Catechol-O-methyltransferase haplotypes are associated with psychosis in Alzheimer disease

Abstract

Psychotic symptoms in subjects with Alzheimer disease (AD with psychosis, AD þ P) define a phenotype characterized by greater cognitive burden than in AD without psychosis. We have proposed that genes of small effect may contribute to the risk for expression of psychosis in multiple disorders, including AD. Recently, sex-differential association of a three-locus haplotype, including a G-A transition at codon 108/158 of catechol-O-methyltransferase (COMT) resulting in a Val-Met substitution, has been reported to confer an increased risk for schizophrenia. The main objective of the study was to determine if COMT genetic variation is associated with risk of psychosis in AD, and included a case-control study of 373 individuals diagnosed with AD with, or without, psychosis. All subjects were characterized for alleles at the three loci associated with schizophrenia, RS737865, COMT G-A 108/158 (RS4680), and RS165599, and for a C/T transition adjacent to an estrogen response element (ERE6) in the COMT P2 promoter region. Both single locus and haplotype tests of association were conducted. Logit models were used to examine independent and interacting effects of alleles at the associated loci. All analyses were stratified by sex. In female subjects, RS4680 demonstrated a modest association with AD þ P; RS737865 demonstrated a trend towards an association. There was a highly significant association of AD þ P with the four-locus haplotype, which resulted from additive effects of alleles at RS4680 and ERE6 (or RS737865, as this locus was in almost absolute linkage disequilibrium (LD) with ERE6). In male subjects, no single locus test was significant, but there remained a strong association between AD þ P and the four-locus haplotype. This association appeared to result from interaction of the ERE6/ RS737865, RS4680, and RS165599 loci. Genetic variation in COMT is associated with AD þ P, and thus appears to contribute to psychosis risk across disorders. Sex-differential associations of COMT with psychosis may result from variation at, or in LD with, ERE6. Examination of variation at ERE6 in subjects with schizophrenia, and further examination of the independent and additive effects of variations in COMT on gene expression, is warranted.

Catechol-O-Methyltransferase (COMT): A Gene Contributing to Sex Differences in Brain Function, and to Sexual Dimorphism in the Predisposition to Psychiatric Disorders

“…The authors speculate that the finding may be due to a reduced viability of female fetuses carrying this allele. However, to our knowledge, a sex difference in rs165599 allele frequency has not been replicated (eg Sweet et al, 2005; see also Molero et al, 2007)Falbeit no other study has reported on such a large sampleFand so its significance remains unclear. Table 1 is an extensive but not exhaustive list of the studies that have reported a sex difference in the impact of COMT genotype on a psychiatric phenotype.…”

Catechol-O-Methyltransferase GeneticVariant Associated with the Risk of Alzheimer’s Disease in a Brazilian Population

“…Dopaminergic pathways play an important role in the pathogenesis of dementia [13]. This suggests the potential importance of COMT, which has been shown to moderate dopamine metabolism via inhibitory mechanisms [13,22,40,41], and studies have found that dopamine tissue levels are significantly increased in the frontal cortices in COMT knockout mice [19].…”

“…Candidate genes may be identified based on functional information about the disease on genetic map information obtained by tag SNPs and LD [12,13].…”

“…More than 550 other genes have been proposed as candidates for AD susceptibility, but so far none have been firmly established to have a role in the pathogenesis of the disease [12]. Family, linkage, and association studies [13][14][15][16] have considered BPSD a genetically determined factor. Also, dopaminergic neurotransmission has been implicated in many human behaviors and several studies have investigated its relationship with BPSD.…”

Possible Relationship between the COMT Gene Vel¹⁵⁸Met Polymorphism and Psychometric IQ in Girls of the Qinba Region in China

“…Homozygotes with Met show approximately one third less activity than with Val, and heterozygotes have an intermediate level of COMT activity [11] . Val 158 Met polymorphism of COMT affects PFC cognitive functions [12][13][14] and contributes to some psychological illnesses, including schizophrenia, Alzheimer's disease, attention deficit/hyperactivity disorder, bipolar disorder and cognitive ability impairment [15][16][17][18] . But there exists controversy about the effect of variants of COMT on cognitive abilities in normal populations, especially when gender is considered.…”