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

Abstract

Background. The human serotonin transporter gene (5-HTT) is a strong candidate for involvement in the pathogenesis of mood disorders. Two common polymorphisms have been identified in the gene: a VNTR in intron 2 and a functional deletion/insertion in the promoter region. In previous studies we proposed that allele 12 of the VNTR might increase susceptibility for bipolar disorder.

Methods. We have genotyped 122 parent–offspring trios of British Caucasian origin where the proband had DSM-IV Bipolar I disorder (BPI). The results were analysed with the transmission/disequilibrium test (TDT), which examines whether particular alleles are preferentially transmitted from heterozygous parents to affected offspring.

Results. The 12 repeat in the VNTR in intron 2 was transmitted 72 times and not transmitted 56 times (χ² = 2·0, 1 df, P=0·16). If we exclude 24 families in which the proband was a case in our published case–control studies (Collier et al. 1996a; Rees et al. 1997), the excess transmission of allele 12 reaches conventional levels of statistical significance: χ² = 3·85, 1 df, P<0·05. The deletion/insertion polymorphism in the promoter region was not associated with BPI: 66 parents transmitted the inserted (L) allele and 59 parents transmitted the deleted (S) allele (χ² = 0·39, 1 df, P=0·53).

Conclusions. The 12 repeat of the VNTR in intron 2 of the serotonin transporter gene might be a susceptibility factor in bipolar affective disorder. The genetic effect, if true, is likely to be small, and requires confirmation in further studies using parental controls.