Support for tryptophan hydroxylase-2 as a susceptibility gene for bipolar affective disorder.

Bipolar affective disorder (BPAD) is a highly inherited genetic disorder and may be caused in part by deficits in serotonergic neurotransmission. We investigated whether variants within the tryptophan hydroxylase-2 (TPH2) gene, which is required for the synthesis of serotonin (5-HT), are associated with susceptibility to developing BPAD. Thirteen single nucleotide polymorphisms (SNPs) within TPH2 were genotyped in a collection of 151 Irish BPAD type I trios and were tested for association using the transmission disequilibrium test. SNPs rs1386482 and rs1386486, which are in very strong linkage disequilibrium, were associated with BPAD (P=0.006). The association retained significance after a correction for multiple testing. The associated SNPs are in perfect linkage disequilibrium with SNPs previously associated with BPAD (rs4290270) and impulsivity (rs1386483), a core trait of BPAD. These results strongly support a role for TPH2 in the aetiology of BPAD.