Serotonin system gene variants and regional brain volume differences in pediatric OCD
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ORIGINAL RESEARCH
Serotonin system gene variants and regional brain volume differences in pediatric OCD 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
# Springer Science+Business Media, LLC, part of Springer Nature 2019
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-thalamocortical (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. Keywords Obsessive-compulsive disorder . OCD . Serotonin system genes . Neuroimaging . Intermediate phenotype
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 * Paul D. Arnold [email protected] 1
Institute of Medical Science, University of Toronto, Toronto, ON, Canada
5
Department of Psychiatry, Wayne State University School of Medicine, Detroit, MI, USA
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Faculty of Medicine, University of Toronto, Toronto, ON, Canada
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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
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Program in Genetics & Genome Biology, The Hospital fo
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