Oxytocin Pathway Genes: Evolutionary Ancient System Impacting on Human Affiliation, Sociality, and Psychopathology

Ruth Feldman, Mikhail Monakhov, Maayan Pratt, Richard P. Ebstein

Research output: Contribution to journalReview articlepeer-review

248 Scopus citations


Oxytocin (OT), a nonapeptide signaling molecule originating from an ancestral peptide, appears in different variants across all vertebrate and several invertebrate species. Throughout animal evolution, neuropeptidergic signaling has been adapted by organisms for regulating response to rapidly changing environments. The family of OT-like molecules affects both peripheral tissues implicated in reproduction, homeostasis, and energy balance, as well as neuromodulation of social behavior, stress regulation, and associative learning in species ranging from nematodes to humans. After describing the OT-signaling pathway, we review research on the three genes most extensively studied in humans: the OT receptor (OXTR), the structural gene for OT (OXT/neurophysin-I), and CD38. Consistent with the notion that sociality should be studied from the perspective of social life at the species level, we address human social functions in relation to OT-pathway genes, including parenting, empathy, and using social relationships to manage stress. We then describe associations between OT-pathway genes with psychopathologies involving social dysfunctions such as autism, depression, or schizophrenia. Human research particularly underscored the involvement of two OXTR single nucleotide polymorphisms (rs53576, rs2254298) with fewer studies focusing on other OXTR (rs7632287, rs1042778, rs2268494, rs2268490), OXT (rs2740210, rs4813627, rs4813625), and CD38 (rs3796863, rs6449197) single nucleotide polymorphisms. Overall, studies provide evidence for the involvement of OT-pathway genes in human social functions but also suggest that factors such as gender, culture, and early environment often confound attempts to replicate first findings. We conclude by discussing epigenetics, conceptual implications within an evolutionary perspective, and future directions, especially the need to refine phenotypes, carefully characterize early environments, and integrate observations of social behavior across ecological contexts.

Original languageEnglish
Pages (from-to)174-184
Number of pages11
JournalBiological Psychiatry
Issue number3
StatePublished - 1 Feb 2016

Bibliographical note

Funding Information:
This study was supported, in part, by grants from the Israeli Science Foundation, National Alliance for Research on Schizophrenia and Depression independent investigator award, the German-Israeli Foundation (#1114-101.4/2010), the US-Israel Bi-National Foundation (#2011349), and Israeli Centers for Research Excellence Program of the Planning and Budgeting Committee and The Israel Science Foundation (Grant No. 51/11) to Ruth Feldman; and the AXA Research Fund ("The Biology of Decision Making under risk"), John Templeton Foundation (“Genes, God and Generosity: The Yin Yang of DNA and Culture”), Singapore Ministry of Education (“The Genetic, Neuroimaging and Behavioral Study of Human Decision Making”), and National University of Singapore (“Decision Making Under Urbanization: A Neurobiological and Experimental Economics Approach” and Start-Up Grants) to Richard P. Ebstein.

Publisher Copyright:
© 2016 Society of Biological Psychiatry.


  • CD38
  • Epigenetics
  • Genetics
  • OXT
  • OXTR
  • Oxytocin


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