title: A quantitative-trait analysis of human plasma-dopamine beta-hydroxylase activity: evidence for a major functional polymorphism at the DBH locus.
abstract: Dopamine-beta-hydroxylase (D beta H) catalyzes the conversion of dopamine to norepinephrine and is released from sympathetic neurons into the circulation. Plasma-D beta H activity varies widely between individuals, and a subgroup of the population has very low activity levels. Mounting evidence suggests that the DBH structural gene is itself the major quantitative-trait locus (QTL) for plasma-D beta H activity, and a single unidentified polymorphism may account for a majority of the variation in activity levels. Through use of both sequencing-based mutational analysis of extreme phenotypes and genotype/phenotype correlations in samples from African American, European American (EA), and Japanese populations, we have identified a novel polymorphism (--1021C-->T), in the 5' flanking region of the DBH gene, that accounts for 35%--52% of the variation in plasma-D beta H activity in these populations. In EAs, homozygosity at the T allele predicted the very low D beta H-activity trait, and activity values in heterozygotes formed an intermediate distribution, indicating codominant inheritance. Our findings demonstrate that --1021C-->T is a major genetic marker for plasma-D beta H activity and provide new tools for investigation of the role of both D beta H and the DBH gene in human disease.
authors.affiliation: Department of Psychiatry, Yale University, New Haven, CT, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Zabetian
authors.forename: G M
authors.initials: GM
authors.lastname: Anderson
authors.forename: S G
authors.initials: SG
authors.lastname: Buxbaum
authors.forename: R C
authors.initials: RC
authors.lastname: Elston
authors.forename: H
authors.initials: H
authors.lastname: Ichinose
authors.forename: T
authors.initials: T
authors.lastname: Nagatsu
authors.forename: K S
authors.initials: KS
authors.lastname: Kim
authors.forename: C H
authors.initials: CH
authors.lastname: Kim
authors.forename: R T
authors.initials: RT
authors.lastname: Malison
authors.forename: J
authors.initials: J
authors.lastname: Gelernter
authors.forename: J F
authors.initials: JF
authors.lastname: Cubells
mesh_terms: D019943:Amino Acid Substitution; D000704:Analysis of Variance; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D004299:Dopamine beta-Hydroxylase / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008969:Molecular Sequence Data; D010641:Phenotype; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable
chemical_list: D004247:DNA; D004299:Dopamine beta-Hydroxylase