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

Abstract 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. Competing Interest Statement The authors have declared no competing interest. Funding Statement This research was funded by Research Council of Norway (301767). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The source data were openly available before the initiation of the study. The GWAS summary statistics data is available for download at the consortium's official websites (PGC: https://pgc.unc.edu; GIANT consortium: https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium; DIAGRAM consortium: https://diagram-consortium.org/index.html; GEnetic Factors for OSteoporosis Consortium (GEFOS): http://www.gefos.org/?q=content/data-release-2018 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All produced data are available online at https://osf.io/k46gu/