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

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Abstract

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.

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Funding

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.

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Authors and Affiliations

  1. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    Vanessa M. Sinopoli

  2. Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada

    Vanessa M. Sinopoli, Lauren Erdman, Christie L. Burton, Julie Coste, S-M Shaheen & Paul D. Arnold

  3. Department of Computer Science, University of Toronto, Toronto, ON, Canada

    Lauren Erdman

  4. Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada

    Christie L. Burton

  5. Department of Psychiatry, Wayne State University School of Medicine, Detroit, MI, USA

    Phillip Easter, Gregory Baldwin, Kelli Peterman & David R. Rosenberg

  6. Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Rageen Rajendram

  7. Mathison Centre for Mental Health Research & Education, Hotchkiss Brain Institute, University of Calgary, 4th floor, Teaching, Research and Wellness (TRW) Building, 3280 Hospital Dr NW, Calgary, AB, T2N 4Z6, ON, Canada

    S-M Shaheen & Paul D. Arnold

  8. Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA

    Gregory L. Hanna

  9. Departments of Psychiatry and Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, ON, Canada

    Paul D. Arnold

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  1. Vanessa M. Sinopoli
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Correspondence to Paul D. Arnold.

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Highlights

• Significant effect of genotype-diagnosis interaction on ACC volume in females.

• Effect of HTR2C SNPs on ACC volume differs between OCD patients and controls.

• No significant genotype-diagnosis interaction found in males

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Sinopoli, V.M., Erdman, L., Burton, C.L. et al. Serotonin system gene variants and regional brain volume differences in pediatric OCD. Brain Imaging and Behavior 14, 1612–1625 (2020). https://doi.org/10.1007/s11682-019-00092-w

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  • DOI: https://doi.org/10.1007/s11682-019-00092-w

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