Rare plus common SERT variants in obsessive-compulsive disorder

The serotonin transporter gene (SERT, SLC6A4) remains a candidate of high interest in obsessive-compulsive disorder (OCD) because patients with the disorder respond to central nervous system serotonin-enhancing agents, such as selective serotoning reuptake inhibitors or clomipramine. Furthermore, SERT's most-studied functional polymorphism, 5-HTTLPR, has been associated with both the diagnosis of OCD in several studies1, 2 though not all;3 and also with factor analysis-derived endophenotypic OCD subgroups.4 An uncommon rare functional variant, I425V, which was originally found to segregate with OCD in two families,5 was recently reported in an additional three OCD families.6 In these five families, 10 diagnostically evaluated individuals with I425V all had OCD, and no one of the other eight family members without I425V had OCD (two individuals declined participation). SERT I425V is extremely rare in control populations.5, 6 To extend the investigation of these two SERT variants, 5-HTTLPR and I425V, a selected cohort of individuals with psychiatric interview-assessed OCD were genotyped as described previously for 5-HTTLPR1 and using a pyrosequencing method for I425V.7 Clinical characteristics of this sample have been detailed previously.8 The majority of the OCD sample was Caucasian (over 90%) whereas a similar proportion of the control sample was Caucasian. As indicated in Table 1, an association between SERT 5-HTTLPR and OCD diagnosis in the 149 new OCD patients compared to previously reported healthy volunteers1 a trend for both the SS genotype (Pearson 2(1)=5.521, P=0.063) and the S allele frequency (Pearson 2(1)=2.688, P=0.101). I425V was not detected in any of the OCD probands. Positive I425V and negative assay controls were all correctly genotyped. The OCD sample included 23 individuals with multiple comorbid disorders (here defined as meeting criteria for three or more different axis I diagnoses in addition to OCD), a characteristic of the original I425V phenotype.5 The OCD sample was collected under a protocol approved by the Johns Hopkins University Institutional Review Board. The SS genotype is marginally associated with OCD in this report (0.05更多