Haplotypes in cathechol-O-methyltransferase gene confer increased risk for psychosis in Alzheimer disease

Background: The gene encoding catechol-O-methyltransferase (COMT) has been suggested as a candidate for Alzheimer-related psychosis (AD-P) susceptibility, and an association between AD-P and a functional valine to methionine polymorphism has been reported. Objective: The aim of this study was to assess the genetic contribution of other COMT variants to the risk of AD-P. Methods: Two hundred and forty-six AD patients underwent clinical and neuropsychological examination as well as an evaluation of behavioural and psychiatric disturbances. They were subsequently divided into two subgroups according to the presence (AD-P) or the absence (AD-nP) of psychotic symptoms. Four single-nucleotide polymorphisms (SNPs) within COMT gene were evaluated, i.e. rs737865, rs737864. intron 1 C2754delC, and the well-known valine/methionine variant (rs4680). Analyses were performed on the single locus and pairwise disequilibrium of loci, and multi-locus haplotype. Results: The individual SNP analysis confirmed an association for the valine/methionine variant with AD-P. Haplotype analyses revealed that the alleles at four loci (rs737865, rs737864, intron I C2754delC, rs4680) interacted to create the risk of psychosis in AD, as A-C-C-G haplotype (OR = 2.08, 95% CI = 1.02-4.27, P = 0.044) and G-C-deIC-G haplotype (OR = 2.54, 95% Cl = 1.32-4.90, P = 0.006) in respect to the most common and not-at-risk A-C-C-A haplotype which was significantly overrepresented in AD-P. Conclusions: The present findings provide evidence of COMT genetic vafiations' role in the susceptibility to AD-related psychosis. The observation of a haplotype effect of different polymorphisms within the COMT gene puts emphasis on the usefulness of haplotype analysis in better defining individualized genetic risk profiles in AD. (c) 2006 Elsevier Inc. All rights reserved.