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 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.
Borroni
B
B
Center for Aging Brain and Dementia, Department of Neurology, University of Brescia, Italy. bborroni@inwind.it <bborroni@inwind.it>
Grassi
M
M
Costanzi
C
C
Zanetti
M
M
Archetti
S
S
Franzoni
S
S
Caimi
L
L
Padovani
A
A
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D016009:Chi-Square Distribution; D003071:Cognition / Q000502:physiology; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008715:Methionine / Q000235:genetics; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011618:Psychotic Disorders / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D012306:Risk; D014633:Valine / Q000235:genetics
D008715:Methionine; D002394:Catechol O-Methyltransferase; D014633:Valine