Dopa decarboxylase genotypes may influence age at onset of schizophrenia.

Several lines of evidence implicate dopa decarboxylase (DDC) with schizophrenia. By analysis of two putative functional DDC variants in 173 schizophrenic patients and 204 controls we tested the hypotheses that DDC is involved in: (1) predisposition to schizophrenia; and (2) modulation of age at disease onset. No association was observed with schizophrenia as a whole, whereas an association between DDC genotypes and age at disease onset was suggested in males (P = 0.03). This association was most pronounced in relation to genotypes of haplotypes comprising both variants, suggesting an additive model where one variant mediates early and the other late onset. Accordingly, the haplotype-based genotypes could be assigned into three groups by their possible relative effect on age at onset: an "early", "neutral" and "late" group. Dividing the male schizophrenics into four groups with increasing age at onset, the "early" genotypes were seen to decrease in frequency from 51.5% to 16.7% while the "late" genotypes increased from 12.1% to 33.3% (P = 0.02). The difference in mean age at onset between male patients with "early" genotypes vs patients with "late" genotypes was close to 5 years (95% CI: 0.7-8.8). Thus, DDC may possibly act as a modulator of age at onset in male schizophrenics.

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 neurotransmitters dopamine, norepinephrine, and serotonin. In addition, it participates in the synthesis of trace amines; compounds suggested to act as endogenous modulators of central neurotransmission. Thus, DDC is regarded as a potential susceptibility gene for a variety of neuropsychiatric disorders. The aim of the present study was to examine the role of DDC in bipolar affective disorder (BPAD). By screening 10 individuals for sequence variations in the 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 variants: a 1-bp deletion in the promoter and a 4-bp deletion in the untranslated exon 1. Both deletions affect putative binding sites for known transcription factors, suggesting a possible functional impact at the level of expression. The two variants were applied in an association study including 80 Danish bipolar patients, 112 English bipolar patients, 223 Danish controls, and 349 English controls. Analyzing the combined material, a significant association was found between the 1-bp deletion and BPAD with P-values of 0.037 (allelic) and 0.021 (genotypic). The frequency of the 1-bp deletion was 13.3% in patients and 9.4% in controls with a corresponding odds ratio of 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.