Is the 5-HTTLPR polymorphism associated with bipolar disorder or with suicidal behavior of bipolar disorder patients?

The serotonin transporter gene has a 44 bp insertion/deletion polymorphism within the promoter region (5-HTTLPR) with two allelic forms, the long (L) and the short (S) variants. Association between the low-activity S variant and bipolar disorder (BPD) has been shown but its replication has not been consistent. It has also been described as an association between the S allele and suicidal behavior. Since suicidal behavior is a rather frequent event in BPD, an important question is whether suicidality, instead of bipolarity itself, could be related to S allele. We assessed 351 subjects (167 bipolar inpatients and 184 healthy controls). Diagnosis was conducted by a psychiatrist using a structured interview (MINI-PLUS), according to DSM-IV criteria. Suicidal behavior was assessed using a semi-structured instrument and a review of medical records. Genotyping of the 5-HTTLPR was performed using PCR. There were 77 patients with a history of previous suicide attempts. Bipolar patients and healthy controls showed comparable genotypic and allelic frequencies. Patients carrying the S allele made violent suicide attempts more frequently (chi(2) = 20.2; P = 0.0001) and made more suicide attempts (t = 2.6; P = 0.01). We were able to show an association between the S allele and suicidal behavior but not with BPD. Our data suggest that a phenotypic stratification, taking into account the suicidal behavior history, is of pivotal importance when performing association studies between BPD and 5-HTTLPR genotypes, which could explain previous contradictory results.