Bipolar disorder and the serotonin transporter gene: a family-based association study.
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 (chi2 = 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: chi2 = 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 (chi2 = 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.
Kirov
G
G
Neuropsychiatric Genetics Unit, University of Wales College of Medicine, Cardiff.
Rees
M
M
Jones
I
I
MacCandless
F
F
Owen
M J
MJ
Craddock
N
N
D000328:Adult; D000595:Amino Acid Sequence; D001714:Bipolar Disorder / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D012701:Serotonin / Q000235:genetics* / Q000494:pharmacology
D002352:Carrier Proteins; D012701:Serotonin