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

Borroni, B.; Grassi, M.; Costanzi, C.; Zanetti, M.; Archetti, S.; Franzoni, S.; Caimi, L.; Padovani, A.

doi:10.1016/j.neurobiolaging.2006.05.027

« Previous Next »Neurobiology of Aging
Volume 28, Issue 8 , Pages 1231-1238, August 2007

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

B. Borroni
- Center for Aging Brain and Dementia, Department of Neurology, University of Brescia, Italy
- Corresponding author at: Clinica Neurologica, Università degli Studi di Brescia, Pza Spedali Civili, 1-25100 Brescia, Italy. Tel.: +39 0303995632; fax: +39 0303995027.
M. Grassi
- Department of Health Sciences, Section of Medical Statistics & Epidemiology, University of Pavia, Italy
C. Costanzi
- Center for Aging Brain and Dementia, Department of Neurology, University of Brescia, Italy
M. Zanetti
- Center for Aging Brain and Dementia, Department of Neurology, University of Brescia, Italy
S. Archetti
- III Laboratory of Biotechnology, University of Brescia, Italy
S. Franzoni
- Alzheimer Centre, Palazzolo S/O, Brescia, Italy
L. Caimi
- III Laboratory of Biotechnology, University of Brescia, Italy
A. Padovani
- Center for Aging Brain and Dementia, Department of Neurology, University of Brescia, Italy

Received 2 March 2006; received in revised form 16 May 2006; accepted 21 May 2006. published online 13 July 2006.

Abstract

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 1 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-delC-G haplotype (OR=2.54, 95% CI=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 variations’ 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.

Keywords: Alzheimer disease, Psychosis, Catechol-O-methyltransferase (COMT), Polymorphism, Haplotype