A Highly Significant Association between a COMT Haplotype and Schizophrenia

Abstract

Several lines of evidence have placed the catechol-O-methyltransferase (COMT) gene in the limelight as a candidate gene for schizophrenia. One of these is its biochemical function in metabolism of catecholamine neurotransmitters; another is the microdeletion, on chromosome 22q11, that includes the COMT gene and causes velocardiofacial syndrome, a syndrome associated with a high rate of psychosis, particularly schizophrenia. The interest in the COMT gene as a candidate risk factor for schizophrenia has led to numerous linkage and association analyses. These, however, have failed to produce any conclusive result. Here we report an efficient approach to gene discovery. The approach consists of (i) a large sample size-to our knowledge, the present study is the largest case-control study performed to date in schizophrenia; (ii) the use of Ashkenazi Jews, a well defined homogeneous population; and (iii) a stepwise procedure in which several single nucleotide polymorphisms (SNPs) are scanned in DNA pools, followed by individual genotyping and haplotype analysis of the relevant SNPs. We found a highly significant association between schizophrenia and a COMT haplotype (P=9.5x10-8). The approach presented can be widely implemented for the genetic dissection of other common diseases.

Impact of complex genetic variation in COMT on human brain function

“…However, while effects did not survive correction for multiple comparisons, the haplotype G-G-G (212), corresponding to the previously identified risk haplotype, 18 showed the most inefficient prefrontal response, as confirmed by post hoc testing (Z = 3.24, P < 0.002).…”

“…18 This showed a weak effect on activation during working memory, again with maximum in ventrolateral PFC. Remarkably, this analysis in a group of healthy controls highlighted the previously identified risk haplotype for schizophrenia 18 as having the most inefficient prefrontal response of other haplotypes containing these SNPs, serving as a useful proof of principle for applying haplotype imaging vis a vis population-based studies of clinical phenotypes. Again, this result could be because the haplotype more reliably tags another occult causative variant.…”

“…11,36 In addition, we propose that our results provide a mechanistic explanation for inconsistencies in the clinical genetics literature of association with the val/met polymorphism. Owing to apparent balancing effects of functional variations in putative cis elements in COMT, which, like val/met, show considerable population variation in allele frequencies, 18,20 all val individuals do not show the same pattern of brain functional associations. Our data demonstrate that to the extent that the association of COMT with schizophrenia (or other psychoses) is related to prefrontal functional effects, only a subpopulation of val containing chromosomes will have inefficient prefrontal activity, and some met containing chromosomes will also have a similar functional profile.…”

“…One reason contributing to this apparent discrepancy is that additonal genetic variability in COMT may be important. In support additional genetic of this hypothesis, a haplotype combining rs4680 with two common SNPs, one upstream in intron 1 (rs737865) and the other in the 3 0 untranslated region (rs165599), was highly associated with schizophrenia in a large sample of Israelis of Ashkenazi descent, 18 and differentially affected expression of rs4680 alleles in human brain tissue, 19 suggesting the presence of a cis acting functional locus within COMT interacting with val/met. Another population study found that this three marker haplotype is markedly heterogeneous in populations worldwide 20 despite the relatively constant prevalence of schizophrenia and suggested the relevance of another possible cis functional variant (rs2097603) linked upstream in the P2 promoter driving transcription of the predominant form of COMT in the brain (MB-COMT) (Figure 1).…”

“…18,19 However, the focus of the present analysis are the three functional SNPs implicated in the literature: the coding val 158 met polymorphism (rs4680), 10 a P2 promoter region SNP (rs2097603) 10 and a SNP in the 3 0 region implicated in differential expression (rs165599). 19 Proceeding hierarchically, we first studied single SNP effects, then a 2-SNP haplotype composed of rs4680 and rs2097603, and finally the 3-SNP haplotype composed of these possibly functional variants.…”