Genetic pathways linking oxytocin-vasotocin hypothalamic subunit architecture with psychiatric and metabolic traits

The neuropeptides oxytocin and vasotocin are predominantly produced in the supraoptic and paraventricular nuclei of the anterior-inferior, anterior-superior and tubular-superior hypothalamic subunits. Evidence suggests that oxytocin and vasotocin signaling play a role in both physiology and behavior and that dysfunction of these signaling systems may contribute to the co-occurrence of metabolic and psychiatric conditions. The genetic pathways, however, that may underlie the connection between these physiological and behavioral traits are yet to be clearly delineated. We deployed bivariate mixture models and conjunctional FDR to estimate the global and local genetic overlap between three oxytocinergic-vasotocinergic hypothalamus subunits and ten psychiatric and metabolic traits related to oxytocin and vasotocin signaling. We show that these three subunits share moderate-to-extensive genetic overlap with the tested traits, therein stronger overlap with psychiatric than metabolic traits. We found most complete overlap between the anterior subunits and systolic blood pressure. We pinpoint 95 novel, unique loci associated across all subunit and trait combinations. The genes associated with these loci were enriched in gene sets linked to neuroimaging and neurodegeneration as well as metabolic markers, and were up-/down-regulated in tissues such as blood vessel and the liver. These findings help shed light on the genetic architecture of the hypothalamic subunits implicated in oxytocin and vasotocin, and selected traits, and provide new avenues for future research.