A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain

Abstract

The gene encoding catechol-O-methyltransferase (COMT) is a strong candidate for schizophrenia susceptibility, owing to the role of COMT in dopamine metabolism, and the location of the gene within the deleted region in velocardiofacial syndrome, a disorder associated with high rates of schizophrenia. Recently, a highly significant association was reported between schizophrenia and a COMT haplotype in a large case-control sample (Shifman et al. 2002). In addition to a functional valine-->methionine (Val/Met) polymorphism, this haplotype included two noncoding single-nucleotide polymorphisms (SNPs) at either end of the COMT gene. Given the role of COMT in dopamine catabolism and that deletion of 22q11 (containing COMT) is associated with schizophrenia, we postulated that the susceptibility COMT haplotype is associated with low COMT expression. To test this hypothesis, we have applied quantitative measures of allele-specific expression using mRNA from human brain. We demonstrate that COMT is subject to allelic differences in expression in human brain and that the COMT haplotype implicated in schizophrenia (Shifman et al. 2002) is associated with lower expression of COMT mRNA. We also show that the 3' flanking region SNP that gave greatest evidence for association with schizophrenia in that study is transcribed in human brain and exhibits significant differences in allelic expression, with lower relative expression of the associated allele. Our results indicate that COMT variants other than the Val/Met change are of functional importance in human brain and that the haplotype implicated in schizophrenia susceptibility is likely to exert its effect, directly or indirectly, by down-regulating COMT expression.

Figure 1

Genomic structure of the COMT gene, which indicates exon usage of the membrane-bound (MB-COMT) and soluble (S-COMT) forms. Location of assayed SNPs are shown, together with estimated haplotype frequencies.

Figure 2

Comparison between observed genomic ratios and corrected cDNA ratios assayed at SNP rs4633 (n=23). Data are expressed as ratio of C:T alleles. The data for genomic DNA are the averages of two measurements for each individual sample. The data for cDNA are the averages of eight estimates for each individual sample.

Figure 3

Comparison between observed genomic ratios and corrected cDNA ratios assayed at SNP rs165599 (n=30). Data are expressed as ratio of G:A alleles. The data for genomic DNA are the averages of two measurements for each individual sample. The data for cDNA are the averages of four estimates for each individual sample.