Sex and Diagnosis-Specific Associations between DNA Methylation of the Oxytocin Receptor Gene with Emotion Processing and Temporal-Limbic and Prefrontal Brain Volumes in Psychotic Disorders

Leah H. Rubin, Jessica J. Connelly, James L. Reilly, C. Sue Carter, Lauren L. Drogos, Hossein Pournajafi-Nazarloo, Anthony C. Ruocco, Sarah K. Keedy, Ian Matthew, Neeraj Tandon, Godfrey D. Pearlson, Brett A. Clementz, Carol A. Tamminga, Elliot S. Gershon, Matcheri S. Keshavan, Jeffrey R. Bishop, John A. Sweeney

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


Background The oxytocin (OT) system, including receptor epigenetic mechanisms, has been shown to influence emotion processing, especially in females. Whether OT receptor (OXTR) epigenetic alterations occur across psychotic disorders in relation to illness-related disturbances in social cognition and brain anatomy is unknown. Methods Participants with affective and nonaffective psychotic disorders (92 women, 75 men) and healthy controls (38 women, 37 men) from the Chicago site of the Bipolar and Schizophrenia Network on Intermediate Phenotypes study completed the Penn Emotion Recognition Test, a facial emotion recognition task. We measured cytosine methylation at site -934 upstream of the OXTR start codon in DNA from whole blood and for the first time their relationship with plasma OT levels assessed by enzyme-immunoassay. Volumes of brain regions supporting social cognition were measured from magnetic resonance imaging scans using FreeSurfer. Results Patients with prototypic schizophrenia features showed higher levels of DNA methylation than those with prototypic bipolar features. Methylation was higher in women than men and was associated with poorer emotion recognition only in female patients and controls. Greater methylation was associated with smaller volumes in temporal-limbic and prefrontal regions associated previously with social cognition but only in healthy women and females with schizophrenia. Conclusions DNA methylation of the OXTR site -934 was higher in schizophrenia spectrum than bipolar patients. Among patients, it was linked to behavioral deficits in social cognition and neuroanatomic structures known to support emotion processing only in schizophrenia spectrum individuals.

Original languageEnglish (US)
Pages (from-to)141-151
Number of pages11
JournalBiological Psychiatry: Cognitive Neuroscience and Neuroimaging
Issue number2
StatePublished - Feb 1 2016

Bibliographical note

Funding Information:
Dr. Bishop has served as an advisory board member for Physician Choice Laboratory Services. Dr. Sweeney has consulted to Eli Lilly, Roche, and Takeda and with Dr. Bishop received grant support from Janssen. Dr. Keshavan received research support from Sunovion and GlaxoSmithKline. Dr. Connelly received grant support from the Fetzer Institute. Dr. Tamminga has served on a drug development advisory board for Intracellular Therapies, as an expert witness for Kaye Scholer LLP, and has served as a consultant for Astellas, Eli Lilly, Lundbeck, and Puretech Ventures/Karuna. All other authors report no biomedical financial interests or potential conflicts of interest.

Funding Information:
This work was supported in part by a 2012 National Alliance for Research on Schizophrenia and Depression Young Investigator Grant from the Brain and Behavior Research Foundation to Dr. Rubin and by the National Institutes of Health (Grant Nos. K12HD055892, K08MH083888, MH083126, MH077851, MH078113, MH077945, MH077852, and MH077862). The funding agencies had no role in the design and conduct of the study collection; management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.

Publisher Copyright:
© 2016 Society of Biological Psychiatry.


  • Emotion recognition
  • Epigenetics
  • Oxytocin
  • Psychosis
  • Sex differences
  • Structural imaging


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