W. J. Muir

Auditory P300 event-related potentials and neuropsychological performance in schizophrenia and bipolar affective disorder

The auditory P300 event-related potential (ERP) and performance on neuropsychological tests were evaluated in 26 subjects with schizophrenia, 19 with bipolar affective disorder, and 27 controls. The schizophrenic and the bipolar groups were similar in having prolonged P300 latency recorded from central and temporal leads. The P300 was significantly reduced in amplitude in the schizophrenic group at midline leads and the left temporal lead but was not significantly reduced in amplitude at any electrode site when the bipolar group was compared to controls. Schizophrenics performed significantly less well than bipolars and controls on tests of verbal fluency and, within this group, a significant correlation was found between the latency of P300 and verbal fluency test scores. While the bipolar group of patients was similar to the schizophrenic group in having prolonged P300 latency, these groups differed in P300 amplitude, performance on verbal fluency tests, and the relationship between the physiological and neuropsychological variables.

A common variant in the 3′UTR of the GRIK4 glutamate receptor gene affects transcript abundance and protects against bipolar disorder

Underactivity of the glutamatergic system is an attractive model for the pathophysiology of several major mental illnesses. We previously described a chromosome abnormality disrupting the kainate class ionotropic glutamate receptor gene, GRIK4/KA1, in an individual with schizophrenia and learning disability (mental retardation). We also demonstrated in a case-control study that two physically separated haplotypes within this gene were significantly associated with increased risk of schizophrenia and decreased risk of bipolar disorder, respectively. The latter protective haplotype was located at the 3′ end of the gene. We now report the identification from carriers of the protective haplotype of a deletion variant within the 3′ untranslated region of the gene. The deletion allele also was found to be negatively associated with bipolar disorder in both initial (P = 0.00000019) and replication (P = 0.0107) case-control studies. Expression studies indicated that deletion-carrying mRNA transcripts were relatively more abundant. We postulate that this may be a direct consequence of the differences in the RNA secondary structures predicted for the insertion and deletion alleles. These data suggest a mechanism whereby the genetic protective effect is mediated through increased kainate receptor expression.

Genetic survival analysis of age-at-onset of bipolar disorder: evidence for anticipation or cohort effect in families

Age-at-onset (AAO) in a number of extended families ascertained for bipolar disorder was analysed using survival analysis techniques, fitting proportional hazards models to estimate the fixed effects of sex, year of birth, and generation, and a random polygenic genetic effect. Data comprised the AAO (for 171 affecteds) or age when last seen (ALS) for 327 unaffecteds, on 498 individuals in 27 families. ALS was treated as the censored time in the statistical analyses. The majority of individuals classified as affected were diagnosed with bipolar I and II (nu2005 =u2005103) or recurrent major depressive disorder (nu2005 =u200568). In addition to the significant effects of sex and year of birth, a fitted ‘generation’ effect was highly significant, which could be interpreted as evidence for an anticipation effect. The risk of developing bipolar or unipolar disorder increased twofold with each generation descended from the oldest founder. However, although information from both affected and unaffected individuals was used to estimate the relative risk of subsequent generations, it is possible that the results are biased because of the ‘Penrose effect’. Females had a twofold increased risk in developing depressive disorder relative to males. The risk of developing bipolar or unipolar disorder increased by approximately 4% per year of birth. A polygenic component of variance was estimated, resulting in a ‘heritability’ of AAO of approximately 0.52. In a family showing strong evidence of linkage to chromosome 4p (family 22), the ‘affected haplotype’ increased the relative risk of being affected by a factor of 46. In this family, there was strong evidence of a time trend in the AAO. When either year of birth or generation was fitted in the model, these effects were highly significant, but neither was significant in the presence of the other. For this family, there was no increase in trinucleotide repeats measured by the repeat expansion detection method in affected individuals compared with control subjects. Proportional hazard models appear appropriate to analyse AAO data, and the methodology will be extended to map quantitative trait loci (QTL) for AAO.

Cytogenetics and gene discovery in psychiatric disorders

The disruption of genes by balanced translocations and other rare germline chromosomal abnormalities has played an important part in the discovery of many common Mendelian disorder genes, somatic oncogenes and tumour supressors. A search of published literature has identified 15 genes whose genomic sequences are directly disrupted by translocation breakpoints in individuals with neuropsychiatric illness. In these cases, it is reasonable to hypothesise that haploinsufficiency is a major factor contributing to illness. These findings suggest that the predicted polygenic nature of psychiatric illness may not represent the complete picture; genes of large individual effect appear to exist. Cytogenetic events may provide important insights into neurochemical pathways and cellular processes critical for the development of complex psychiatric phenotypes in the population at large.

Reduced expression of HLA-B35 in schizophrenia.

The frequencies of HLA class I (HLA-A, B, C) and class 11 (HLA-DR, DQ) antigens were measured in 107 unrelated schizophrenic subjects and the results compared with 264 controls from south-east Scotland and a second control group of 133 individuals from north-east England. The expression of HLA-B35 was significantly reduced in the schizophrenic population compared to both control populations and these differences remained significant after correction for multiple testing. Linkage of schizophrenia and the major histocompatibility complex region of chromosome 6p was, however, excluded in a group of 17 families multiply affected with schizophrenia. Linkage was also excluded with several red cell antigens, red cell enzymes and plasma proteins. A negative association between the frequency of an HLA antigen and schizophrenia suggests that immune mechanisms may contribute to the aetiology of the disease in some subjects.

Segregation analysis of complex phenotypes: an application to schizophrenia and auditory P300 latency.

: Traditional models of the genetic transmission of human diseases have often assumed that the phenotype is a simple dichotomous trait, which is unrealistic for many psychiatric conditions, and may result in loss of valuable information. We describe a new model for complex phenotypes, implemented in the program COMDS, which subclassifies normal and affected individuals into polychotomies correlated with the underlying genetic liability to the disorder. The model is applied to 18 Scottish pedigrees ascertained for schizophrenia, in which auditory P300 latency had been measured as a possible correlate of the genetic predisposition to schizophrenia. The results suggest that there may be a major locus for schizophrenia, but that there are also other familial determinants, possibly a second modifier locus. In addition, the results indicate that auditory P300 latency may be a useful measure of the genetic predisposition to schizophrenia among asymptomatic relatives, although the relationship between P300 latency and the degree of genetic predisposition in clinical cases was not significant, presumably because other factors are operating on P300 latency. Because of the possible selection biases in this sample, there is a need to replicate these findings in systematically ascertained pedigrees.

A long-range restriction map across 3 Mb of the chromosome 11 breakpoint region of a translocation linked to schizophrenia: localization of the breakpoint and the search for neighbouring genes

A balanced t(1;11)(q42.1;q14.3) translocation segregates with schizophrenia and related mental illness in a single large Scottish pedigree. We have constructed a long-range restriction map covering at least 3 Mb of the chromosome 11 breakpoint region and conducted searches for genes whose expression could be altered by the translocation, resulting in schizophrenia. Novel transcribed sequences of unknown function clustered around putative CpG islands, located approximately 500 kb and 700 kb above the breakpoint, represent the only evidence to date for expressed genes within the mapped region.

An allelic association study of two polymorphic markers in close proximity to a balanced translocation t(1:11) that co-segregates with mental illness

We report a case control association study using polymorphic markers D1S1621 and D11S931 in unrelated individuals with schizophrenia, unipolar depression and a matched control group. The two polymorphic markers were identified during the positional cloning of the translocation breakpoint t(1:11)(q43:q14.3) that cosegregates with schizophrenia and affective disorders. These markers provided an opportunity to investigate linkage disequilibrium with a postulated schizophrenia susceptibility gene close to the translocation breakpoint in random populations of schizophrenia and unipolar depression individuals compared with a normal control population. No significant differences between allele frequencies for either of the markers in the affected populations were observed in comparison with the control group, which provides evidence against a nearby gene of major effect in the populations studied.

Molecular biology of schizophrenia

To date, the molecular biology of and the genes responsible for schizophrenia are unknown. However, the powerful techniques for gene mapping and mutation analysis now available mean the situation should change and it is likely that a variety of genes involved in schizophrenia are likely to be mapped, cloned and characterized within the next few years. Initial over-optimism should not be replaced by pessimism as to the future prospects.

Segregation analysis of complex phenotypes: An application to schizophrenia and auditory P300 latency

Traditional models of the genetic transmission of human diseases have often assumed that the phenotype is a simple dichotomous trait, which is unrealistic for many psychiatric conditions, and may result in loss of valuable information. We describe a new model for complex phenotypes, implemented in the program COMDS, which subclassifies normal and affected individuals into polychotomies correlated with the underlying genetic liability to the disorder. The model is applied to 18 Scottish pedigrees ascertained for schizophrenia, in which auditory P300 latency had been measured as a possible correlate of the genetic predisposition to schizophrenia. The results suggest that there may be a major locus for schizophrenia, but that there are also other familial determinants, possibly a second modifier locus. In addition, the results indicate that auditory P300 latency may be a useful measure of the genetic predisposition to schizophrenia among asymptomatic relatives, although the relationship between P300 latency and the degree of genetic predisposition in clinical cases was not significant, presumably because other factors are operating on P300 latency. Because of the possible selection biases in this sample, there is a need to replicate these findings in systematically ascertained pedigrees.