Reconstruction of ancestral haplotypes in a 12-generation schizophrenia pedigree.

We searched for candidate chromosomal regions inherited identical by descent in 19 patients suffering from schizophrenia or schizoaffective disorder that are related 12 generations back, to an ancestral couple born in the middle of the seventeenth century. To accomplish this goal, we constructed complete chromosomal haplotypes for each patient using genotype data from 450 markers. In total, 12 haplotype regions (with sizes ranging from 0.6 to 10.9 cM) constituted by three markers each were identical in three or more of the affected individuals. The largest genomic segment was located on 6q25, a region previously shown to be significantly more frequent in patients than controls, and proposed to contain a schizophrenia susceptibility locus. For the remaining 11 candidate haplotypes, we estimated haplotype frequencies from all the 43 affected members collected from the same family and 46 unrelated control individuals. This analysis indicated that at least four of the 11 candidate haplotypes are ancestral, since the frequencies were significantly higher in patients than in controls. Five additional haplotypes showed higher estimated frequencies in the patients but the differences were not significant. Interestingly, five of these 11 genomic regions are located in, or close to, candidate regions previously suggested to contain susceptibility genes for schizophrenia. The regions are 5q21-23, 8p21-22, 10p13-15, 13q12-13 and 22q12-13. Several of these haplotypes are probably ancestral linkage disequilibrium blocks inherited from the original couple. There exists, however, the possibility that one or more of these regions harbour schizophrenia susceptibility loci that may have epistatic interactions among them.

Increased monoamine oxidase messenger RNA expression levels in frontal cortex of Alzheimer's disease patients.

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia in the industrialised world. The two monoamine oxidase (MAO) enzymes, monoamine oxidase A (MAOA) and monoamine oxidase B (MAOB), are important in the metabolism of monoamine neurotransmitters. AD and ageing have been shown to increase enzyme activity for both MAOA and MAOB. An increase (rather than decrease) of enzyme activity is a rare event in a disease that results in a decrease in the number of cells in the brain. The mechanism, transcriptional or post-transcriptional, responsible for the increase in protein activity, is not known. In this study, we investigate for the first time the messenger RNA (mRNA) expression levels of both MAOA and MAOB in 246 cortical brain samples obtained at autopsy from 62 AD patients and 61 normal controls. We found a significant increase in mRNA levels for both MAOA (P=0.001) and MAOB (P=0.002) in disease brain tissue. This indicates that both MAO enzymes might be important in the progression of AD.