SIR—Recently, a rare functional variant, I425V, in the serotonin transporter gene (SLC6A4) has been reported to be associated with a complex neuropsychiatric phenotype that includes obsessive–compulsive disorder (OCD), alcohol abuse/dependence, anorexia nervosa, and pervasive developmental disorder (PDD).1 Our study, performed in a large population of patients with these disorders, confirms the occurrence and the segregation of V425 in OCD.
The neurotransmitter serotonin (5-hydroxytryptamine (5-HT)) has been implicated in numerous psychiatric disorders, mostly because of the efficacy of serotonin reuptake inhibitors (SRIs). Among the polymorphisms identified in SLC6A4, three have been shown to be functional. The rare I425V variation, located in exon 9, increases the transport activity of the protein,2 whereas the two more frequent polymorphisms, 5-HTTLPR located in the 5′-UTR of the gene, and STin2 located in intron 2, modify the transcriptional activity of the gene.3, 4 Despite a large number of studies, the functional implications of the two frequent SLC6A4 polymorphisms in psychiatric disorders are still a matter of debate. In the present study, we sought to further explore the influence of the rare but clearly functional I425V variant in a large sample of patients with OCD and other psychiatric conditions previously reported in the two families carrying I425V, that is, PDD, anorexia nervosa, and alcohol abuse/dependence.
To be included in the study, patients had to meet the DSM-IV criteria for OCD, anorexia nervosa, alcohol abuse/dependence, or PDD. The diagnosis of PDD was confirmed using the Autism Diagnostic Interview—Revised.5 For the other disorders, lifetime psychiatric evaluation was carried out using the Diagnostic Interview for Genetic Studies (DIGS)6 for adult patients, or the Kiddie Schedule for Affective Disorders and Schizophrenia for children.7 Healthy controls were included after being interviewed with the DIGS and the Family Interview for Genetic Studies8 to confirm the absence of both personal and family history of major psychiatric disorders. The local Research Ethics Boards reviewed and approved the study.
The V425 was found in 3/254 probands with OCD, 1/284 with PDD, 1/124 with anorexia nervosa, in 1/285 healthy controls, but not in alcohol abusers/dependents (0/128) (Table 1). In OCD family 1, V425 was transmitted by the father who also had a lifetime history of OCD and single phobia. The paternal grandfather was alcoholic and tobacco dependant (died of throat cancer). The grandmother had no history of major psychiatric disorders (died of breast cancer). No DNA was available for the paternal grandparents. In OCD family 2, the mother and two siblings of the proband had committed suicide and the father was also dead, so no DNA was available for these individuals. OCD case 1 had only one brother, who committed suicide some years ago, and no DNA was available. No other clinical data were available concerning the first-degree relatives of OCD case 1. In PDD family 1, V425 was transmitted by the father and was present in the proband and two brothers. The father and one of the brothers carrying the V425 were both alcohol dependent. However, the youngest brother (19 years old), also carrying the V425 variant, did not suffer from alcoholism or any other psychiatric disorder at the time of evaluation.
Our results are in accordance with those previously reported by Ozaki et al1 on four points. First, we report a possibly higher occurrence of the V425 variant in OCD compared to controls. Although the variant is rare, the combined results of the two studies indicate a significantly higher frequency of V425 in OCD compared to controls1, 9 (5/457 vs 2/884, Fisher's exact test, P=0.02). Second, despite the limited clinical and genotypic information on the families carrying the V425 variant, our results suggest a possible cosegregation between the V425 and neuropsychiatric phenotypes, specifically in OCD. Third, Ozaki et al hypothesized that the V425 variant may confer treatment resistance to SRIs. This was indirectly supported by our findings since all OCD probands carrying the V425 variant in our study were considered resistant to SRIs, that is, the severity of their obsessive and compulsive symptoms decreased less than 25% with multiple trials of a high dose of SRIs and a good compliance. Specifically, the three probands with OCD carrying the variant showed poor or no response to multiple trials of SRIs at adequate doses over several years. Fourth, the analysis of the two additional polymorphisms of the SCL6A4 gene indicated that the V425 polymorphism might be associated with the L allele of 5-HTTLPR. However, our results do not confirm the hypothesis of a combined gain of functional effect of both V425 and L/L genotype as a genetic risk for OCD, since this combined genotype was not present in all affected patients and, by contrast, was present in the control subject carrying the V425 variant.
In conclusion, our results are similar to those of the original report by Ozaki et al and, therefore, lend support for a role of SLC6A4 V425 in the susceptibility to complex neuropsychiatric phenotypes. However, due to its global low frequency and to the fact that it was detected in a few controls, the role of V425 remains uncertain and should be interpreted with caution. We encourage other investigators, especially in the field of OCD, to screen for V425 in their samples. Indeed, the replication of these findings could ultimately implicate SLC6A4 as a true susceptibility gene to complex neuropsychiatric disorders, and consequently shed further light on the results obtained with the more frequent polymorphisms.
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SCL6A4 polymorphisms rs25533 and I425V: Association with obsessive–compulsive disorder and its treatment response in Iranian patients
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