Role of GAD2 and HTR1B genes in early-onset obsessive-compulsive disorder: Results from transmission disequilibrium study

Abstract

One of the leading biological models of obsessive-compulsive disorder (OCD) is the frontal-striatal-thalamic model. This study undertakes an extensive exploration of the variability in genes related to the regulation of the frontal-striatal-thalamic system in a sample of early-onset OCD trios. To this end, we genotyped 266 single nucleotide polymorphisms (SNPs) in 35 genes in 84 OCD probands and their parents. Finally, 75 complete trios were included in the analysis. Twenty SNPs were overtransmitted from parents to early-onset OCD probands and presented nominal pointwise P<0.05 values. Three of these polymorphisms achieved P<2×10-4, the significant P-value after Bonferroni corrections: rs8190748 and rs992990 localized in GAD2 and rs2000292 in HTR1B. When we stratified our sample according to gender, different trends were observed between males and females. In males, SNP rs2000292 (HTR1B) showed the lowest P-value (P=0.0006), whereas the SNPs in GAD2 were only marginally significant (P=0.01). In contrast, in females HTR1B polymorphisms were not significant, whereas rs8190748 (GAD2) showed the lowest P-value (P=0.0006). These results are in agreement with several lines of evidence that indicate a role for the serotonin and γ-Aminobutyric acid (GABA) pathways in the risk of early-onset OCD and with the gender differences in OCD pathophysiology reported elsewhere. However, our results need to be replicated in studies with larger cohorts in order to confirm these associations. Association results of 266 validated SNPs using parentTDT analysis in 75 early-onset OCD trios are shown. The X-axis indicates various SNPs ordered by gene and chromosome position. The horizontal lines at -log(P) 1.3 and 3.6 correspond to nominal P=0.05 and P=0.0002, respectively. These results are in agreement with several lines of evidence that indicate a role for the serotonin and GABA pathways in the risk of early-onset OCD and with the gender differences in OCD pathophysiology reported elsewhere. However, our results need to be replicated in studies with larger cohorts in order to confirm these associations. © 2014 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.