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W Byerley

Publications and source records attributed to W Byerley.

At least 19 recordsLinked to original sources
PubMed2000

The ascertainment of multiplex schizophrenia pedigrees from Daghestan genetic isolates (Northern Caucasus, Russia).

This article describes the preliminary ascertainment of multiplex schizophrenia pedigrees from the isolated mountain region of Daghestan (Northern Caucasus, Russia). Daghestan has a population of two million people and contains 26 aboriginal ethnic groups. Many of the ethnic groups reside in remote mountain villages that can be classified as 'primary isolates'. Prolonged reproductive isolation and severe environmental conditions in the highlands have created diverse, genetically isolated ethnic populations in Daghestan. A number of the isolates in this region contain large extended multiplex schizophrenia pedigrees that are ideal for genetic analyses. During summer expeditions of 1996 and 1997, 14 separate large multiplex schizophrenia pedigrees were ascertained from 14 different mountain villages. Of the 14 kindreds, one had 50 schizophrenic cases available for ascertainment, one had 32, and another had 24. Seven of the remaining pedigrees had between 11 and 23 living cases. Within the kindreds, the number of males with chronic schizophrenia was at least twice that of females. The average age of onset of schizophrenia is 21.2 years for offspring of consanguineous marriages and 17.4 years for offspring of nonconsanguineous marriages (P = 0.033). Although the pedigrees ascertained from the remote mountain villages may not be representative of the general population, they are unique kindreds for mapping schizophrenia susceptibility genes.

Ethnicity↗
PubMed1999

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.

Acoustic Stimulation↗
PubMed1999

Genetic epidemiological study of schizophrenia in Palau, Micronesia: prevalence and familiality.

We are studying the genetic etiology of schizophrenia in the Republic of Palau, a remote island nation in Micronesia that has been geographically and ethnically isolated for approximately 2,000 years. The first epidemiological phase sought to estimate the lifetime prevalence of schizophrenia and evaluate the familiality of the illness based on complete ascertainment of cases and families segregating schizophrenia. A total of 160 strictly defined cases of schizophrenia were ascertained in a population of 13,750 adults who were 15 years of age and older. The lifetime prevalence of strictly defined schizophrenia in Palau was 1.99% overall and 2.77% in males vs. 1.24% in females. This greater than 2:1 male-to-female risk ratio for schizophrenia was accompanied by an earlier mean age of onset for males (23.3 years) than for females (27.5 years). These 160 cases of strict schizophrenia represent 59 separate families each identified by a single common founder. Eleven of these families have 5 to 14 cases and represent nearly half of the strict schizophrenia cases in Palau. Although schizophrenia is clearly aggregating in these 11 families, cases are distributed sparsely throughout the large sibships. In the entire sample of 160 cases of strict schizophrenia, there were only 11 sib-pairs and 2 sib-trios. When a family was defined to include third-degree relatives, only 11 cases (6.9%) were nonfamilial. The majority of the ascertained cases can be linked together into extended pedigrees with complex multilineal inheritance patterns. These intricately interconnected families may pose challenges for traditional linkage techniques. However, these Palauan families represent a valuable resource for studying the genetic etiology of schizophrenia because there may be fewer susceptibility genes for schizophrenia in this genetic isolate than in the heterogeneous populations that are common throughout the world today.

Adolescent↗
PubMed1999

Measuring liability for schizophrenia using optimized antisaccade stimulus parameters.

The ability to identify unaffected gene carriers within families may be crucial to the success of schizophrenia genetics studies. Data collected from three family samples (N = 365) demonstrated that poor antisaccade performance is an exceptionally promising indicator of liability for schizophrenia. A particular antisaccade task version provides large separations (5-6 sigma) between proband and normal groups. Poor antisaccade performance alone correctly identified 70% of patients in California, Utah, and Micronesia schizophrenia samples. Twenty-five to 50% of these patients' nonpsychotic first-degree relatives also had poor antisaccade performance, yielding risk ratios around 20:1 for simplex and 50:1 for multiplex schizophrenia families. Poor antisaccade performance is associated with dorsolateral prefrontal cortex pathology, suggesting that dysfunction of this circuitry also may predispose individuals to developing this disease.

Adult↗
PubMed1998

The sensitivity of the Spontaneous Selective Attention Test (SSAT): a study of schizophrenic inpatients and outpatients versus normal controls.

The Spontaneous Selective Attention Task (SSAT) is a visual word-identification task that measures the type of selective attention that occurs spontaneously when there are multiple stimuli, all potentially relevant, and insufficient time to process each of them fully. The present study was designed to examine the sensitivity of the SSAT by comparing the performance of 40 schizophrenic inpatients and 30 schizophrenic outpatients to that of 70 normal controls. The pattern of results reported previously for schizophrenic inpatients versus normals was replicated, and these findings were extended to include schizophrenic outpatients in partial symptom remission. Schizophrenic inpatients and outpatients were just as accurate in identifying words as normals, but spontaneous selective attention under conditions of predictability was abnormal in both patient groups. Furthermore, the ability of the SSAT to discriminate between schizophrenic patients and controls was confirmed. A ratio measure of spontaneous selective attention had a sensitivity of 77% and a base rate of 9% in a normal population (when a cutoff value was set to minimize false positives and false negatives). Thus, the SSAT is a sensitive measure of an attentional phenotype that may be useful in genetic studies of schizophrenia.

Adult↗
PubMed1998

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 approximately 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.

Adult↗
PubMed1998

Analysis of chromosome 6 markers in eight Utah schizophrenia pedigrees.

Eight multiplex Utah schizophrenia pedigrees were screened for linkage by applying a non-parametric linkage program, GENEHUNTER, using 30 chromosome 6 DNA markers. The overall maximum NPL score of the combined pedigrees was 1.50 (P = 0.079) at marker D6s281, located near the q terminus. The highest overall maximum NPL score for an individual pedigree was 2.81 (P = 0.043). In the chromosome 6p region, where numerous positive findings have been reported, we obtained no positive results.

Chromosomes, Human, Pair 6↗
PubMed1997

Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus.

Inheritance of a defect in a neuronal mechanism that regulates response to auditory stimuli was studied in nine families with multiple cases of schizophrenia. The defect, a decrease in the normal inhibition of the P50 auditory-evoked response to the second of paired stimuli, is associated with attentional disturbances in schizophrenia. Decreased P50 inhibition occurs not only in most schizophrenics, but also in many of their nonschizophrenic relatives, in a distribution consistent with inherited vulnerability for the illness. Neurobiological investigations in both humans and animal models indicated that decreased function of the alpha 7-nicotinic cholinergic receptor could underlie the physiological defect. In the present study, a genome-wide linkage analysis, assuming autosomal dominant transmission, showed that the defect is linked [maximum logarithm of the odds (lod) score = 5.3 with zero recombination] to a dinucleotide polymorphism at chromosome 15q13-14, the site of the alpha 7-nicotinic receptor. Despite many schizophrenics' extremely heavy nicotine use, nicotinic receptors were not previously thought to be involved in schizophrenia. The linkage data thus provide unique new evidence that the alpha 7-nicotinic receptor gene may be responsible for the inheritance of a pathophysiological aspect of the illness.

Auditory Perception↗
PubMed1996

Analysis of chromosome 18 DNA markers in multiplex pedigrees with manic depression.

Six pedigrees segregating manic-depressive illness (MDI) were analyzed for linkage to 21 highly polymorphic microsatellite DNA markers on chromosome 18. These markers span almost the entire length of the chromosome, and gaps between markers are less than 20 cM. In particular, we analyzed several markers localizing to the pericentromeric region of chromosome 18 which generated lod scores suggestive of linkage in an independent study. Lod score analysis was performed and results were examined by family. One region produced positive lod scores, though at 18q23 and not in the pericentromeric region. We additionally used two nonparametric methods because the true mode of transmission of MDI is unknown; results were again somewhat suggestive for markers in the region of 18q23 but not in the pericentromeric region.

Adult↗
PubMed1996

A combined analysis of D22S278 marker alleles in affected sib-pairs: support for a susceptibility locus for schizophrenia at chromosome 22q12. Schizophrenia Collaborative Linkage Group (Chromosome 22).

Several groups have reported weak evidence for linkage between schizophrenia and genetic markers located on chromosome 22q using the lod score method of analysis. However these findings involved different genetic markers and methods of analysis, and so were not directly comparable. To resolve this issue we have performed a combined analysis of genotypic data from the marker D22S278 in multiply affected schizophrenic families derived from 11 independent research groups worldwide. This marker was chosen because it showed maximum evidence for linkage in three independent datasets (Vallada et al., Am J Med Genet 60:139-146, 1995; Polymeropoulos et al., Neuropsychiatr Genet 54:93-99, 1994; Lasseter et al., Am J Med Genet, 60:172-173, 1995. Using the affected sib-pair method as implemented by the program ESPA, the combined dataset showed 252 alleles shared compared with 188 alleles not share (chi-square 9.31, 1df, P = 0.001) where parental genotype data was completely known. When sib-pairs for whom parental data was assigned according to probability were included the number of alleles shared was 514.1 compared with 437.8 not shared (chi-square 6.12, 1df, P = 0.006). Similar results were obtained when a likelihood ratio method for sib-pair analysis was used. These results indicate that may be a susceptibility locus for schizophrenia at 22q12.

Alleles↗
PubMed1996

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.

Adolescent↗
PubMed1996

Nicotinic receptor function in schizophrenia.

Schizophrenia can be partially characterized by deficits in sensory processing. Biochemical, molecular, and genetic studies of one such endophenotype, the P50 auditory-evoked potential gating deficit, suggest that one of the neuronal nicotinic receptors, the alpha 7 nicotinic receptor, may function in an inhibitory neuronal pathway involved in this phenotype. The P50 deficit is normalized in nongating subjects by nicotine. Although most schizophrenia patients are heavy smokers, the effects of nicotine may be transient, as alpha 7 receptors are known to desensitize rapidly. In an animal model of the P50 gating deficit, antagonists of the alpha 7 nicotinic receptor block normal gating of the second of paired auditory stimuli. Regional localization of receptor expression includes areas known to function in sensory filtering. An inhibitory mechanism, in the hippocampus, may involve nicotinic stimulation of gamma-aminobutyric acid (GABA)ergic interneurons, resulting in decreased response to repetitive stimuli. Expression of the alpha 7 receptor is decreased in hippocampal brain tissue, dissected postmortem, from schizophrenia subjects. The P50 deficit is inherited in schizophrenia pedigrees, but it is not sufficient for disease development and thus represents a predisposition factor. Linkage analysis between the P50 deficit in multiplex schizophrenia pedigrees and deoxyribonucleic acid (DNA) markers throughout the genome yielded positive lod scores to DNA markers mapping to a region of chromosome 15 containing the alpha 7 nicotinic receptor gene. Elucidation of possible interactions of the P50 with other factors, known to be important in the etiology of the disease, is important in determining an overall pathobiology of schizophrenia.

Animals↗
PubMed1996

Anticipation in multiplex schizophrenia pedigrees.

Anticipation, a phenomenon in which the symptoms of an inherited disease become more severe and age of onset occurs earlier across generations, has become an issue of importance in schizophrenia. If anticipation is found in families manifesting the illness, a possible type of genetic mutation would be implicated for predisposition to schizophrenia, as anticipation is now known to result from expansion of unstable trinucleotide repeat sequences. Two recent studies have tested for evidence of this phenomenon in schizophrenia families and came to differing conclusions; it is possible that anticipation occurs only in a subset of families. Our sample shows significant decreases in age of onset and increases in severity across generations. To investigate possible ascertainment bias, we looked at early onset parents and found no consistent anticipation effects in this group. We did find some increase in anticipation for mother-child vs father-child pairs; this possible imprinting effect may indicate true anticipation, though the evidence is not strong in our small sample, and the most conservative interpretation of our results is that the differences are due to ascertainment bias.

Adult↗
PubMed1995

Sensory gating deficits in parents of schizophrenics.

Although schizophrenia clusters in families, it is not inherited in Mendelian fashion. This suggests that there may be alternative phenotypic expressions of genes that convey risk for schizophrenia, such as more elementary physiological or biochemical defects. One proposed phenotype is impaired inhibitory gating of the auditory evoked potential to repeated stimuli. Normally, the amplitude of the P50 response to the second stimulus is significantly less than the response to the first, but this gating of response is generally impaired in schizophrenia. Clinically unaffected individuals within a pedigree who have both an ancestral and descendant history of schizophrenia may be useful for studying whether this physiological defect is a possible alternative phenotype. We have studied inhibitory gating of the auditory P50 response to pairs of auditory stimuli in 17 nuclear families. In 11, there was one parent who had another relative with a chronic psychotic illness, in addition to the schizophrenic proband. All of the parents with family histories of schizophrenia had gating of the P50 response similar to their schizophrenia offspring, whereas only 7% of the parents without family history had gating of the P50 response in the abnormal range. These results support loss of gating of the auditory P50 wave as an inherited deficit related to schizophrenia and suggest that studies of parents may help elucidate the neurobiological expression of genes that convey risk for schizophrenia.

Evoked Potentials, Auditory↗
PubMed1995

Search for a gene predisposing to manic-depression on chromosome 21.

Six kindreds containing multiple cases of Manic-depressive illness (MDI) were genotyped with seven highly polymorphic microsatellite loci used in the construction of an index map for chromosome 21. The kindreds were also genotyped with a microsatellite polymorphism for PFKL, a chromosome 21 locus that has shown suggestive linkage to MDI in one pedigree [Straub et al., 1993: The American Society of Human Genetics]. Evidence of linkage was not found assuming either autosomal dominant or recessive inheritance. The nonparametric affected sib pair test did not yield significant evidence of linkage.

Biomarkers↗
PubMed1995

Mutation scan of the D1 dopamine receptor gene in 22 cases of bipolar I disorder.

In a previous study [Coon et al., Am J Hum Genet 52:1234-1249, 1993], we found suggestive evidence of linkage between manic-depressive illness (MDI) in eight multiplex pedigrees and D5S62, a DNA marker mapping to the telomeric region of 5q. As the D1 dopamine receptor gene (DRD1) maps to this region and as alterations in dopaminergic neurotransmission have been indirectly implicated in the pathogenesis of MDI, we directly searched for mutations in the coding region of the DRD1 gene in 22 unrelated cases of bipolar I (BPI) disorder derived from multiplex families. Using single strand conformation polymorphism (SSCP) analysis, we did not observe any abnormal SSCP variants in the BPI cases that differed from controls.

Adult↗