AbstractAnorexia nervosa is a complex human trait that is primarily expressed in females but also observed in males. The disorder originates from an interplay of environmental factors with a genetic liability and develops most commonly around the time of puberty. Individuals with anorexia nervosa exhibit disordered eating behaviour as they severely restrict their calorie intake relative to their energy expenditure, and may engage in binge-eating and/or purging behaviour. Some individuals with anorexia nervosa exercise excessively to control their weight. These behaviours often coupled with distorted body perception and undue influence of body weight or shape on self-evaluation, result in extremely low and sometimes life-threatening body weight. No first line pharmacological treatment for anorexia nervosa is available, but psychotherapy coupled with therapeutic renourishment can be successful. Only 30-40% of individuals with anorexia nervosa seek treatment, and up to 30% of individuals develop a chronic or relapsing course. The mortality ratio of anorexia nervosa with up to 5.9 is one of the highest of all psychiatric disorders, therefore, new treatment options and preventive strategies are critically needed.
During an acute episode of anorexia nervosa, individuals evidence ~50% lower body fat, lower fat-free mass, including losses of bone mineral mass and alterations in biochemical markers. Phenotypically, these body composition alterations are associated with higher insulin sensitivity and cortisol concentrations, but with lower leptin, thyroid hormone, and estradiol concentrations. Most of these alterations tend to return to levels or concentrations seen in healthy controls, but sample sizes are small and follow up periods are short which underscores the need for deep biochemical phenotyping of anorexia nervosa patients through “omics” approaches.
As twin studies report heritabilities of anorexia nervosa between 32 and 74%, the next logical step was to perform genome-wide association studies to detect genomic loci that are associated with anorexia nervosa. Using the genomewide approach, we explain 17% of the variance of anorexia nervosa (i.e., heritability) via the contribution of common genetic variants. We identify eight genomic loci associated with anorexia nervosa, and enrichment analysis presents evidence for an involvement of brain tissue in the illness. Analysis using genetic correlations that are measures of genetic overlap between traits show that anorexia nervosa shares genomic variants with other psychiatric disorders corresponding to its comorbidity profile. Furthermore, anorexia nervosa shares genetics with metabolic traits, including high-density lipoprotein and insulin sensitivity. This sharing of underlying genetics motivates our reconceptualisation of anorexia nervosa as a metabo-psychiatric disorder, which generates a myriad hypotheses for future research endeavours.
Testing the significant genetic correlations of anorexia nervosa with psychiatric and metabolic traits for sex-dependence reveals that body fat percentage in females is more strongly genetically correlated with anorexia nervosa than in males. This suggests that a sex-dependent set of genetic variants is associated with anorexia nervosa and may partially contribute to the observed sex bias.
Other psychiatric traits do not show sex-dependent genetic correlations with body composition traits and do not genetically correlate with metabolic traits like cholesterol or insulin sensitivity. Additionally, anorexia nervosa and obsessivecompulsive disorder—highly genetically correlated with each other—are the only psychiatric disorders that share genetic variants with accelerometer measured physical activity. This combination of metabolic and energy homeostasis-related genetic correlations may be unique characteristics of anorexia nervosa and differentiate it from other psychiatric traits.
This new understanding of anorexia nervosa as a metabo-psychiatric disorder opens up new avenues for future research strategies and underscores the need to collect large international samples with deep phenotyping of not only psychological traits, but also metabolomic, proteomic, and lipidomic markers in anorexia nervosa patients. We strengthen the perspective that anorexia nervosa has a biological component which reduces the stigma associated with anorexia nervosa and set an example for future research on other eating disorders.
|Date of Award||1 Jan 2020|
|Supervisor||Gerome Breen (Supervisor) & Paul O'Reilly (Supervisor)|