Background:

Bipolar disorder (BIP), major depressive disorder (MDD) and schizophrenia (SCZ) are severe mental disorders (SMDs), each associated with poor cardiometabolic health. Mapping the genetic relationships of these highly heritable disorders with blood markers of metabolic activity may uncover biological pathways underlying this important shared clinical feature. Methods We charted global genetic overlap of the three SMDs, type 2 diabetes (T2D), coronary artery disease (CAD), and body mass index (BMI) with 249 circulating metabolic markers through linkage disequilibrium score regression and bivariate Gaussian mixture modeling. We estimated causal relationships, functionally annotated shared genetic variants, and investigated enrichment across diverse brain and body tissues. Results All three SMDs had extensive overlap with the metabolic markers. The pattern of genetic correlations was highly similar between MDD, T2D, CAD, and BMI (Spearmans correlation rs>.93), opposite in direction to the pattern found for SCZ and BIP (MDD-BIP rs=-.74; MDD-SCZ rs=-.83). The metabolic markers had widespread, robust causal effects on the SMDs and cardiometabolic traits. We mapped 1056 genes shared between the individual SMDs and the metabolic markers to disorder-specific processes related to metabolic activity, mitochondrial function, and synaptic processes. These genes were most prominently expressed throughout the brain, heart and liver. Discussion SMDs have strong associations with metabolic markers, whereby MDD has a distinctly different genetic relationship than BIP and SCZ. Our findings suggest that metabolic pathways are involved in the development of SMDs and can play a central role in disentangling disorder-specific etiologies. Our metabolic psychiatry approach has high potential to guide the development of targeted interventions.