THE SEROTONIN TRANSPORTER IS A POTENTIAL SUSCEPTIBILITY FACTOR FOR BIPOLAR AFFECTIVE-DISORDER

THE serotonin transporter is a strong candidate for aetiological invol vement in affective disorders and psychosis. We analysed a VNTR in int ron 2 of the human serotonin transporter gene (hSERT) for allelic asso ciation with bipolar affective disorder, unipolar depression and schiz ophrenia. An increased frequency of allele 12 of the VNTR was observed in subjects with bipolar affective disorder (n = 191; chi(2) p = 0.00 048 by allele) but not unipolar depression (n = 86; chi(2) p = 0.18, n s) or schizophrenia (tr = 129; chi(2) p = 0.08, ns), although a trend towards an excess of allele 12 was observed for the latter. There was also a significant difference in the frequency of allele 12 between bi polar affective disorder and unipolar depression (p = 0.0087). The rel ative risk for bipolar affective disorder with respect to allele 12 wa s 1.84 (95% CI 0.97-3.56) for heterozygotes, and 3.10 (95% CI 1.60-6.0 7) for homozygotes, with evidence for a gene-dosage effect. Because al lele 12 is common in the population, the attributable risk is 50.8% (9 5% CI 14.5%-73.3%). We hypothesize that either the VNTR affects regula tion of expression of hSERT at the transcriptional level or it is in l inkage disequilibrium with another functional polymorphism in the gene , and this results in an increased risk for the development of bipolar affective disorder.