Identification of polymorphisms within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2, and an investigation of their association with schizophrenia and bipolar affective disorder.

We have undertaken a search for polymorphic sequence variation within Disrupted in Schizophrenia 1 and Disrupted in Schizophrenia 2 (DISC1 and DISC2), which are both novel genes that span a translocation breakpoint strongly associated with schizophrenia and related psychoses in a large Scottish family. A scan of the coding sequence, intron/exon boundaries, and part of the 5' and 3' untranslated regions of DISC1, plus 2.7 kb at the 3' end of DISC2, has revealed a novel microsatellite and 15 novel single nucleotide polymorphisms (SNPs). We have tracked the inheritance of four of the SNPs through multiply affected families, and carried out case-control association studies using the microsatellite and four common SNPs on populations of patients with schizophrenia or bipolar affective disorder versus normal control subjects. Neither co-segregation with disease status nor significant association was detected; however, we could not detect linkage disequilibrium between all these markers in the control population, arguing that an even greater density of informative markers is required to test rigorously for association in this genomic region.

Unexplained swelling symptoms in women (idiopathic oedema) comprise one component of a common polysymptomatic syndrome.

BACKGROUND: Non-menstrually-related swelling symptoms (idiopathic oedema) are common in women. The community prevalence of such symptoms, their association with other symptoms, and their underlying aetiology, are uncertain. AIM: To determine the community prevalence of swelling symptoms and the independent contributions of major risk factors. DESIGN: Comparison of major risk factors in women with and without swelling symptoms. METHODS: We assessed 196 women attending a menopause clinic, 201 women attending a fracture clinic and 201 women attending their general practitioner. Each documented family histories of swelling symptoms and diabetes mellitus, age, height and current weight. Women attending the menopause and fracture clinics also completed Visual Analogue Symptom (VAS) scales documenting the perceived severity of swelling symptoms, and of 20 affective, somatic and functional autonomic symptoms. The independent contributions of risk factors to swelling symptom risk were estimated by logistic regression analysis. RESULTS: Of those attending a fracture clinic or their general practitioner, 28% and 33%, respectively, experienced non-menstrually-related swelling symptoms in the month before interview. Severe (RR 43, 95%CI 16-112, p < 0.001) and moderate (RR 7.8, 95%CI 4-15, p < 0.001) affective symptoms, a family history of swelling symptoms (RR 4.5, 95%CI 2.3-8.8, p < 0.001) and a body mass index (BMI) >or=25 kg/m(2) (RR 4.8, 95%CI 2.5-8.9, p < 0.001) were significantly associated with the presence of mild to severe swelling symptoms (VAS 1-9). The prevalence of swelling symptoms increased from 8% in women with no risk factors to 100% in women with three risk factors, which included severe affective symptoms. DISCUSSION: Affective symptom severity provides the principal independent contribution to swelling symptom risk. BMI >or=25 and a family history of swelling symptoms provide smaller independent contributions. The nature of the mechanisms underlying these associations remains uncertain.

The role of diuretics in the aetiology of idiopathic oedema.

The hypothesis that diuretic use and abuse and other purging behaviours cause idiopathic oedema was investigated in 102 patients. Of 91 symptomatic idiopathic oedema patients tested at referral, 16 (17.6%) had diuretic and four (4.4%) laxative in their urine. None had grossly disturbed serum urea and electrolytes. Examination of primary care records from 41 idiopathic oedema patients who denied current diuretic consumption, and denied or were uncertain about past consumption, showed that 20 had not been prescribed diuretics by their general practitioners at any time; a further 18 had not been prescribed diuretics for between seven months and 12 years before referral. The absence of evidence of plasma volume depletion (as judged by similar concentrations of mean serum urea, creatinine, total protein and albumin in patient and age-matched control groups) suggests that neither systematic diuretic and laxative use or abuse, nor episodic overeating and vomiting were responsible for symptoms of idiopathic oedema in our patients. Idiopathic oedema has a strong genetic basis, and correction of major and minor risk factors for this condition leads to substantial amelioration of symptoms in most cases.

Needs for care from a demand led community psychiatric service: a study of patients with major mental illness.

UNLABELLED: OBJECTIVE--To measure needs for care of patients aged 18-65 years with major mental illness. DESIGN: Identification of everyone in one area seen by a health professional within the previous five years because of a psychotic disorder. Interview of a one in three sample of patients and their main carers with the cardinal needs schedule. SETTING--Hamilton, a socially deprived district of Scotland. SUBJECTS--71 subjects were interviewed from the original sample of 263 patients. MAIN OUTCOME MEASURES--"Cardinal problems" in seven clinical and eight social areas of functioning; these are defined as problems requiring action. "Needs"-cardinal problems for which suitable interventions exist but have not been tried recently. RESULTS--High levels of morbidity were found. 30 interviewed patients (42%; 95% confidence interval 31% to 54%) had one or more clinical needs. 35 (49%; 38% to 61%) had one or more social needs. Skills to deal with all but seven needs in the sample were available at the time of investigation. Patients not being seen by the community mental health team were similar in severity and levels of need to those who were on the community team's caseload. Care was unequivocally and severely inadequate for four patients. Shortcomings in service delivery usually arose from failure to monitor some patients at home. Problems were not due to shortage of acute psychiatric beds nor the absence of an elaborate assertive community care team. CONCLUSIONS--Systematic assessment of needs with research instruments can give valuable insights into the successes and failures of community care of people with major mental illness. Most needs could be dealt with in these patients but in our area (and probably most other parts of the United Kingdom) this would entail diversion of resources from people with less severe disorders.

Dimensions and classes of psychosis in a population cohort: a four-class, four-dimension model of schizophrenia and affective psychoses.

BACKGROUND: Classification of psychosis lacks a biological basis and current diagnostic categories may obscure underlying continuities. Data reduction methods of symptom profiles within a population-based cohort of people with a wide range of affective and non-affective psychoses may permit an empirical classification of psychosis. METHOD: OPCRIT (operational criteria) analysis was performed on 387 adults aged 18-65 years in an attempted ascertainment of all patients with psychosis from a geographical area with a stable population. The data were analysed firstly using principal components analysis with varimax rotation to identify factors, and secondly to establish latent classes. Information relating to key variables known to be of relevance in schizophrenia was coded blind to the establishment of the classes and dimensions. RESULTS: Striking correspondence was obtained between the two methods. The four dimensions emerging were labelled 'depression', 'reality distortion', 'mania' and 'disorganization'. Latent classes identified were 'depression', 'bipolar', 'reality distortion/depression' and 'disorganization'. The latent classes corresponded well with DSM-III-R diagnoses, but also revealed groupings usually obscured by diagnostic boundaries. The latent classes differed on gender ratio, fertility, age of onset and self-harming behaviour, but not on substance misuse or season of birth. CONCLUSIONS: Both dimensional and categorical approaches are useful in tapping the latent constructs underlying psychosis. Broad agreement with other similar studies suggests such findings could represent discrete pathological conditions. The four classes described appear meaningful, and suggest that the term non-affective psychosis should be reserved for the disorganization class, which represents only a subgroup of those with schizophrenia.

Mutational screening and association study of glutamate decarboxylase 1 as a candidate susceptibility gene for bipolar affective disorder and schizophrenia.

Recent evidence from postmortem studies suggests that GAD1 encoding the gamma-aminobutyric acid (GABA) synthetic enzyme GAD67 is a functional candidate susceptibility gene for both bipolar affective disorder (BPAD) and schizophrenia. Previous studies suggest linkage between D2S326 near GAD1 and BPAD. We systematically screened GAD1 exons, flanking intronic sequences, and the promoter sequence for polymorphisms in 16 BPAD patients and five controls from Denmark. We identified eight single nucleotide polymorphisms (SNPs) including two in the promoter sequence. An association study of SNPs covering GAD1 was performed in a Danish sample of 82 BPAD subjects and 120 controls and in a Scottish sample of 197 individuals with schizophrenia, 200 BPAD subjects and 199 controls. Linkage disequilibrium (LD) and haplotype frequencies were estimated from genotype data from eight SNPs. Strong pairwise LD was observed among all pairs of neighboring markers. In the Danish sample, we found weak association between BPAD and two promoter SNPs spaced 1 kb apart. Furthermore, one, two, and three loci haplotype analysis showed weak association with BPAD in the Danish sample. The results from the association studies indicate that promoter variants are of importance for the Danish BPAD cases and we cannot reject the hypothesis of GAD1 as a functional candidate gene for BPAD. No association was observed between BPAD or schizophrenia and any of the investigated SNPs in the Scottish sample set. Thus the results obtained from the Scottish sample suggest that the GAD1 gene variants do not play a major role in the predisposition to schizophrenia.