A genetic atlas of relationships between circulating metabolites and liability to psychiatric conditions

Observational studies have reported alteration of circulating metabolites across several psychiatric conditions, but these studies cannot resolve causal relationships. Emerging evidence suggests a genetic relationship exists between these traits requiring further investigation to identify clinically actionable biology. Here, we used the largest genome-wide association studies available to investigate genetic correlation and causal relationships between 10 psychiatric conditions and 249 circulating metabolites. This revealed 1,100 significantly correlated trait pairings, involving fatty acids, lipoproteins and other metabolites, with evidence for causal effects on the liability for major depressive disorder, post-traumatic stress disorder and anorexia nervosa. Notably, the most robust association was a putative causal effect of high-density lipoprotein properties on anorexia nervosa. We also observed significant relationships between metabolic traits and cortical thickness and surface area, as well as evidence of shared gene-level common variant associations amongst 23 metabolite-psychiatric pairings, converging in pathways with metabolic and neuronal function. These findings highlight specific metabolites as potential biomarkers and therapeutic targets in the clinical management of psychiatric disorders.