A haplotype at the DBH locus, associated with low plasma dopamine beta-hydroxylase activity, also associates with cocaine-induced paranoia

Low levels of dopamine beta-hydroxylase (D beta H) protein in the plasma or cerebrospinal fluid (CSF) are associated with greater vulnerability to pos itive psychotic symptoms in several psychiatric disorders. D beta H level i s a stable, genetically controlled trait. DBH, the locus encoding D beta H protein, is the major quantitative trait locus controlling plasma and CSF D beta H revels. We therefore hypothesized that DBH variants or haplotypes, associated with low levers of D beta H in the plasma, would also associate with greater vulnerability to cocaine-induced paranoia. To test this hypoth esis, we first showed that a di-allelic variant, DBH*5'-ins/del, located ap proximately 3 kb 5' to the DBH transcriptional start site, significantly as sociates with plasma D beta H activity in European-Americans (n = 66), Link age disequilibrium analysis of that polymorphism and DBH*444g/a, another di -allelic Variant associated with D beta H levels, demonstrated that alleles of similar association to D beta H levels are in positive disequilibrium. We then estimated DBH haplotype frequencies in cocaine-dependent European A mericans rated for cocaine-induced paranoia (n = 45), As predicted, the tow -D beta H-associated haplotype, Del-a, was significantly more frequent (P = 0.0003) in subjects endorsing cocaine-induced paranoia (n = 29) than in th ose denying it (n = 16). Comparison to control haplotype frequencies (n = 1 45 healthy European-Americans) showed that the association predominantly re flected under-representation of Del-a haplotypes in those denying cocaine-i nduced paranoia, We conclude that: (a) the two DBH polymorphisms we studied are associated with plasma DBH levels; (b) those two polymorphisms are in significant linkage disequilibrium in European Americans, with alleles of s imilar association to D beta H levels in positive disequilibrium; and (c) t he haplotype associated with low DBH activity is also associated with cocai ne-induced paranoia.