Elisabeth Dawson

Genetic association between alleles of pancreatic phospholipase A2 gene and bipolar affective disorder.

Chromosome 12q is a region of interest for the genetics of bipolar affective disorder because of reports of apparent cosegregation between this disorder and Dariers disease in a small number of families. Findings from a recent linkage study suggest that this chromosomal region may contain a susceptibility gene for bipolar affective disorder. We have found evidence of an allelic association between bipolar disorder and a marker at the pancreatic phospholipase A2 gene (PLA2A) in this region (p ≤ 0.01). These results are consistent with the linkage study, and warrant additional investigations.

β-1,3-Glucuronyltransferase-1 gene implicated as a candidate for a schizophrenia-like psychosis through molecular analysis of a balanced translocation

We have mapped and sequenced both chromosome breakpoints of a balanced t(6;11)(q14.2;q25) chromosome translocation that segregates with a schizophrenia-like psychosis. Bioinformatics analysis of the regions revealed a number of confirmed and predicted transcripts. No confirmed transcripts are disrupted by either breakpoint. The chromosome 6 breakpoint region is gene poor, the closest transcript being the serotonin receptor 1E (HTR1E) at 625 kb telomeric to the breakpoint. The chromosome 11 breakpoint is situated close to the telomere. The closest gene, β-1,3-glucuronyltransferase (B3GAT1 or GlcAT-P), is 299 kb centromeric to the breakpoint. B3GAT1 is the key enzyme during the biosynthesis of the carbohydrate epitope HNK-1, which is present on a number of cell adhesion molecules important in neurodevelopment. Mice deleted for the B3GAT1 gene show defects in hippocampal long-term potentiation and in spatial memory formation. We propose that the translocation causes a positional effect on B3GAT1, affecting expression levels and making it a plausible candidate for the psychosis found in this family. More generally, regions close to telomeres are highly polymorphic in both sequence and length in the general population and several studies have implicated subtelomeric deletions as a common cause of idiopathic mental retardation. This leads us to the hypothesis that polymorphic or other variation of the 11q telomere may affect the activity of B3GAT1 and be a risk factor for schizophrenia and related psychoses in the general population.

An association study of a neurotrophin-3 (NT-3) gene polymorphism with schizophrenia.

Since abnormalities of brain development play a role in the aetiology of schizophrenia, growth factors, known to play a role in neurodevelopment, such as neurotrophin‐3 (NT‐3), are therefore candidate genes for this disorder. The A3/147 bp allele of a dinucleotide repeat polymorphism in the promoter region of the NT‐3 gene has been reported as occurring more frequently in a sample of Japanese schizophrenics compared to controls. We have determined the frequency of alleles of this polymorphism in 175 Caucasian schizophrenic patients and 147 control subjects. The patient and control samples showed no significant deviation from Hardy‐Weinberg equilibrium and, in a test of all alleles, the patients and controls did not differ significantly in allele frequencies. However, the male schizophrenics were more likely than male controls to have the A3/147 bp allele (P= 0.029).

A transmission/disequilibrium study of the DRB1*04 gene locus on chromosome 6p21.3 with schizophrenia.

Patients with schizophrenia rarely develop rheumatoid arthritis, an autoimmune disease that exhibits genetic association with the HLA DRB1*04 gene. We previously investigated the hypothesis that schizophrenia is negatively associated with DRB1*04, and found that only half the expected number of schizophrenic patients had this gene when compared with controls. We now report the results of DRB1*04 genotyping in pedigrees multiply affected with schizophrenia. Polymerase chain reaction amplification and sequence-specific oligonucleotide probes were used to determine the DRB1 genotypes of the 187 members of 23 pedigrees multiply affected with RDC schizophrenia. DQA1, DQB1 and DPB1 genotypes were similarly determined. We analysed data using the extended transmission/disequilibrium test and found a trend for the preferential non-transmission of DRB1*04 alleles from heterozygous parents to their schizophrenic offspring (16 of 23 alleles not transmitted, chi 2 = 3.5, p = 0.06). We found no evidence for a gene of major effect using GENEHUNTER for parametric and non-parametric linkage analysis. The results from this small sample need to be interpreted with caution, but they are in keeping with previous reports and suggest that HLA DRB1*04 alleles may be associated with a reduced risk of schizophrenia.

An association study of debrisoquine hydroxylase (CYP2D6) polymorphisms in schizophrenia

The cytochrome P450 mono-oxygenases are a group of enzymes that metabolize a variety of exogenous and endogenous compounds, some of which are potentially toxic. Individual variations in the metabolism of potential toxins could influence susceptibility to disorders having genetic and environmental components, such as schizophrenia. The frequency of two common mutant alleles of the gene for the cytochrome P450 enzyme debrisoquine-4-hydroxylase (CYP2D6) was determined in 264 Caucasian schizophrenic patients and 217 controls, using the polymerase chain reaction and restriction enzyme digestions. The patient and control samples showed no significant deviation from Hardy-Weinberg equilibrium and the frequency of each mutant allele (CYP2D6A and CYP2D6B) did not differ between patients and controls.

Schizophrenia: A gene at 6p?

Abstract Schizophrenia often exhibits familial clustering; this is suggestive of heritable factors, but the whereabouts of responsible gene(s) has remained elusive. Recent research suggests that a region of chromosome 6p may hold some of the answers.

Genetic mapping of 14 short tandem repeat polymorphisms on human chromosome 22

We have constructed a linkage map of 14 short tandem repeat polymorphisms (11 with heterozygosity > 70%) on the long arm of human chromosome 22 using 23 non-CEPH pedigrees. Twelve of the markers could be positioned uniquely with a likelihood of at least 1,000:1, and distributed at an average distance of 6.62 cM (range 1.5–16.1 cM). The sex-combined map covers a total of 79.6 cM, the female map 93.2 cM and the male map 64.6 cM. Based on comparisons between physical maps and other genetic maps, we estimate that our map covers 70%–80% of the chromosome. The map integrates markers from previous genetic maps and uniquely positions one marker (D22S307). Data from physical mapping on the location of four genetic markers correlates well with our linkage map, and provides information on an additional marker (D22S315). This map will facilitate high resolution mapping of additional polymorphic loci and disease genes on chromosome 22, and act as a reference for building and verifying physical maps.