (BED). The neurobiological basis of food intake are well characterized. Epidemiological studies reported a heritability about 70% in AN and 60% in BN, suggesting that genetic factors are playing a significant role. AN is the most severe disorder in terms of morbidity in psychiatric illnesses, with the highest mortality rate increased by 23 fold. Treatments have a limited effectiveness, however, one third of the AN patients evolve to the remission. Goal We and collaborators from the Genetic Consortium for Anorexia Nervosa/Wellcome Trust Case Control Consortium-3 (GCAN/WTCCC3), the Anorexia Nervosa Genetics Initiative (ANGI) and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED), are currently investigating molecular biology and physiology in AN patients, subjects in remission and healthy control women in the goal to identify and characterize biomarkers of diagnosis and prognosis of AN to propose precision medicine and adapted treatments. Methods Extensive clinical evaluation, genotyping of polymorphisms, exome sequencing of candidate genes or whole-exome sequencing (WES), and measure of DNA methylation levels of the whole genome or candidate genes, and blood concentration levels of candidate neuropeptides and hormones are performed in current AN patients, subjects in remission and healthy control women. Results Common genetic variants of vulnerability for AN are found by GWAS. Furthermore, rare variants or mutations are identified using the next-generation sequencing in the screening of sporadic cases or AN families. Significant differences are observed for specific DNA methylation sites and concentration levels of molecules between current AN patients compared to controls. Conclusions Convergent molecular and physiological studies suggest that the pathophysiological bases of eating disorder, and especially AN, involve both “psychiatric” and “metabolic” pathways. These omictools will allow us to enter in the precision medicine in eating disorders.