Two novel variants in the DOPA decarboxylase gene: association with bipolar affective disorder

DOPA decarboxylase (DDC), also known as aromatic L-amino acid decarboxylase (AADC), is an enzyme involved in the synthesis of the important neurotrans mitters dopamine, norepinephrine, and serotonin. In addition, it participat es in the synthesis of trace amines; compounds suggested to act as endogeno us modulators of central neurotransmission. Thus, DDC is regarded as a pote ntial susceptibility gene for a variety of neuropsychiatric disorders. The aim of the present study was to examine the role of DDC in bipolar affectiv e disorder (BPAD). By screening 10 individuals for sequence Variations in t he coding region of the DDC gene as well as in the neuron-specific promoter and 5' untranslated regions we were able to identify two fairly frequent v ariants: a 1-bp deletion in the promoter and a 4-bp deletion in the untrans lated exon 1. Both deletions affect putative binding sites for known transc ription factors, suggesting a possible functional impact at the level of ex pression. The two Variants were applied in an association study including 8 0 Danish bipolar patients, 112 English bipolar patients, 223 Danish control s, and 349 English controls. Analyzing the combined material, a significant association was found between the l-bp deletion and BPAD with P-values of 0.037 (allelic) and 0.021 (genotypic). The frequency of the l-bp deletion w as 13.3% in patients and 9.4% in controls with a corresponding odds ratio o f 1.48 (95% CI: 1.02-2.15), The results presented suggest that DDC may act as a minor susceptibility gene for bipolar affective disorder.