The association of HTR2A polymorphisms with obsessive-compulsive disorder and its subtypes: A meta-analysis

Background: Genetic risk factors that contribute to obsessive-compulsive disorder (OCD) have yet to be elucidated. Historically, serotonergic dysfunction has been implicated. Evidence from the literature points towards the serotonin receptor 2A gene (HTR2A) as a primary candidate. Our meta-analysis investigated whether polymorphisms in HTR2A are associated with OCD or its subtypes, based on sex and age of onset. Methods: Studies employing case-control or family-based designs were systematically searched, and those meeting eligibility underwent quality assessment, resulting in 18 studies. A random-effects meta-analysis using standard inverse-variance weighting to compute odds ratio (OR) was conducted. To examine sensitivity, results were also obtained using a more conservative statistical method. Results: Three HTR2A variants were identified: T102C, G-1438A, and C516T. T102C and G-1438A were analyzed together due to strong linkage disequilibrium, where the 102T allele co-occurs with -1438A allele. Results reported as OR [95%CI] showed that the T/A allele were significantly associated with OCD, 1.14 [1.01, 1.29]. After stratification, results remained significant for females, 1.20 [1.00, 1.45], and early-onset OCD, 1.27 [1.02, 1.58], but not males, 1.06 [0.91, 1.23]. No associations were found for late-onset OCD, 0.98 [0.70, 1.37], or C516T, 1.22 [0.14, 10.37], but conclusions cannot be drawn from two studies. Limitations: Associations no longer reached significance with the conservative statistical approach. HTR2A alone cannot explain OCD complexity and limited samples reporting genetic data according to subtypes. Conclusions: These results suggest a possible association of HTR2A polymorphisms with OCD, but further investigations considering sex and age of onset with larger samples is needed.