Marina Myles-Worsley

Schizophrenia and nicotinic receptors

&NA; Patients with schizophrenia often cannot respond to important features of their environment and filter out irrelevant stimuli. This dysfunction could be related to an underlying defect in inhibition‐i.e., the brains ability to alter its sensitivity to repeated stimuli. One of the neuronal mechanisms responsible for such inhibitory gating involves the activation of cholinergic nicotinic receptors in the hippocampus. These receptors are diminished in many specimens of hippocampal brain tissue obtained postmortem from schizophrenic patients. In living schizophrenic patients, stimulation of cholinergic receptors by nicotine transiently restores inhibitory gating of evoked responses to sensory stimuli. Many people with schizophrenia are heavy smokers, but the properties of the nicotinic receptor favor only short‐term activation, which may explain why cigarette smoking is only a transient symptomatic remedy. This paper reviews the clinical phenomenology of inhibitory gating deficits in people with schizophrenia, the neurobiology of such gating mechanisms, and the evidence that some individuals with the disorder may have a heritable deficit in the nicotinic cholinergic receptors involved in this neurobiological function. Inhibitory gating deficits are only partly normalized by neuroleptic drugs and are thus a target for new therapeutic strategies for schizophrenia.

Meta-analysis of 32 genome-wide linkage studies of schizophrenia

A genome scan meta-a nalysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (PSR) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142–168 Mb) and 2q (103–134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119–152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for ‘aggregate’ genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16–33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.

The influence of expertise on X-ray image processing.

Observers with four different levels of radiological experience performed a recognition memory task on slides of faces and chest X-ray films. Half of the X-ray films revealed clinically significant abnormalities and half did not. Recognition memory for faces was uniformly high across all levels of radiological experience. Memory for abnormal X-ray films increased with radiological experience and, for the most experienced radiologists, was equivalent to memory for faces. Surprisingly, recognition memory for normal films actually decreased with radiological experience from above chance to a chance level. These results indicate that radiological expertise is associated with selective processing of clinically relevant abnormalities in X-ray images. Expert radiologists appear to process X-ray images the way that we all process faces, by quickly detecting and devoting processing resources to features that distinguish one stimulus from another. However, the selective processing of X-ray films appears to be restricted to clinically relevant abnormalities. As they develop the ability to detect these abnormalities, radiologists appear to lose the ability to detect variations in normal features.

Codistribution of a sensory gating deficit and schizophrenia in multi-affected families

Because the clinical diagnosis of schizophrenia has not generally been an adequate phenotypic marker to detect the genes that convey risk for schizophrenia, efforts have been directed toward the identification of more elementary neuronal dysfunctions in schizophrenic patients and their families. Psychophysiological studies of sensory gating and selective attention suggest that defects in these brain functions are present in schizophrenic patients and some of their relatives. This study examines one of these defects in sensory gating, failure to suppress the P50 evoked response to repeated auditory stimuli. Six pedigrees, chosen because of the presence of large sibships containing several cases of schizophrenia, were studied. A mathematical model was developed to assess the familial association of the P50 defect with schizophrenia. The model preserves the quantitative nature of the data and is suitable for use in a sample with small numbers of pedigrees comprising many individuals. It is thus suitable for the evaluation of putative phenotypes in families to be studied by linkage analysis with polymorphic genetic markers. The results suggest that the P50 defect is familially associated with schizophrenia.

Linkage of a composite inhibitory phenotype to a chromosome 22q locus in eight Utah families

Eight Utah multigenerational families, each with three to six cases of schizophrenia, were phenotyped with two specific measures of inhibitory neurophysiological functioning, P50 auditory sensory gating (P50), and antisaccade ocular motor performance (AS). A genomewide linkage analysis was performed to screen for loci underlying a qualitative phenotype combining the P50 and AS measures. For this composite inhibitory phenotype, the strongest evidence for linkage was to the D22s315 marker on chromosome 22q (lod score = 3.55, theta = 0) under an autosomal dominant model. Simulation analyses indicate that this 3.55 lod score is unlikely to represent a false positive result. Lod scores were 2.0 or greater for markers flanking D22s315. A nonparametric linkage (NPL) analysis of the chromosome 22 data showed evidence for allele sharing over the broad region surrounding D22s315 with a maximum NPL score of 3.83 (p = .002) for all pedigrees combined.

Evidence for a chromosome 2p13-14 schizophrenia susceptibility locus in families from Palau, Micronesia

A large multiplex schizophrenia pedigree ascertained from the Micronesian nation of Palau was genotyped with 406 microsatellite DNA markers evenly distributed throughout the genome. Assuming autosomal dominant inheritance, the highest genome-wide lod scores were found for DNA loci mapping to 2p13–14; the maximum lod score was 2.17 (theta = 0.05) at D2S441. A nonparametric APM analysis was also suggestive at D2S441 (APM score = 2.96, P = 0.011). Of the 14 affected cases in this extended family, eight share a large haplotype in this region spanning ∼11 cM. When 16 other families containing 65 schizophrenic cases were typed in a follow-up study of this region, the maximum lod score remained positive (maximum at D2S441 1.69, theta = 0.20). APM results also remained positive at D2S441 for all 17 families (APM score = 4.87, P = 0.0006). The linkage and haplotype sharing results provide suggestive evidence for a 2p locus predisposing to schizophrenia in a subset of families in the Palauan population.

P50 sensory gating in adolescents from a pacific island isolate with elevated risk for schizophrenia

BACKGROUND Gating or inhibition of the P50 auditory evoked potential is a heritable neurobiological trait that has shown strong potential to serve as an endophenotype for schizophrenia. P50 sensory gating deficits have been found repeatedly in schizophrenic patients and in their unaffected first-degree relatives. P50 sensory gating has not yet been studied in high-risk (HR) offspring nor in prodromal adolescents. METHODS A paired-stimulus auditory event-related potential paradigm was used to examine P50 sensory gating in 44 genetically HR adolescent offspring and 43 clinically HR prodromal adolescents with the same low genetic liability as a comparison group of 39 normal adolescents. RESULTS Auditory sensory gating, as measured by the P50 ratio, was impaired in both genetically HR offspring and also in the clinically HR prodromal adolescents with no close affected relatives. In the genetically HR group, abnormal P50 sensory gating was found only in offspring who met criteria for the schizophrenia prodrome. CONCLUSIONS Our findings suggest that P50 deficits are associated with the presence of prodromal symptoms, regardless of genetic risk. The results are consistent with the hypothesis that genetic liability in HR offspring increases risk for prodromal symptoms, and prodromal symptoms, in turn, increase risk for impaired sensory gating.

Genomewide Multipoint Linkage Analysis of Seven Extended Palauan Pedigrees with Schizophrenia, by a Markov-Chain Monte Carlo Method

Palauans are an isolated population in Micronesia with lifetime prevalence of schizophrenia (SCZD) of 2%, compared to the world rate of approximately 1%. The possible enrichment for SCZD genes, in conjunction with the potential for reduced etiological heterogeneity and the opportunity to ascertain statistically powerful extended pedigrees, makes Palauans a population of choice for the mapping of SCZD genes. We have used a Markov-chain Monte Carlo method to perform a genomewide multipoint analysis in seven extended pedigrees from Palau. Robust multipoint parametric and nonparametric linkage (NPL) analyses were performed under three nested diagnostic classifications-core, spectrum, and broad. We observed four regions of interest across the genome. Two of these regions-on chromosomes 2p13-14 (for which, under core diagnostic classification, NPL=6.5 and parametric LOD=4.8) and 13q12-22 (for which, under broad diagnostic classification, parametric LOD=3.6, and, under spectrum diagnostic classification, parametric LOD=3.5)-had evidence for linkage with genomewide significance, after correction for multiple testing; with the current pedigree resource and genotyping, these regions are estimated to be 4.3 cM and 19.75 cM in size, respectively. A third region, with intermediate evidence for linkage, was identified on chromosome 5q22-qter (for which, under broad diagnostic classification, parametric LOD=2.5). The fourth region of interest had only borderline suggestive evidence for linkage (on 3q24-28; for this region, under broad diagnostic classification, parametric LOD=2.0). All regions exhibited evidence for genetic heterogeneity. Our findings provide significant evidence for susceptibility loci on chromosomes 2p13-14 and 13q12-22 and support both a model of genetic heterogeneity and the utility of a broader set of diagnostic classifications in the population from Palau.

Developmental and genetic influences on the p50 sensory gating phenotype

Evoked potentials to pairs of click stimuli were recorded from 127 subjects ranging in age from 10 to 39 years to examine the developmental course of auditory sensory gating. The ratio of the amplitude of the second response to that of the first provides a quantitative measure of auditory sensory gating. Contrary to earlier results, the distribution of P50 ratios was unchanged between children and younger adolescents (10-14 years), older adolescents (15-19 years), and adults (20-29 and 30-39 years). Included in the sample were 39 adolescent twins, allowing assessment for possible genetic effects underlying the P50 sensory gating phenotype, by comparison of the similarity of the measure in monozygotic and same-sex dizygotic twin pairs. The monozygotic twins had significantly higher similarity for the P50 ratio within each twin pair than the dizygotic twins. These results are consistent with the presence of genetic influences on the P50 sensory gating phenotype.

Use of a neurophysiological trait in linkage analysis of schizophrenia

Traditional diagnostic techniques may not provide all the information necessary to reveal the genetic causes of schizophrenia through linkage analysis. Use of neurophysiological indicator variables that are associated with the disease may increase the probability of detecting linkage. Such variables not only produce simpler phenotypes for analysis, but they also may be more proximal to the gene products involved in neurological dysfunctions underlying schizophrenia. We have used a previously characterized neurophysiological variable, the P50 evoked-auditory response, to search for chromosomal regions that may be of interest in the study of schizophrenia. Although our scan of over 300 markers did not show strong evidence for linkage to P50 in nine families, this exploratory analysis has revealed several chromosomal regions that may deserve further study.