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Dopamine beta-hydroxylase (DBH) is the biosynthetic enzyme catalyzing formation of norepinephrine. Changes in DBH expression or activity have been implicated in the pathogenesis of cardiovascular and neuropsychiatric disorders. Genetic determination of DBH enzymatic activity and its secretion are only incompletely understood. We began with a genome-wide association search for loci contributing to DBH activity in human plasma. Initially, in a population sample of European ancestry, we identified the proximal  DBH  promoter as a region harboring three common trait-determining variants (top hit rs1611115,  P  = 7.2 × 10 −51 ). We confirmed their effects on transcription and showed that the three variants each acted additively on gene expression. Results were replicated in a population sample of Native American descent (top hit rs1611115,  P  = 4.1 × 10 −15 ). Jointly,  DBH  variants accounted for 57% of DBH trait variation. We further identified a genome-wide significant SNP at the  LOC338797  locus on chromosome 12 as  trans -quantitative trait locus (QTL) (rs4255618,  P  = 4.62 × 10 −8 ). Conditional analyses on  DBH  identified a third genomic region contributing to DBH variation: a likely  cis -QTL adjacent to  DBH  in  SARDH  (rs7040170,  P  = 1.31 × 10 −14 ) on chromosome 9q. We conclude that three common SNPs in the  DBH  promoter act additively to control phenotypic variation in DBH levels, and that two additional novel loci ( SARDH  and  LOC338797 ) may also contribute to the expression of this catecholamine biosynthetic trait. Identification of  DBH  variants with strong effects makes it possible to take advantage of Mendelian randomization approaches to test causal effects of this intermediate trait on disease.

human molecular genetics

The catecholamine biosynthetic enzyme dopamine β-hydroxylase (DBH): first genome-wide search positions trait-determining variants acting additively in the proximal promoter