Haplotype-based testing of rs25532 and all other known non-coding functional SLC6A4 variants revealed a highly significant omnibus association with OCD in a large case-control sample.
These results are discussed in terms of their implications for our understanding of the sex-specific role of the different sections of the SLC6A4 gene in OCD.
However, taking in account OCD phenotypes, we found indication towards an association of the 5-HTTLPR S-allele with female OCD patients, and the 5-HT2A G-allele and GG genotype with patients with a positive family history of OCD and an early onset of disease.
In this cross-sectional study, we have examined the allelic and genotypic frequencies of a Val-158-Met substitution in the COMT gene, a 44-base pair (bp) length variation in the regulatory region of the serotonin transporter gene (5-HTTLPR) and the T102C and C516T variants in the serotonin receptor type 2A (5HT2A) gene in 79 OCD patients and 202 control subjects.
We previously reported that brain-specific diacylglycerol kinase (DGK) δ-knockout (KO) mice showed obsessive-compulsive disorder (OCD)-like behaviors, which were alleviated by a serotonin (5-HT) transporter (SERT) inhibitor.
Haplotype-based testing of rs25532 and all other known non-coding functional SLC6A4 variants revealed a highly significant omnibus association with OCD in a large case-control sample.
Similarly, three individuals (two with OCD/OCPD) carried the rare I425VSLC6A4 variant, but none of them passed it on to their six OCD-affected offspring, suggesting that it is unlikely to be solely responsible for the 'OCD plus syndrome', as reported by Ozaki et al.
We conclude that the 5-HTTLPR is currently the single best supported risk variant for OCD, in regards of early-onset OCD, albeit of modest effect size and the possibility that the conferred risk might not be specific to OCD.
Within autism, rare hSERT coding variants associate with rigid-compulsive traits, suggesting both phenotypic overlap with OCD and a shared relationship with disrupted 5-HT signalling.
By using random effects model, data from these studies were pooled to compare the genotypes and allelic distribution of the 5-HTTLPR polymorphism between OCD patients and control subjects.
Likewise, the higher expressing LAC haplotype (5-HTTLPR/rs25531/rs25532) was more frequent in TD probands than in controls (P = 0.024; OR, 1.33) and also in the TD alone group versus the TD plus OCD group (P = 0.0013; OR, 2.14).
However, taking in account OCD phenotypes, we found indication towards an association of the 5-HTTLPR S-allele with female OCD patients, and the 5-HT2A G-allele and GG genotype with patients with a positive family history of OCD and an early onset of disease.
While the hypo-activity of serotonin signaling is involved in the pathogenesis of depression, anxiety and obsessive compulsive disorder; LSD, an agonist of serotonin type 2 receptor (5-HTR2A) induces psychosis.
Although we did not observe any statistically significant association between the HTR2A gene polymorphisms and OCD or its clinical features, SLC6A4 STin2 polymorphism was significantly more common among OCD patients as compared to health controls.
Serotonin and catecholamine system studies provide increasing evidence for the importance of genetic factors in obsessive-compulsive disorder (OCD); we found that genetic linkage disequilibrium with OCD existed in the 5-HT2A-receptor promoter polymorphism -1438G/A.