Biomedical subjects
P Asherson
Publications and source records attributed to P Asherson.
Failure to find linkage between schizophrenia and genetic markers on chromosome 21.
We sought evidence for the involvement of mutations in the amyloid precursor protein gene (APP) in the pathogenesis of schizophrenia in two ways. First, linkage analysis was performed in a sample of 24 families multiply affected with schizophrenia. The genotypes were studied for GT12 (D21S210), a highly polymorphic microsatellite marker at the APP locus. Second, we used single strand conformation analysis (SSCA) to screen for mutations in exon 17 of APP in one affected member from each family and in a sample of 44 unrelated patients. In addition, we looked for linkage between schizophrenia and a series of highly polymorphic markers situated at approximately 20cM intervals along the long arm of chromosome 21. We were unable to find evidence for linkage to GT12 or the other markers studied. SSCA did not reveal any mutations in exon 17 of AP. We conclude that mutations within APP are an unlikely cause of schizophrenia. Moreover, this study provides no evidence for a major gene for schizophrenia on chromosome 21, and linkage can be excluded from much of this region under some genetic models.
A linkage study of schizophrenia with DNA markers from the long arm of chromosome 11.
We report the results of a collaborative linkage study using 12 polymorphic markers (9 loci) from the long arm of chromosome 11, and 24 families multiply affected with schizophrenia and other closely related disorders. This region is of interest because several families have been reported in which balanced translocations involving 11q apparently co-segregate with psychotic illness. In addition, the dopamine D2 receptor, porphobilinogen deaminase, and tyrosinase genes map within the region studied and may be aetiologically involved in schizophrenia. We have primarily analysed genotypic data by the LOD score method using a range of single gene models. In order to minimize error due to mis-specification of genetic parameters we have analysed data from markers at candidate gene loci by the non-parametric extended sib-pair method in addition to the LOD score method. Our results suggest that most of the region can be excluded from containing a gene of major effect in the aetiology of this disease.
Schizophrenia scepticism.
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Association between schizophrenia and homozygosity at the dopamine D3 receptor gene.
Disturbances in dopamine neurotransmission have been postulated to underlie schizophrenia. We report data from two independent studies of a BalI polymorphism in the dopamine D3 receptor gene in patients with schizophrenia. In both studies, more patients than controls were homozygous (p = 0.005, p = 0.008). When pooled data were analysed, this difference was highly significant (p = 0.0001) with a relative risk of schizophrenia in homozygotes of 2.61 (95% confidence intervals 1.60-4.26).
No evidence for a pseudoautosomal locus for schizophrenia. Linkage analysis of multiply affected families.
Evidence for a pseudoautosomal locus for a schizophrenia susceptibility gene was sought by two forms of analysis of 25 multiply affected families. Firstly, in the sample as a whole there was an excess of same-sex over mixed-sex siblings compared with that expected. Secondly, linkage analysis was performed in six of the families. The genotypes were studied for DXYS14, a highly polymorphic marker in the telomeric pseudoautosomal region. No evidence for positive linkage was found with two-point analysis under eight different genetic models for the mode of transmission. A non-parametric, sibling-pair analysis also failed to detect linkage. Our findings provide no evidence for linkage within the pseudoautosomal region; same-sex concordance must arise from some other mechanism.
No association between RFLPs at the porphobilinogen deaminase gene and schizophrenia.
An association study of restriction fragment length polymorphisms (RFLPs) in the porphobilinogen deaminase (PBGD) gene and schizophrenia was conducted. RFLPs detected by MspI, PstI, ApaLI and BstNI in intron 1 of the gene were studied in 49 patients and 79 controls. There were no significant differences between the groups in allele frequencies, genotype counts or haplotype distribution.
No evidence for linkage between schizophrenia and eight microsatellite markers on chromosome 19.
We report the results of a linkage study of eight markers on chromosome 19 in a sample of 24 families multiply affected with schizophrenia and related psychoses. This study forms part of a systematic search of the entire genome using microsatellite markers spaced at 10-20 cM intervals. These data provide no evidence for the presence of a gene of major effect on chromosome 19 under the assumption of genetic homogeneity or heterogeneity. We have attempted to describe the extent to which this region has been excluded and demonstrate that while it is possible to exclude near-dominant and recessive models under the assumption that all families are linked to the same locus, power for exclusion falls away rapidly when incomplete penetrance and heterogeneity are invoked.