Integrating genetic variation with DNA methylation at SKA2 rs7208505 in analyses of obsessive-compulsive disorder disease risk and symptom severity

Abstract

BackgroundObsessive-Compulsive Disorder (OCD) has a complex genetic component and may be preceded by environmental stressors. The spindle and kinetochore associated complex subunit 2 (SKA2)gene interacts with the glucocorticoid receptor and is implicated in mediating hypothalamic–pituitary-adrenal (HPA) axis function but has yet to be examined in OCD. We hypothesized that genetic and epigenetic variation of SKA2 may be involved in OCD disease risk and symptom severity. MethodsOCD patients (n = 54) were rated for disease severity using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Genotyping of SKA2 rs7208505 was performed using Taqman TM, while DNA methylation levels were quantified using bisulfite pyrosequencing. OCD genotype frequencies were compared to the general population (n = 379, 1000 Genomes Project Consortium) using Pearson’s chi-square test. The relationships among the rs7208505 variant, methylation density, and symptom severity were modeled using linear regression. ResultsGenotype distributions significantly differed between OCD patients and the 1000 Genomes sample (χ2 (2, n = 433) = 8.66, p = 0.013). The odds of having OCD was 1.66 times more likely for individuals carrying a C allele (OR 1.66 [95% CI: 1.09–2.55]; p = 0 0.02). Specifically, the odds of having the CC genotype was 2.58 times more likely for OCD patients (OR 2.58 [95% CI: 1.23–5.23]; p = 0.007). When examining symptom severity there was no effect of genotype (p > 0.05). Finally, epigenetic variation was not significantly associated with symptom severity in our statistical models. ConclusionsThese results provide preliminary evidence that SKA2 genetic variation may be associated with OCD disease status, while no association was detected when examining symptom severity, or methylation density at this locus. The rs7208505 minor allele occurs more frequently in OCD patients than in the general population, suggesting that there is merit in pursing further studies of this marker in larger sample sizes.