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Linkage analysis of plasma dopamine ?-hydroxylase activity in families of patients with schizophrenia.

ABSTRACT: Dopamine ?-hydroxylase (D?H) catalyzes the conversion of dopamine to norepinephrine. D?H enters the plasma after vesicular release from sympathetic neurons and the adrenal medulla. Plasma D?H activity (pD?H) varies widely among individuals, and genetic inheritance regulates that variation. Linkage studies suggested strong linkage of pD?H to ABO on 9q34, and positive evidence for linkage to the complement fixation locus on 19p13.2-13.3. Subsequent association studies strongly supported DBH, which maps adjacent to ABO, as the locus regulating a large proportion of the heritable variation in pD?H. Prior studies have suggested that variation in pD?H, or genetic variants at D?H, associate with differences in expression of psychotic symptoms in patients with schizophrenia and other idiopathic or drug-induced brain disorders, suggesting that DBH might be a genetic modifier of psychotic symptoms. As a first step toward investigating that hypothesis, we performed linkage analysis on pD?H in patients with schizophrenia and their relatives. The results strongly confirm linkage of markers at DBH to pD?H under several models (maximum multipoint LOD score, 6.33), but find no evidence to support linkage anywhere on chromosome 19. Accounting for the contributions to the linkage signal of three SNPs at DBH, rs1611115, rs1611122, and rs6271 reduced but did not eliminate the linkage peak, whereas accounting for all SNPs near DBH eliminated the signal entirely. Analysis of markers genome-wide uncovered positive evidence for linkage between markers at chromosome 20p12 (multi-point LOD = 3.1 at 27.2 cM). The present results provide the first direct evidence for linkage between DBH and pD?H, suggest that rs1611115, rs1611122, rs6271 and additional unidentified variants at or near DBH contribute to the genetic regulation of pD?H, and suggest that a locus near 20p12 also influences pD?H.

SUBMITTER: Cubells JF

PROVIDER: S-EPMC3193571 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Linkage analysis of plasma dopamine β-hydroxylase activity in families of patients with schizophrenia.

Cubells Joseph F JF Sun Xiangqing X Li Wenbiao W Bonsall Robert W RW McGrath John A JA Avramopoulos Dimitri D Lasseter Virginia K VK Wolyniec Paula S PS Tang Yi-Lang YL Mercer Kristina K Pulver Ann E AE Elston Robert C RC

Human genetics 20110421 5

Dopamine β-hydroxylase (DβH) catalyzes the conversion of dopamine to norepinephrine. DβH enters the plasma after vesicular release from sympathetic neurons and the adrenal medulla. Plasma DβH activity (pDβH) varies widely among individuals, and genetic inheritance regulates that variation. Linkage studies suggested strong linkage of pDβH to ABO on 9q34, and positive evidence for linkage to the complement fixation locus on 19p13.2-13.3. Subsequent association studies strongly supported DBH, which ...[more]

PMID: 21509519

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Project description:INTRODUCTION:Despite the importance of dopamine neurotransmission in schizophrenia, very few studies have addressed anomalies in the mesencephalic dopaminergic neurons of the substantia nigra/ventral tegmental area (SN/VTA). Tyrosine hydroxylase (TH) is the rate-limiting enzyme for the production of dopamine, and a possible contributor to the anomalies in the dopaminergic neurotransmission observed in schizophrenia. OBJECTIVES:In this study, we had three objectives: (1) Compare TH expression (mRNA and protein) in the SN/VTA of schizophrenia and control postmortem samples. (2) Assess the effect of antipsychotic medications on the expression of TH in the SN/VTA. (3) Examine possible regional differences in TH expression anomalies within the SN/VTA. METHODS:To achieve these objectives three independent studies were conducted: (1) A pilot study to compare TH mRNA and TH protein levels in the SN/VTA of postmortem samples from schizophrenia and controls. (2) A chronic treatment study was performed in rodents to assess the effect of antipsychotic medications in TH protein levels in the SN/VTA. (3) A second postmortem study was performed to assess TH and phosphorylated TH protein levels in two types of samples: schizophrenia and control samples containing the entire rostro-caudal extent of the SN/VTA, and schizophrenia and control samples containing only mid-caudal regions of the SN/VTA. RESULTS AND CONCLUSION:Our studies showed impairment in the dopaminergic system in schizophrenia that could be mainly (or exclusively) located in the rostral region of the SN/VTA. Our studies also showed that TH protein levels were significantly abnormal in schizophrenia, while mRNA expression levels were not affected, indicating that TH pathology in this region may occur posttranscriptionally. Lastly, our antipsychotic animal treatment study showed that TH protein levels were not significantly affected by antipsychotic treatment, indicating that these anomalies are an intrinsic pathology rather than a treatment effect.

Dataset Information

Linkage analysis of plasma dopamine ?-hydroxylase activity in families of patients with schizophrenia.

Publications

Linkage analysis of plasma dopamine β-hydroxylase activity in families of patients with schizophrenia.

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