Serotonin system gene variants and regional brain volume differences in pediatric OCD

  • Vanessa M. Sinopoli
  • Lauren Erdman
  • Christie L. Burton
  • Phillip Easter
  • Rageen Rajendram
  • Gregory Baldwin
  • Kelli Peterman
  • Julie Coste
  • S-M Shaheen
  • Gregory L. Hanna
  • David R. Rosenberg
  • Paul D. ArnoldEmail author


Obsessive-compulsive disorder (OCD) is phenotypically heterogeneous and genetically complex. This study aimed to reduce heterogeneity using structural brain imaging to study putative intermediate phenotypes for OCD. We hypothesized that select serotonin gene variants would differ in their relationship with brain volume in specific regions of the cortico-striato-thalamo-cortical (CSTC) circuits between OCD patients and controls. In a total of 200 pediatric subjects, we genotyped candidate serotonin genes (SLC6A4, HTR2A, HTR1B, and HTR2C) and conducted structural magnetic resonance imaging (sMRI) to measure regional brain volumes within CSTC circuits. In males and females separately, we first tested the association between serotonin gene variants and OCD and the effect of serotonin gene variants on brain volume irrespective of diagnosis. We then carried out a series of analyses to assess the effect of genotype-diagnosis interaction on brain volume. In females, but not in males, we identified a statistically significant genotype-diagnosis interaction for two single nucleotide polymorphisms (SNPs) in HTR2C, rs12860460 (interaction term estimate of 5.45 cc and interaction P value of 9.70e-8) and rs12854485 (interaction term estimate of 4.28 cc and interaction P value of 2.07e-6). The tested allele in each SNP was associated with decreased anterior cingulate cortex (ACC) volume in controls and with increased ACC volume in OCD patients. Our findings suggest that, in females, sequence variation in HTR2C influences ACC volume in pediatric OCD. The variants may contribute to differences in ACC volume and to OCD in a sex-specific manner when acting together with other genetic, biological, and/or environmental factors.


Obsessive-compulsive disorder OCD Serotonin system genes Neuroimaging Intermediate phenotype 



This work was supported by the National Institutes of Health (NIH) grants R01-MH101493, R01-MH085300, R01-MH085321, and R01-MH59299. Dr. Arnold receives support from the Alberta Innovates Health Solutions (AIHS) Translational Research Chair in Child and Youth Mental Health. Dr. Rosenberg receives support from the Lycaki-Young Fund, State of Michigan, Miriam L. Hamburger Endowed Chair of Child Psychiatry, Paul and Anita Strauss Endowment, Children’s Hospital of Michigan Foundation, and Donald and Mary Kosch Foundation. Vanessa Sinopoli received funding from the Canadian Institutes of Health Research (CIHR) Master’s Award: Frederick Banting and Charles Best Canada Graduate Scholarships, Ontario Graduate Scholarship (OGS), and the Hospital for Sick Children Restracomp Studentship.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to disclose.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Written and informed consent and assent was obtained for all participants. Each site received study approval from its Human Investigation Committee prior to recruitment of participants.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Vanessa M. Sinopoli
    • 1
    • 2
  • Lauren Erdman
    • 2
    • 3
  • Christie L. Burton
    • 2
    • 4
  • Phillip Easter
    • 5
  • Rageen Rajendram
    • 6
  • Gregory Baldwin
    • 5
  • Kelli Peterman
    • 5
  • Julie Coste
    • 2
  • S-M Shaheen
    • 2
    • 7
  • Gregory L. Hanna
    • 8
  • David R. Rosenberg
    • 5
  • Paul D. Arnold
    • 2
    • 7
    • 9
    Email author
  1. 1.Institute of Medical ScienceUniversity of TorontoTorontoCanada
  2. 2.Program in Genetics & Genome BiologyThe Hospital for Sick ChildrenTorontoCanada
  3. 3.Department of Computer ScienceUniversity of TorontoTorontoCanada
  4. 4.Program in Neurosciences and Mental HealthThe Hospital for Sick ChildrenTorontoCanada
  5. 5.Department of PsychiatryWayne State University School of MedicineDetroitUSA
  6. 6.Faculty of MedicineUniversity of TorontoTorontoCanada
  7. 7.Mathison Centre for Mental Health Research & Education, Hotchkiss Brain InstituteUniversity of CalgaryCalgaryCanada
  8. 8.Department of PsychiatryUniversity of MichiganAnn ArborUSA
  9. 9.Departments of Psychiatry and Medical Genetics, Cumming School of MedicineUniversity of CalgaryCalgaryCanada

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