Abstract
BACKGROUND: Anorexia Nervosa (AN) has a high mortality rate and often a chronic illness course, yet few existing treatments are effective. AN is heritable and shares genetic architecture with cardiometabolic traits, while the relationship to metabolomic markers is unknown. METHODS: We analyzed genome-wide association studies (GWAS) of 249 circulating plasma metabolomic biomarkers and AN to map their shared genetic architecture and compare with related mental health, anthropometric and cardiometabolic traits. We leveraged multiple methods to estimate genetic overlap, including global genetic correlations with linkage disequilibrium score regression, conjunctional false discovery rate, and bivariate Gaussian mixture modeling. We mapped shared genetic variants to genes and biological pathways, as well as gene expression enrichment across body and brain tissue. We also explored causal relationships between AN, body mass index (BMI), and metabolomic biomarkers. RESULTS: Significant genetic correlations were found between AN and 142 circulating metabolomic biomarkers, which were opposite in direction to metabolic traits such as BMI and type 2 diabetes (r(s)<-0.94), and stronger than correlations with anxiety. Shared variants between AN and metabolomic biomarkers, particularly lipid-based metabolites, exhibited a mixture of positive and negative effects. These were mapped to genes involved in lipid-related cell signals, developmental growth, inflammation and canonical cellular processes, and were widely expressed in the brain, most internal organs and female reproductive organs. Finally, causal bidirectional influences between AN and metabolomic biomarkers were found to act through their respective influence on BMI. CONCLUSIONS: Our findings point to strong associations between AN and metabolomic markers, opposite in direction to anthropometric and cardiometabolic traits. Our results suggest a mediating role for BMI and implicate developmental and lipid-based biological processes with a bidirectional causal relationship. The findings offer a novel perspective on the etiology of AN and suggest opportunities for targeting specific metabolomic biomarkers in weight restoration approaches.