Bipolar disorder and the serotonin transporter gene: a family-based association study

Background. The human serotonin transporter gene (5-HTT) is a strong candid ate for involvement in the pathogenesis of mood disorders. Two common polym orphisms have been identified in the gene: a VNTR in intron 2 and a functio nal deletion/insertion in the promoter region. In previous studies we propo sed that allele 12 of the VNTR might increase susceptibility for bipolar di sorder. Methods. We have genotyped 122 parent-offspring trios of British Caucasian origin where the proband had DSM-IV Bipolar I disorder (BPI). The results w ere analysed with the transmission/disequilibrium test (TDT), which examine s whether particular alleles are preferentially transmitted from heterozygo us parents to affected offspring. Results. The 12 repeat in the VNTR in intron 2 was transmitted 72 times and not transmitted 56 times (chi(2) = 2.0, 1 df, P = 0.16). If we exclude 24 families in which the proband was a case in our published case-control stud ies (Collier et al. 1996a; Rees et al. 1997), the excess transmission of al lele 12 reaches conventional levels of statistical significance: chi(2) = 3 .85, Idf, P < 0.05. The deletion/insertion polymorphism in the promoter reg ion was not associated with BPI: 66 parents transmitted the inserted (L) al lele and 59 parents transmitted the deleted (S) allele (chi(2) = 0.39, 1 df , P = 0.53). Conclusions. The 12 repeat of the VNTR in intron 2 of the serotonin transpo rter gene might be a susceptibility factor in bipolar affective disorder. T he genetic effect, if true, is likely to be small, and requires confirmatio n in further studies using parental controls.