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Dopa decarboxylase (DDC) is involved directly in the synthesis of dopamine and serotonin and indirectly in the synthesis of noradrenaline. The present study investigated two Danish families for linkage between manic depressive illness, a marker at the DDC locus which has been mapped to 7p11-p13 and 10 microsatellite markers covering chromosome 7q11-p15. No evidence of linkage was found assuming a dominant or a recessive mode of inheritance. We have earlier reported evidence against linkage between manic depressive illness and tyrosine hydroxylase and dopamine beta-hydroxylase. Mutations of major importance in the genes encoding the three enzymes involved in the synthesis of dopamine and noradrenaline seem less likely in the families we have studied. Further investigations of genetic and other pathophysiological mechanisms in relation to the monoamine hypotheses for manic depressive illness are still of relevance. There is a need for further linkage and association studies as well as a search for possible mutations in the relevant genes involved in the monoaminergic pathways to clarify their possible role in the aetiology of manic depressive illness.

The dopamine beta-hydroxylase (DBH) gene is a candidate gene in manic depressive illness. DBH is required for conversion of dopamine to norepinephrine, the third step in catecholamine biosynthesis. A few earlier linkage studies have found low to moderately positive lod scores in manic depressive families for ABO which is closely linked to DBH. Based on several studies an association between manic depressive illness and ABO blood type has been suggested. Mutations at the DBH locus might thus be involved in the etiology of manic depressive illness in some families. The DBH gene is reported here as unlikely to be a major gene causing manic depressive illness in a large family. Linkage was excluded assuming a dominant mode of transmission. Several methods were used to minimize misclassification.