Dopamine β-hydroxylase: two polymorphisms in linkage disequilibrium at the structural gene DBH associate with biochemical phenotypic variation

Cubells, Joseph F.; Kammen, Daniël P. van; Kelley, Mary E.; Anderson, George M.; O’Connor, Daniel T.; Price, Lawrence H.; Malison, Robert T.; Rao, Peter A.; Kobayashi, Kei; Nagatsu, Toshiharu; Gelernter, Joel

doi:10.1007/s004390050736

Cited by 124 publications

(120 citation statements)

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“…[25][26][27][28] Current study We previously showed that a silent single nucleotide polymorphism at the 3Ј end of DBH exon 2, DBH* 444g/a, comprised of either guanidine (g) or adenine (a) at cDNA nucleotide position 444 29 associated with plasma and CSF D␤H in European-Americans (EA). 22 The a-containing allele, DBH*444a, associates with low D␤H levels, while the g-containing allele, DBH* 444g, associates with higher D␤H levels. Here, we report a second di-allelic polymorphism at DBH that associates with plasma levels of D␤H in EA.…”

Section: Molecular Psychiatrymentioning

confidence: 99%

“…Strong evidence shows that: (1) plasma and cerebrospinal fluid D␤H levels are genetic traits; 17,18 (2) DBH is the major locus controlling both of these traits, [19][20][21][22] accounting for Ͼ80% of the genetic variance in plasma D␤H levels; 20 and (3) specific alleles of polymorphisms located near the 5Ј portion of the DBH gene are associated with lower D␤H levels in both plasma and CSF. 22 D␤H phenotypes and psychosis: association of low plasma and CSF D␤H levels with vulnerability to positive psychotic symptoms Previous studies support associations between low plasma or CSF levels of D␤H and elevated vulnerability to psychosis. Thus, schizophrenic patients with low CSF levels of D␤H exhibit more acute psychotic symp-…”

Section: Evidence For Genetic Influences On Vulnerability To Drug-indmentioning

confidence: 99%

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

et al. 2000

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Low levels of dopamine ␤-hydroxylase (D␤H) protein in the plasma or cerebrospinal fluid (CSF) are associated with greater vulnerability to positive psychotic symptoms in several psychiatric disorders. D␤H level is a stable, genetically controlled trait. DBH, the locus encoding D␤H protein, is the major quantitative trait locus controlling plasma and CSF D␤H levels. We therefore hypothesized that DBH variants or haplotypes, associated with low levels of D␤H in the plasma, would also associate with greater vulnerability to cocaine-induced paranoia. To test this hypothesis, we first showed that a di-allelic variant, DBH*5Ј-ins/del, located approximately 3 kb 5Ј to the DBH transcriptional start site, significantly associates with plasma D␤H activity in European-Americans (n = 66). Linkage disequilibrium analysis of that polymorphism and DBH*444g/a, another di-allelic variant associated with D␤H levels, demonstrated that alleles of similar association to D␤H levels are in positive disequilibrium. We then estimated DBH haplotype frequencies in cocaine-dependent European Americans rated for cocaine-induced paranoia (n = 45). As predicted, the low-D␤H-associated haplotype, Del-a, was significantly more frequent (P = 0.0003) in subjects endorsing cocaine-induced paranoia (n = 29) than in those denying it (n = 16). Comparison to control haplotype frequencies (n = 145 healthy European-Americans) showed that the association predominantly reflected under-representation of Del-a haplotypes in those denying cocaine-induced 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 similar association to D␤H levels in positive disequilibrium; and (c) the haplotype associated with low DBH activity is also associated with cocaine-induced paranoia. Molecular Psychiatry (2000) 5, 56-63.Keywords: psychotic disorders; substance-related disorders; central nervous system stimulants; norepinephrine; catecholamines; schizophrenia; alleles; genes More than 60% of experienced cocaine users report paranoia during cocaine intoxication, while the remainder deny even mild cocaine-induced paranoia (CIP), despite reporting similar routes of administration, duration of cocaine dependence, and lifetime and per-binge quantities of cocaine ingested. 1-3 Satel and Edell 4 reported elevated scores on a measure of psychosis proneness in cocaine-dependent subjects who endorsed CIP compared to those who did not. These data suggest the presence of substantial interindividual variation in vulnerability to CIP. Evidence for genetic influences on vulnerability to drug-induced paranoiaSeveral lines of evidence support genetic factors as modulators of individual vulnerability to CIP. Numerous animal studies support the importance of genetic factors in behavioral responses to cocaine. 5 Abstinent human cocaine users who endorse CIP exhibit deficits in P50 sensory gating of auditory stimuli, 6 a heritable p...

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Section: Molecular Psychiatrymentioning

confidence: 99%

Section: Evidence For Genetic Influences On Vulnerability To Drug-indmentioning

confidence: 99%

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

et al. 2000

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“…9 The DBH gene contains 12 exons that span approximately 23 kb of human chromosome 9 ( Figure 1). A schematic representation of the DBH gene, showing the relative positions of the SNPs, is shown as Figure 1 below.…”

Section: Samplesmentioning

confidence: 99%

“…19 The primers were: 5 0 -CTGTATTTG GAACTTGGCATC-3 0 (forward) and 5 0 -AGG CATTTTACTACCCAGAGG-3 0 (reverse). Methods for genotyping the other SNPs have been published previously 7,9,11 and are available from the corresponding author (JFC).…”

Section: Samplesmentioning

confidence: 99%

Genotypic and haplotypic associations of the DBH gene with plasma dopamine β-hydroxylase activity in African Americans

et al. 2007

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Several variants at DBH are significantly associated with plasma DbH activity (pDbH). However, the overwhelming majority of data on this genotype -phenotype relationship has been gathered in samples from Europeans and European Americans (EAs). In this study, we examined the relationship between DBH polymorphisms and pDbH in samples from African-American (AA) subjects. Genotypes were determined at a 19-bp insertion/deletion polymorphism (ins/del) and four single-nucleotide polymorphisms (SNPs) at DBH in 109 samples. Analyses were performed using analyses of variance (ANOVAs) (for individual SNPs) and regression procedures (to assess the joint effects and the specific SNP-based haplotypes). We found:(1) single-variant analysis of all polymorphisms revealed apparent associations to pDbH, with rs1611115 accounting for the largest proportion of the variance in pDbH (28.7%) and ins/del the smallest (6.5%); (2) modest but significant linkage disequilibrium (LD) existed between ins/del and rs1611115; (3) LD between all other pairs of variants was not observed; (3) stepwise regression showed that a model containing rs1611115, rs2519152 and rs6271 accounted for 37.6% of the variance in pDbH, with rs6271 showing additional 7.6% above the effect of rs1611115, and rs2519152 showing additional 2% above rs1611115 and rs6271; (4) two common haplotypes, C-T-C and T-C-C at rs1611115-rs2519152-rs6271 were significantly associated with pDbH (P ¼ 0.0025 and 0.0036, respectively). The data support the validity of prior reported associations and underscore the importance of analyzing multiple SNPs across DBH in future association studies examining disease and biochemical phenotypes.

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“…27, NO. 4 study is known to be in significant linkage disequilibrium (Daly et al 1999) with polymorphisms (in promoter and exon 2 regions) associated with reduced DBH enzyme activity (Cubells et al 1998). In experimental animals with decreased serum DBH, reduced conversion of dopamine to noradrenaline lessens negative feedback on tyrosine hydroxylase (Anden et al 1973; Axelrod and Weinshilboum 1972).…”

Section: The Contribution Of Molecular Genetic Studies To a Dopamine mentioning

confidence: 99%

Dopaminergic System Genes in ADHD Toward a Biological Hypothesis

Kirley

Hawi

Daly

et al. 2002

Neuropsychopharmacology

106

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Converging evidence has implicated abnormalities of dopamine neurotransmission to the pathology of attention deficit hyperactivity disorder (ADHD).Attention Deficit Hyperactivity Disorder (ADHD) is a common condition of childhood affecting 3-6% of school age children worldwide (Barkley 1990), with males being affected three times more than females (Anderson et al. 1987; Baumgartel et al. 1995). Its core clinical features include excessive motor activity, impaired attention, and impulsivity. ADHD causes marked educational, social, and family difficulties for sufferers and their relatives. The condition is of early onset (usually before age 7) and tends to persist throughout childhood. Moreover, approximately 30-60% of children with ADHD have persisting psychopathology in adulthood (Gittelman et al. 1985;Weiss and Hechtman 1986; Barkley 1990;Swanson et al. 1998a). The exact etiology of ADHD is Received March 8, 2001; revised February 12, 2002; accepted February 20, 2002. Online publication: 2/28/02 at www.acnp.org/citations/ Npp022802254. 608 A. Kirley et al. N EUROPSYCHOPHARMACOLOGY 2002 -VOL . 27 , NO . 4 unknown, but a substantial genetic element exists. This has been demonstrated by family (Biederman et al. 1990(Biederman et al. , 1992Faraone et al., 1992Faraone et al., , 1994, twin (Thapar et al. 1995;Silberg et al. 1996;Levy et al. 1997), and adoption studies (Alberts-Corush et al. 1986; Cadoret and Stewart 1991). The heritability (h 2 ) of ADHD has been estimated to be .50-.98 (Gjone et al. 1996;Levy et al. 1997). The exact mode of transmission remains unknown. Segregation analyses (Morrison and Steward 1974;Deutsch et al. 1990, Faraone et al. 1992, Hess et al. 1995 have proposed models of inheritance from major gene effects through oligogenic to polygenic and multifactorial models, but the differences in statistical "fit" between multifactorial genetic models and single gene inheritance is modest. The multifactorial concept is consistent with ADHD's high population prevalence (2-7%), high concordance in monozygotic twins (68-81%), but modest recurrence risks to first-degree relatives.Dysregulation in catecholamine neurotransmission is implicated in the pathophysiology of ADHD (Faraone and Biederman 2002). The dopaminergic neurotransmitter system has been most extensively studied. This article will focus mainly on its role in the etiology of ADHD. Evidence to support dopaminergic dysfunction in ADHD derives from three research areas: the neuropharmacology of stimulant medication (Zametkin and Rapoport 1987; Amara and Kuhar 1993), the behavior and biochemistry of animal models (Giros et al. 1996;Gainetdinov et al. 1999, Russell 2000, and neuroimaging studies in ADHD adults (Dougherty et al. 1999, Krause et al. 2000, and Faraone and Biederman 2002. For this reason, many molecular genetic studies have focused on dopamine system genes.The gene encoding the dopamine transporter, DAT1, was the initial candidate gene studied. This gene is of particular interest, as the transporter is the principal target...

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Dopamine β-hydroxylase: two polymorphisms in linkage disequilibrium at the structural gene DBH associate with biochemical phenotypic variation

Cited by 124 publications

References 37 publications

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

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

Genotypic and haplotypic associations of the DBH gene with plasma dopamine β-hydroxylase activity in African Americans

Dopaminergic System Genes in ADHD Toward a Biological Hypothesis

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