Haplotype-controlled analysis of the association of a non-synonymous single nucleotide polymorphism at DBH (+ 1603C → T) with plasma dopamine β-hydroxylase activity

The DBH locus controls plasma dopamine β‐hydroxylase activity (pDβH). A 5′‐upstream single nucleotide polymorphism (SNP) at DBH (−1021C → T) explains ∼45% of the variance in pDβH, and a non‐synonymous SNP in exon 11 (+ 1603C → T) an additional 2%. However, that regression result underestimates the effect of + 1603C → T because of its low minor allele frequency. We estimated the biological effect of + 1603C → T on pDβH by comparing subjects of identical −1021CγT genotype, in a diagnostically heterogeneous group of subjects of European origin (N = 367). + 1603C → T genotype associated with pDβH within groups of identical genotype at −1021 C → T, accounting for 5%–16% of the variance. There was no significant linkage disequilibrium between −1021C → T and + 1603C → T (D = 0.0058, D′ = 0.4774, d2 = 0.0011, P > 0.05), confirming the validity of assessing the two polymorphisms independently. These results suggest that altered homospecific activity of the enzyme can contribute to variation in pDβH. This conclusion informs how associations between DBH and psychiatric disorders should be approached. © 2005 Wiley‐Liss, Inc.