Universal, robust, highly quantitative SNP allele frequency measurement in DNA pools.

Detecting alleles that confer small increments in susceptibility to disease will require large-scale allelic association studies of single-nucleotide polymorphisms (SNPs) in candidate, or positional candidate, genes. However, current genotyping technologies are one to two orders of magnitude too expensive to permit the analysis of thousands of SNPs in large samples. We have developed and thoroughly validated a highly accurate protocol for SNP allele frequency estimation in DNA pools based upon the SNaPshot (Applied Biosystems) chemistry adaptation of primer extension.

Dopamine transporter gene (DAT1) VNTR polymorphism in major psychiatric disorders: family-based association study in the Bulgarian population.

Objective: A 40-bp variable number tandem repeat in the 3'-UTR of dopamine transporter gene (DAT1) has been examined for association with major psychiatric disorders in several case-control studies. No significant results have been found. We used a new collection of parent-offspring trios to test for association with schizophrenia (SZ), bipolar 1 disorder (BPI) and schizoaffective (SA) disorder.

Sibling pairs with affective disorders: resemblance of demographic and clinical features.

Background: As part of a collaborative linkage study, the authors obtained clinical and demographic data on 160 families in which more than one sibling was affected with a bipolar illness. The aim of the study was to identify clinical characteristics that had a high degree of familiality.

Method: Data on age at onset, gender, frequency of illness-episodes and proportion of manic to depressive episodes were examined to determine intra-pair correlations in affected sibling pairs.

The Wellcome trust UK-Irish bipolar affective disorder sibling-pair genome screen: first stage report.

We have completed the first stage of a two-stage genome wide screen designed to identify chromosomal regions that may harbour susceptibility genes for bipolar affective disorder. The first stage screening sample included 509 subjects from 151 nuclear families recruited within the United Kingdom and Republic of Ireland. This sample contained 154 narrowly defined affected sibling pairs (DSM-IV BPI) and 258 broadly defined affected sibling pairs (DSM-IV BPI, SABP, BPII, BPNOS or MDD(R)), approximately two thirds of all families contained at least one other additional typed individual.

Screening ABCG1, the human homologue of the Drosophila white gene, for polymorphisms and association with bipolar affective disorder.

ABCG1 encodes a transporter protein that may be involved in the cellular uptake of tryptophan. Tryptophan is the precursor for serotonin, which is implicated in the regulation of mood. The gene maps to chromosome 21q22.

[Plastic surgical repair according to Lazar da Silva in large median eventrations].

Lazaro da Silva's technique is postulated as a method free of relapses provided autologous endogenous tissues are made use of. It consists in the raising of three flaps cut from the hernial sac, anterior and posterior sheats of the rectus abdominis muscles. The suture lines lie in three different anatomical planes, thereby promoting restoration of the integrity and anatomical patterns of the anterior abdominal wall.

Association analysis of NOTCH4 loci in schizophrenia using family and population-based controls.

A genetic association between NOTCH4 and schizophrenia has previously been proposed. Unsing all markers previously shown to be associated, we found no evidence for such in three independent family-based samples (n=519 parent-offspring trios), and a case-control sample derived from the same ethnic background as the original observation. These data strongly suggest that NOTCH4 is not a significant susceptibility allele for schizophrenia.

A functional polymorphism in the promoter of monoamine oxidase A gene and bipolar affective disorder.

The genes encoding for the enzymes monoamine oxidase (MAO) A and B are good candidates to investigate bipolar affective disorder. A 30 bp repeat in the MAOA promoter was recently demonstrated to be polymorphic and to affect transcriptional activity. In a family-based association design we found that none of the different repeat copies was preferentially transmitted from mothers (n = 131) to their children affected with bipolar disorder (chi(2) = 2.

No evidence of association from transmission disequilibrium analysis of the hKCa3 gene in bipolar disorder.

Objective: A recent case control study has suggested that modest enlargements of a highly polymorphic CAG repeat in exon 1 of the gene encoding potassium channel hKCa3 may be associated with bipolar disorder (BPD). We have examined this hypothesis by genotyping this locus in a family-based association study.

Method: One hundred and twenty-eight parent offspring trios of British Caucasian origin were examined where the proband was diagnosed with the American Psychiatric Association's Diagnostic and Statistical Manual (DSM)-IV BPD I (n = 123) or II (n = 5).

Cheap, accurate and rapid allele frequency estimation of single nucleotide polymorphisms by primer extension and DHPLC in DNA pools.

At present, the cost of genotyping single nucleotide polymorphisms (SNPs) in large numbers of subjects poses a formidable problem for molecular genetic approaches to complex diseases. We have tested the possibility of using primer extension and denaturing high performance liquid chromatography to estimate allele frequencies of SNPs in pooled DNA samples. Our data show that this method should allow the accurate estimation of absolute allele frequencies in pooled samples of DNA and also of the difference in allele frequency between different pooled DNA samples.

Pooled genotyping of microsatellite markers in parent-offspring trios.

We studied the extent to which genotyping of simple sequence repeat polymorphisms (SSRs) in pooled DNA samples can be used to predict differences in allele frequencies between parents and their affected offspring. We also developed a simple method of correction for the effects of stutter and differential amplification on the analysis of SSRs in pooled DNA samples based on widely available software. We genotyped individually eight polymorphic microsatellite markers in 110 parent-offspring trios affected with bipolar affective disorder (BP).

Family-based association studies of bipolar disorder with candidate genes involved in dopamine neurotransmission: DBH, DAT1, COMT, DRD2, DRD3 and DRD5.

The dopaminergic system has been implicated in the aetiology of mood disorders. We conducted family-based association studies for polymorphisms at three genes involved in the metabolism of dopamine: dopamine transporter (DAT1), dopamine-beta-hydroxylase (DBH) and catechol-O-methyl transferase (COMT); and three dopamine receptors: DRD2, DRD3 and DRD5. We used a sample of 122 parent-offspring trios of British Caucasian origin where the proband had bipolar disorder I (BPI), and analysed the results with the transmission/disequilibrium test (TDT) which is robust to hidden population stratification.

Two novel variants in the DOPA decarboxylase gene: association with bipolar affective disorder.

DOPA decarboxylase (DDC), also known as aromatic L-amino acid decarboxylase (AADC), is an enzyme involved in the synthesis of the important neurotransmitters dopamine, norepinephrine, and serotonin. In addition, it participates in the synthesis of trace amines; compounds suggested to act as endogenous modulators of central neurotransmission. Thus, DDC is regarded as a potential susceptibility gene for a variety of neuropsychiatric disorders.

Bipolar disorder and the serotonin transporter gene: a family-based association study.

Background: The human serotonin transporter gene (5-HTT) is a strong candidate for involvement in the pathogenesis of mood disorders. Two common polymorphisms have been identified in the gene: a VNTR in intron 2 and a functional deletion/insertion in the promoter region. In previous studies we proposed that allele 12 of the VNTR might increase susceptibility for bipolar disorder.

Ethnic differences in the presentation of bipolar affective disorder.

There have been repeated reports that Afro-Caribbean people living in the UK are more prone than white people to be diagnosed as having schizophrenia and mania, along with some evidence that they are less likely to receive a diagnosis of depression. We attempted to replicate these findings in a population of patients on lithium prophylaxis. We therefore assessed the clinical characteristics of people under the age of 55 from three ethnic groups attending a lithium clinic in south London, those of (1) white British (n = 88); (2) Afro-Caribbean (n = 31); and, (3) African (n = 15) origin.

Linkage studies of bipolar disorder with chromosome 18 markers.

Evidence consistent with the existence of genetic linkage between bipolar disorder and three regions on chromosome 18, the pericentromeric region, 18q21, and 18q22-q23 have been reported. Some analyses indicated greater evidence for linkage in pedigrees in which paternal transmission of disease occurs. We have undertaken linkage analyses using 12 highly polymorphic markers spanning these three regions of interest in a sample of 48 U.

Association analysis between dopamine receptor genes and bipolar affective disorder.

We have performed a case-control analysis of dopamine D2-like receptor (DRD2, DRD3 and DRD4) gene polymorphisms in 118 Han Chinese cases with bipolar affective disorder and 196 control subjects, and replication analysis in 157 English cases and 143 control subjects. We found association between a functional DRD2 promoter variant (P = 0.03 by allele) and the DRD2 taq1A polymorphism (P = 0.

Linkage analysis between bipolar affective disorder and markers on chromosome X.

Since 1969, several classical linkage studies suggested an X-chromosome locus for bipolar affective disorder. However, methods using highly polymorphic DNA markers have provided conflicting evidence for linkage, and an X-chromosomal locus for bipolar disorder remains controversial. More recently, Pekkarinen et al.

Cost-effectiveness evaluation of compliance therapy for people with psychosis.

Background: Non-compliance rates with antipsychotic medication can be high, and the personal and societal costs are considerable. A new psychological intervention, compliance therapy seeks to improve compliance and patient outcomes and reduce treatment costs.

Method: A randomised controlled study examined the cost-effectiveness of compliance therapy compared to non-specific counselling over 18 months for 74 people with psychosis admitted as inpatients at the Maudsley Hospital.