Linkage studies of catechol-O-methyltransferase (COMT) and dopamine-beta-hydroxylase (DBH) cDNA expression levels.

Chao Xing,Robert C Elston,Guan Xing,Tao Wang,Qing Lu,Monica Torres-Caban

doi:10.1186/1753-6561-1-s1-s95

Abstract

The COMT and DBH genes are physically located at chromosomes 22q11 and 9q34, respectively, and both COMT and DBH are involved in catecholamine metabolism and are strong candidates for certain psychiatric and neurological disorders. Although the genetic determinants for both enzymes' activities have been widely studied, their genetic involvement on gene mRNA expression levels remains unclear. In this study we performed quantitative linkage analysis of COMT and DBH cDNA expression levels, identifying transcriptional regulatory regions for both genes. Multiple Haseman-Elston regression was used to detect both additive and interactive effects between two loci. We found that the master transcriptional regulatory region 20q13 had an additive effect on the COMT expression level. We also found that chromosome 19p13 showed both additive and interactive effects with 9q34 on DBH expression level. Furthermore, a potential interaction between COMT and DBH was indicated.

Highlights

Catechol-O-methyltransferase (COMT) (MIM 116790) catalyzes the transfer of a methyl group from S-adenosylmethionine to catecholamines [1], and dopamine-betahydroxylase (DBH) (MIM 223360) catalyzes the conversion of dopamine to norepinephrine [2]; both enzymes are involved in the catecholamine metabolism system, in which abnormalities are hypothesized to be related to the development of psychiatric and neurological disorders such as schizophrenia and depression
There are two distinct forms of COMT, a membrane-bound COMT (MB-COMT) and a soluble COMT (S-COMT) found in the cell cytoplasm [5]; the former is predominantly expressed in brain neurons, whereas the latter is predominantly expressed in other tissues such as liver and kidney
There has been intensive research on the genetic determinants of plasma COMT and DBH activities, and findings so far strongly suggest that the structural genes COMT and DBH encoding these proteins are the major quantitative trait loci for their respective plasma activities; in both genes single-nucleotide polymorphisms (SNPs) have been identified that may account for most of the variation in the enzyme activity levels

Summary

Introduction

Catechol-O-methyltransferase (COMT) (MIM 116790) catalyzes the transfer of a methyl group from S-adenosylmethionine to catecholamines [1], and dopamine-betahydroxylase (DBH) (MIM 223360) catalyzes the conversion of dopamine to norepinephrine [2]; both enzymes are involved in the catecholamine metabolism system, in which abnormalities are hypothesized to be related to the development of psychiatric and neurological disorders such as schizophrenia and depression (for reviews, see [3,4]). BMC Proceedings 2007, 1(Suppl 1):S95 http://www.biomedcentral.com/1753-6561/1/S1/S95 secreotry cells [6]. The COMT and DBH genes are physically located at chromosomes 22q11 and 9q34, respectively [7,8]. On the common functional SNP rs165688, a G→A substitution in exon 4 of COMT produces a valine→methionine (Val/Met) substitution at codons 158 and 108 in the MB-COMT and SCOMT transcripts, respectively. This polymorphism has been shown to have a functional effect on enzyme activity; in particular, Val is a predominant factor that determines higher COMT activity [9]. The SNP rs1611115 (1021C→T) located in the 5' flanking region of the DBH gene accounts for 35% to 52% of the variance in plasma DBH activity in populations from diverse geographic origins [10]

Methods

Results

Conclusion