Following on from previous work by our group where we showed that early onset anorexia nervosa (AN) and obsessive-compulsive disorder (OCD) shared a common genetic background, the aim of the present study is to assess genetic pleiotropy related to the serotonergic system (SLC6A4, 5HTR2A, 5HTR2C, TPH2, SLC18A1), in a common phenotype such as very-early age of onset.
The current study set three questions: Firstly, whether the high expressing loci of the SLC6A4 polymorphisms, 5-HTTLPR + rs25531, rs25532 and rs16965628 are associated with family-based (n = 164 trios) and case-control OCD (n = 186, 152, respectively).
The comparison of serotonin transporter linked polymorphic region (5-HTTLPR) in 102 OCD patients and 223 controls showed an increased L-allele frequency but no difference was observed when rs25531 was included.
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.
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.
Although findings to date are mixed, serotonin transporter polymorphism 5-HTTLPR and HTR2A polymorphism rs6311 (or rs6313) are most consistently associated with OCD.
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.
In the main meta-analysis, OCD was associated with serotonin-related polymorphisms (5-HTTLPR and HTR2A) and, in males only, with polymorphisms involved in catecholamine modulation (COMT and MAOA).
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).
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.
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.
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.
The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology and treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism, and obsessive-compulsive disorder (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.
The promoter region of the serotonin transporter gene (SLC6A4) shows a 22-bp tandem repeat polymorphism, indicated as polymorphism C, that has been associated to depression, obsessive-compulsive disorder, memory impairment, and anxiety.
Further meta-analyses based on individual patient data would be helpful in determining whether age of OCD onset, gender and the presence of comorbid illness (e.g., tics) moderates the relationship between 5-HTTLPR and OCD.
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.