Robert D. Sanders

A systematic genomewide linkage study in 353 sib pairs with schizophrenia

We undertook a genomewide linkage study in a total of 353 affected sib pairs (ASPs) with schizophrenia. Our sample consisted of 179 ASPs from the United Kingdom, 134 from Sweden, and 40 from the United States. We typed 372 microsatellite markers at approximately 10-cM intervals. Our strongest finding was a LOD score of 3.87 on chromosome 10q25.3-q26.3, with positive results being contributed by all three samples and a LOD-1 interval of 15 cM. This finding achieved genomewide significance (P<.05), on the basis of simulation studies. We also found two regions, 17p11.2-q25.1 (maximum LOD score [MLS] = 3.35) and 22q11 (MLS = 2.29), in which the evidence for linkage was highly suggestive. Linkage to all of these regions has been supported by other studies. Moreover, we found strong evidence for linkage (genomewide P<.02) to 17p11.2-q25.1 in a single pedigree with schizophrenia. In our view, the evidence is now sufficiently compelling to undertake detailed mapping studies of these three regions.

Polymorphisms in the MAOA, MAOB, and COMT genes and aggressive behavior in schizophrenia

Some studies have reported associations between COMT and MAO genotypes and aggression, though results have been inconsistent. We examined the relationship between Overt aggression scale (OAS) scores, and both MAOA and MAOB polymorphisms in a well‐powered sample of 346 subjects with schizophrenia. We also examined COMT in a Stage II replication sample of 150 individuals, and combined these results with our previously reported (Stage I) findings for COMT. We found no evidence of any associations between OAS ratings and any of the polymorphisms investigated under different genetic models. There was no evidence of epistatic interaction between MAOA and COMT on OAS scores. These results fail to support the theory that functional polymorphisms within the MAOA, MAOB, or COMT genes, as determinants of catecholamine enzymatic activity, are risk factors for aggressive behavior.

The high affinity neurotensin receptor gene (NTSR1): comparative sequencing and association studies in schizophrenia

Neurotensin and its high affinity receptor (NTSR1) localise within dopaminergic neurones in the mesocortical, mesolimbic and nigrostriatal systems1, 2, 3, 4, 5 and it is now clear that neurotensin can selectively modulate dopaminergic neurotransmission.2, 3, 6, 7, 8, 9, 10, 11 This has led to the hypothesis that altered neurotensin function contributes to the pathogenesis of schizophrenia and other psychoses. This hypothesis has been supported circumstantially by a number of lines of evidence. (1) Central administration of neurotensin produces effects similar to those produced by the peripheral administration of atypical antipsychotics.12, 13, 14, 15 (2) Observations of low levels of neurotensin in the CSF of schizophrenics.16, 17 (3) Reduced numbers of neurotensin receptors in the brains of schizophrenics.18, 19 Given the above link between neurotensin and dopamine, and the evidence implicating altered neurotensin function in psychosis, we20 have postulated that DNA sequence variation in neurotensin or its receptors might be associated with schizophrenia. In keeping with this hypothesis, an association has recently been reported21 between schizophrenia and the gene encoding the neurotensin high affinity receptor (NTSR1). However, caution is required because the associated marker, a tetranucleotide repeat, is located 3 kb away from the 3′ end of the gene and there is no evidence that it is functional. Therefore, as a follow-up to our earlier work on neurotensin,20 we have now sought to test the hypothesis that DNA sequence variants that alter the structure or expression of the NTSR1 gene (VAPSEs)22 are associated with schizophrenia. However, while we found 14 novel sequence variants in 28 probands with psychosis, none resulted in an amino acid change, and neither direct nor indirect association studies suggested these are involved in susceptibility to schizophrenia.

No evidence for association between a non-synonymous polymorphism in the gene encoding human metabotropic glutamate receptor 7 and schizophrenia.

The cDNA sequence of the gene encoding human metabotropic glutamate receptor type 7 (mGluR7) contains the single nucleotide polymorphism 1536A > T [GenBank sequence X94552 (Makoff et al., 1996)]. This sequence variation is predicted to result in an amino acid change (F433Y) in the gene product and thus has the potential to affect receptor function. Since disturbances in glutamate function have been implicated in the pathophysiology of schizophrenia, we have used a novel and robust polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay to genotype this polymorphism in a case-control sample comprising 181 schizophrenic patients and 182 group-matched unaffected individuals. No evidence was found for association between this polymorphism and schizophrenia. We have also localised mGluR7 to chromosome 3p25-22 using radiation hybrid (RH) mapping.

Comparative sequencing and association studies of aromatic L-amino acid decarboxylase in schizophrenia and bipolar disorder

Aromatic L-amino acid decarboxylase (AADC) is a relatively non specific enzyme involved in the biosynthesis of several classical neurotransmitters including dopamine and 5-hydroxytryptamine (5HT; serotonin).1 AADC does not catalyse the rate limiting step in either pathway, but is rate limiting in the synthesis of 2-phenylethylamine (2PE) which is a positive modulator of dopaminergic transmission and a candidate natural psychotogenic compound.1 We and others have proposed that polymorphism in AADC resulting in altered 2PE activity might contribute to the pathogenesis of psychosis.1,2 In order to test this hypothesis, we have used denaturing high performance liquid chromatography (DHPLC)3 to screen 3943 bases of the aadc gene and its promoter regions for variants that might affect protein structure or expression in 15 unrelated people with schizophrenia, and 15 unrelated people with bipolar disorder. three polymorphisms were identified by dhplc: a insertion/deletion polymorphism in the 5′ utr of the neuronal specific mrna (g.-33–30delagag, bases 586–589 of genbank m77828), a t>a variant in the non-neuronal exon 1 (g.-67t>a, genbank m88070), and a g>a polymorphism within intron 8 (g.ivs8 +75g>A, GenBank M84598). Case-control analysis did not suggest that genetic polymorphism in the AADC gene is associated with liability for developing schizophrenia or bipolar disorder.

Phenotype evaluation and genomewide linkage study of clinical variables in schizophrenia

Genetic factors are likely to influence clinical variation in schizophrenia, but it is unclear which variables are most suitable as phenotypes and which molecular genetic loci are involved. We evaluated clinical variable phenotypes and applied suitable phenotypes in genome‐wide covariate linkage analysis. We ascertained 170 affected relative pairs (168 sibling‐pairs and two avuncular pairs) with DSM‐IV schizophrenia or schizoaffective disorder from the United Kingdom. We defined psychotic symptom dimensions, age at onset (AAO), and illness course using the OPCRIT checklist. We evaluated phenotypes using within sibling‐pair correlations and applied suitable phenotypes in multipoint covariate linkage analysis based on 372 microsatellite markers at ∼10 cM intervals. The statistical significance of linkage results was assessed by simulation. The positive and disorganized symptom dimensions, AAO, and illness course qualified as suitable phenotypes. There were no genome‐wide significant linkage results. There was suggestive evidence of linkage for the positive dimension on chromosomes 2q32, 10q26, and 20q12; the disorganized dimension on 8p21 and 17q21; and illness course on 2q33 and 22q11. The linkage peak for disorganization on 17q21 remained suggestive after correction for multiple testing. To our knowledge, this is the first study to integrate phenotype evaluation and genome‐wide covariate linkage analysis for symptom dimensions and illness history variables in sibling‐pairs with schizophrenia. The significant within‐pair correlations strengthen the evidence that some clinical variables within schizophrenia are suitable phenotypes for molecular genetic investigations. At present there are no genome‐wide significant linkage results for these phenotypes, but a number of suggestive findings warrant further investigation.

Introducing the Measurement of Quality of Life into Clinical Practice: Technology and Mechanisms

Health-related quality of life (QL) is a recognised and important patient-related outcome of anti-cancer treatment, which can be measured by carefully developed, psychometrically robust, questionnaires. Although the validity and sensitivity of the cancer QL questionnaires is now widely accepted and they are frequently used in therapeutic clinical trials, they have yet to impact fully on patients’ care and are little used by practising oncologists. Several barriers have hampered the practical use of QL measures for individual patients, including the logistic barrier of collection and analysis of large amounts of data, the conceptual barrier of determining the clinical meaning of QL scores, the theoretical concerns over whether instruments developed for group comparisons can be used for individual patients, and the lack of research data on the possible benefits for individual patients. Thus, whilst oncology professionals are broadly convinced of the value of the concept and measurement of QL and its utilisation in clinical trials is increasing, its impact on routine clinical practice remains small.