Neil Hunt

Life events and relapse in bipolar affective disorder

In a 2 year study of life events and relapse in a cohort of 62 patients with bipolar affective disorder, an excess of events was found during the month immediately preceding relapse. Of 52 relapses 19% were preceded by a severe event in the previous month, compared to a background rate of 5% of patients experiencing a severe event each month at other times. The rate of life events prior to relapse was not apparently different between manic and depressive relapse, though the number of depressive episodes was small.

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.

Does puerperal illness distinguish a subgroup of bipolar patients

Puerperal psychosis was found to be the 1st illness for 13 (36%) of a series of 36 mothers with bipolar affective disorder. The risk of recurrence with childbirth in those with established bipolar disorder was found to be 25-40%. Those women who survived childbirth without illness but then became ill at a later time reported a worse illness course. Recent fatherhood was not a precipitant of 1st affective illness for any of the 28 bipolar men.

Tyrosine hydroxylase polymorphisms and bipolar affective disorder

A reported genetic association between bipolar affective disorder and DNA polymorphisms at the tyrosine hydroxylase gene is not confirmed by the present study. The combined allele frequencies in the patients, from studies published to date, are significantly different from the frequencies in the controls for the TY7/BglII polymorphism.

Association and haplotype analysis at the tyrosine hydroxylase locus in a combined German-British sample of manic depressive patients and controls.

Tyrosine hydroxylase (TH) is the key enzyme in the synthesis of catecholamines and may therefore be of aetiological relevance in the development of psychiatric illness. Hipolar affective disorder association studies, with restriction fragment length polymorphisms located in flanking regions of the TH gene, have shown conflicting results. Alleles of a tetranucleotide repeat polymorphism (TH4) located in intron 1 of the gene were tested for association with bipolar affective disorder in a combined German and British sample of 183 bipolar patients and 209 healthy control probands. No differences in TH4 allele frequencies were found in the two groups. A subset of patients and controls was typed with the flanking markers Ty7/Bg/II and pJ4.7/TaqI and frequencies of two-locus haplotypes were estimated. Linkage disequilibrium was found between TH4-Ty7 and TH4-pJ4.7. Haplotype frequencies did not differ between patients and controls.

The dopamine D3 receptor gene: no association with bipolar affective disorder

Bipolar affective disorder and schizophrenia share many clinical and genetic characteristics, and are thought by some to be different expressions of the same underlying disorder. A recent study showed an excess of homozygosity at a BalI polymorphism in the dopamine D3 receptor gene in schizophrenic patients compared with controls, from two independent centres. We have found no evidence of such an excess in a comparable sample of patients with bipolar affective disorder compared with matched controls. If these findings are confirmed then at least one genetic distinction between these two disorders will have been ascertained and doubt cast upon theories of a common genetic aetiology.

Tardive dyskinesia in bipolar affective disorder : a catchment area study

The prevalence of tardive dyskinesia in a consecutive series of 69 patients with bipolar affective disorder admitted to a catchment area service was found to be 19%. Prevalence increased with age and was related to the age of onset of bipolar disorder and number of previous episodes. Patients with tardive dyskinesia were significantly slower on a simple test of cognitive function (Trails B).

GABAA receptor subunit genes as candidate genes for bipolar affective disorder - an association analysis

Polymorphic DNA segments can be used as genetic markers to test for allelic association between a disease and a candidate gene locus. Here we report the results of a study of 60 unrelated bipolar patients in which we sought for evidence of association between bipolar affective disorder and alleles at two candidate genes (GABRA1 and GABRA3) involved in GABAergic neurotransmission. The data obtained were analysed in a number of ways. None of these produced conclusive evidence for association, although allele A6 at the GABRA1 locus was significant (p = 0.025) before correcting for multiple testing.

GABA-A receptor subunit genes. An association analysis

GABA is the main inhibitory neurotransmitter in the brain. The main GABA receptor, GABA-A, contains several receptor subunits. cDNA clones for 4 of these subunits have been mapped to their respective genetic loci (Buckle et al., 1989) and dinucleotide repeat polymorphisms for two of these genes, coding the alpha-l (5~34-35) and alpha-3 (Xq28) receptor subunits, have been identified (Sander et al., 1991; Hicks et al., 1991). Genes involved in the GABA system may be considered candidate genes in psychoses. Using the dinucleotide repeat polymorphisms at Xq28 (subunit alpha-3) and 5~34-35 (subunit alpha-l) we examined for evidence of allelic association with bipolar affective disorder. This was achieved by comparing the distribution of allele frequencies in a sample of unrelated affected individuals (n= 60) with the distribution in a sample of unrelated matched controls (n = 59). Enzymatic amplification of genomic DNA was performed using the polymerase chain reaction and synthetic oligonucleotide primers flanking the dinucleotide repeats. Products were electrophorised on 6% polyacrylamide gels. Genotyping was conducted blind to diagnostic status. Allele frequencies at both loci were determined. These data were analysed for evidence of association by: (I) testing each allele separately; (2) testing all alleles at each locus simultaneously; (3) logistic regression. When each allele at the GABA alpha-l locus was tested separately the difference in frequency of allele 5 (A5) reached the 0.05 level of significance (p=O.O16). However, this was not maintained when corrected for multiple testing (critical pvalue = 0.0073).