The role of 5-hydroxytryptamine receptor 2A (HTR2A) gene polymorphisms in treatment-resistant obsessive–compulsive disorder: a comparative study with other treatment-resistant mental disorders

Background: This study investigates the role of genetic variations in the 5-Hydroxytryptamine Receptor 2A (HTR2A) gene in subjects with treatment-resistant obsessive–compulsive disorder (TR-OCD), compared to individuals with other treatment-resistant mental disorders (TRMDs). The goal is to explore whether specific HTR2A polymorphisms contribute to distinguishing TR-OCD from other TRMDs, thereby advancing our understanding of the underlying pathophysiological mechanisms. Methods: A retrospective observational study was conducted with 210 individuals affected by TRMDs (72 with major depressive disorder, 62 with bipolar disorder, 37 with schizophrenia, 30 with OCD, and 9 with other diagnoses). Genetic analyses focused on three HTR2A single nucleotide polymorphisms (SNPs) (rs6314, rs7997012, and rs6311), using next-generation sequencing from blood samples. Chi-square testing and single- and multiple-SNP analyses were employed to study the association between these SNPs and the TR-OCD diagnosis. Results: The analysis revealed that the HTR2A rs7997012 A|A vs. G|G genotype was significantly associated with a higher likelihood of belonging to the TR-OCD group compared to other TRMDs, with an odds ratio of 6.85 (95% CI = 2.44–19.26; p < 0.001). The same genotype, compared to the combined G|G and A|G genotypes, showed a significant association with TR-OCD (OR = 7.68; 95% CI = 2.90–20.34; p < 0.001). Haplotype analyses demonstrated a significant global association between the combined rs6314 rs7997012-rs6311 variants and TR-OCD (p = 0.028). Specifically, the G-G-C haplotype was significantly associated with a reduced likelihood of TR-OCD (OR = 0.32; 95% CI = 0.11–0.93; p = 0.038) compared to the reference haplotype G-G-T. Conclusions: This preliminary study identifies the rs7997012 polymorphism in the HTR2A gene as a potential genetic marker for TR-OCD, distinguishing it from other TRMDs. The study of rs7997012 and other genetic variants within the serotonergic system may enhance our understandings of the biological mechanisms underlying OCD and contribute to the development of precision psychiatry approaches.