Modest evidence for linkage and possible confirmation of association between NOTCH4 and schizophrenia in a large Veterans Affairs Cooperative Study sample.

Wei and Hemmings [2000: Nat Genet 25:376-377], using 80 British parent-offspring trios, identified a number of NOTCH4 variants and haplotypes that showed statistically significant evidence of association to schizophrenia. Specifically, the 10 repeat allele of a (CTG)(n) marker and the 8 repeat allele of a (TAA)(n) marker demonstrated excess transmission to affected individuals; SNP21 and haplotypes SNP2-(CTG)(n) and SNP12-SNP2-(CTG)(n) also showed significant associations. In an attempt to replicate these findings, we tested for linkage and association between the same five markers used by Wei and Hemmings in 166 families collected from a multi-center study conducted by the Department of Veterans Affairs (DVA) Cooperative Study Program (CSP). The families include 392 affected subjects (schizophrenia or schizoaffective disorder, depressed) and 216 affected sibling pairs. The families represent a mix of European Americans (n = 62, 37%), African Americans (n = 60, 36%), and racially mixed or other races (n = 44, 27%). We identified moderate evidence for linkage in the pooled race sample (LOD = 1.25) and found excess transmission of the 8 (P = 0.06) and 13 (P = 0.04) repeat alleles of the (TAA)(n) marker to African American schizophrenic subjects. The 8 and 13 repeat alleles were previously identified to be positively associated with schizophrenia by Wei and Hemmings [2000: Nat Genet 25:376-377] and Sklar et al. [2001: Nat Genet 28:126-128], respectively.

Examination of genetic linkage of chromosome 15 to schizophrenia in a large Veterans Affairs Cooperative Study sample.

Previous studies have reported genetic linkage evidence for a schizophrenia gene on chromosome 15q. Here, chromosome 15 was examined by genetic linkage analysis using 166 schizophrenia families, each with two or more affected subjects. The families, assembled from multiple centers by the Department of Veterans Affairs Cooperative Study Program, consisted of 392 sampled affected subjects and 216 affected sibling pairs. By DSM-III-R criteria, 360 subjects (91.8%) had a diagnosis of schizophrenia and 32 (8.2%) were classified as schizo-affective disorder, depressed. Participating families had diverse ethnic backgrounds. The largest single group were northern European American families (n = 62, 37%), but a substantial proportion was African American kindreds (n = 60, 36%). The chromosome 15 markers tested were spaced at intervals of approximately 10 cM over the entire chromosome and 2-5 cM for the region surrounding the alpha-7 nicotinic cholinergic receptor subunit gene (CHRNA7). These markers were genotyped and the data analyzed using semiparametric affecteds-only linkage analysis. In the European American families, there was a maximum Z-score of 1.65 between markers D15S165 and D15S1010. These markers are within 1 cM from CHRNA-7, the site previously implicated in schizophrenia. However, there was no evidence for linkage to this region in the African America kindreds.

Neuropsychologic functioning among the nonpsychotic relatives of schizophrenic patients: the effect of genetic loading.

BACKGROUND: We previously reported that the nonpsychotic relatives of schizophrenic patients exhibited disturbances in executive functioning, verbal and visual memory, auditory attention, mental control, and verbal ability. In a 4-year follow-up, we showed that the discriminating power of most of these tests was stable over time. METHODS: In this report we compare 41 nonpsychotic persons who have only one schizophrenic first-degree relative (simplex families) with 36 nonpsychotic persons who have two schizophrenic first-degree relatives (multiplex families). Our goal was to test a hypothesis that neuropsychologic deficits would be worse among the latter. RESULTS: Relatives from multiplex families differed significantly from controls on estimated intelligence, immediate and delayed logical memories, and immediate visual reproductions. In contrast, in comparisons with controls, relatives from simplex families only differed on immediate logical memories. Comparisons between relatives from multiplex and simplex families showed that the former group had significantly worse scores for estimated intelligence, immediate and delayed logical memories, and immediate visual reproductions. We also found group x gender interactions: the worse performance of the multiplex group was seen for females. CONCLUSIONS: These results are consistent with the idea that neuropsychologic deficits in relatives of schizophrenic patients reflect their degree of genetic predisposition to schizophrenia. They also suggest hypotheses about gender differences in the familial transmission of the disorder.

Department of Veterans Affairs Cooperative Studies Program genetic linkage study of schizophrenia: ascertainment methods and sample description.

To help clarify the genetics of schizophrenia, the Department of Veterans Affairs Cooperative Studies Program has completed data collection for a genetic linkage study of schizophrenia. This article describes the methodological details of the data collection. Subsequent articles will describe the results of our genome scan, which is now in progress. The data collection protocol included the Diagnostic Interview for Genetic Studies, the Family Interview for Genetic Studies, a review of medical records, and the collection of blood for transformation into lymphoblast cell lines. Among relatives of schizophrenic probands, we assessed auditory attention and verbal memory with neuropsychological tests. Among the 166 families ascertained for the study, 143 had a single affected sib-pair, 17 had three affected siblings, one had five affected siblings and five had two sets of affected siblings. There was a total of 216 affected sib-pairs in these families. Using the n-1 rule, these families contain 188 independent affected sib-pairs.

Suggestive linkage of chromosome 10p to schizophrenia is not due to transmission ratio distortion.

The genome scan of the European-American schizophrenia families from the Human Genetics Initiative of the National Institute of Mental Health (NIMH) reported a suggestive linkage to chromosome 10p. Subsequently, Paterson and Petronis [1999] reported evidence for transmission ratio distortion on 10p to females. They suggested that transmission ratio distortion to females might have created spurious evidence for linkage to 10p. To address this issue, we reanalyzed our 10p data using only male-male affected sibling pairs. The two chromosome 10p markers that gave the most evidence for linkage in our prior report continued to show evidence for linkage: D10S1423 (NPL Z = 3.0, P = 0.001) and its neighbor D10S582 (NPL Z = 2.9, P = 0.002). These data suggest that our prior report of suggestive linkage of schizophrenia to markers on 10p cannot be attributed to the transmission ratio distortion to females reported by Paterson and Petronis. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:607-608, 1999.

Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: a 4-year follow-up study.

In a prior study of 54 relatives of patients with schizophrenia and 72 control participants, 3 neuropsychological functions met the criteria for risk indicators of the schizophrenia genotype: executive functioning, memory, and auditory attention. In an assessment of the stability of these findings, the sample was reexamined 4 years after the initial assessment. Three test scores were found to differ between groups (Immediate Verbal Memory, Delayed Verbal Memory, and Dichotic Listening Digits Detected) or to show a significant Group x Gender interaction (immediate and delayed verbal and visual memories). None of the test scores showed Group x Time interactions, suggesting that the discriminating power of the tests was stable over time. Evidence for deficits in working memory and rule learning on the object alternation test was also found. These results support the idea that neuropsychological dysfunction among relatives of patients with schizophrenia is a stable trait caused by the familial predisposition to schizophrenia.

Neuropsychological risk indicators for schizophrenia: a preliminary study of female relatives of schizophrenic and bipolar probands.

Evidence of subtle neuropsychological deficits in relatives of schizophrenic probands (REL-SZs) suggests that these are risk indicators for schizophrenia, but little is known about whether neuropsychological performance in REL-SZs differs from that in other groups of relatives. We compared neuropsychological function in female REL-SZs (n = 39), relatives of primarily psychotic bipolar disorder probands (REL-BPs; n = 15), and a normal control group (n = 44). After adjustment for expected intellectual ability (based on reading recognition), REL-SZs showed deficits in verbal and visual memory (Wechsler Memory Scale-Revised logical memories, visual reproductions), and auditory attention (dichotic digits) compared with either REL-BPs or control subjects. Memory, but not dichotic listening differences remained significant after adjusting for current IQ; however, average effect sizes after controlling for either reading or IQ were roughly comparable for these three parameters (d = 0.80, 0.71, and 0.69, respectively). REL-BPs and control subjects showed little difference. Although both schizophrenic and bipolar patients often manifest neuropsychological dysfunction, these preliminary findings indicate subtle neuropsychological deficits only in REL-SZs. Such differences suggest different underlying processes; neuropsychological impairment may, in part, reflect an expression of genetic liability to schizophrenia but not bipolar disorder. Replication with a larger REL-BP sample and with male relatives is needed to evaluate the generalizability of the results.

Association of neuropsychological vulnerability markers in relatives of schizophrenic patients.

We investigated the association of neuropsychological risk indicators in a matched sample of first-degree relatives of schizophrenic patients (n = 54) and normal controls (n = 72). We focussed on three functions previously identified in a smaller, initial sample as putative risk indicators of the schizophrenia genotype: abstraction, verbal memory and auditory attention. The expanded sample of relatives displayed significantly lower scores than controls on abstraction, verbal memory and auditory attention. The relatives demonstrated significant intercorrelations among these three functions. The significant correlations among relatives between attention and verbal memory and between attention and abstraction differed significantly from these correlations among controls. We discuss how the use of multiple risk indicators may help us better identify those relatives that carry the schizophrenia genotype.

NIMH Genetics Initiative Millenium Schizophrenia Consortium: linkage analysis of African-American pedigrees.

The NIMH Genetics Initiative is a multi-site collaborative study designed to create a national resource for genetic studies of complex neuropsychiatric disorders. Schizophrenia pedigrees have been collected at three sites: Washington University, Columbia University, and Harvard University. This article-one in a series that describes the results of a genome-wide scan with 459 short-tandem repeat (STR) markers for susceptibility loci in the NIMH Genetics Initiative schizophrenia sample-presents results for African-American pedigrees. The African-American sample comprises 30 nuclear families and 98 subjects. Seventy-nine of the family members were considered affected by virtue of having received a DSMIII-R diagnosis of schizophrenia (n = 71) or schizoaffective disorder, depressed (n = 8). The families contained a total of 42 independent sib pairs. While no region demonstrated evidence of significant linkage using the criteria suggested by Lander and Kruglyak, several regions, including chromosomes 6q16-6q24, 8pter-8q12, 9q32-9q34, and 15p13-15q12, showed evidence consistent with linkage (P = 0.01-0.05), providing independent support of findings reported in other studies. Moreover, the fact that different genetic loci were identified in this and in the European-American samples, lends credence to the notion that these genetic differences together with differences in environmental exposures may contribute to the reported differences in disease prevalence, severity, comorbidity, and course that has been observed in different racial groups in the United States and elsewhere.

Genome scan of European-American schizophrenia pedigrees: results of the NIMH Genetics Initiative and Millennium Consortium.

The Genetics Initiative of the National Institute of Mental Health (NIMH) was a multisite study that created a national repository of DNA from families informative for genetic linkage studies of schizophrenia, bipolar disorder, and Alzheimer's disease. The schizophrenia families were collected by three sites: Washington University, Harvard University, and Columbia University. This article, one in a series that describes the data collected for linkage analysis by the schizophrenia consortium, presents the results for the European-American sample. The European-American sample comprised 43 nuclear families and 146 subjects. Ninety-six of the family members were considered affected by virtue of having received a DSM-III-R diagnosis of schizophrenia (N = 82) or schizoaffective disorder, depressed (N = 14). The families contained a total of 50 independent sib-pairs. Using the significance threshold criteria suggested by Lander and Kruglyak [(1995): Nat Genet 241-247], no region showed statistically significant evidence for linkage; two markers on chromosome 10p showed statistical evidence suggestive of linkage using the criteria of Lander and Kruglyak [(1995): Nat Genet 241-247]: D10S1423 (nonparametric linkage (NPL) Z = 3.4, P = .0004) and its neighbor, D10S582 (NPL Z = 3.2, P = .0006).

Language processing and memory in ill and well siblings from multiplex families affected with schizophrenia.

The present study was designed to extend the investigation of genetic factors for schizophrenia to cognitive and linguistic signs of central nervous system dysfunction. Of 51 siblings studied from 19 schizophrenia multiplex families, 37 had a DSM-III-R diagnosis of schizophrenia or related schzophrenia spectrum disorder and 14 were well. Controls were 17 unrelated healthy individuals within the same social class and age range. Subjects were tested on measures of memory, attention, reading and expressive language ability. Schizophrenic and spectrum disorder siblings were significantly more impaired in tests of auditory discrimination and memory than their well siblings or controls and displayed significantly reduced syntactic complexity to their speech. While well siblings did not differ from controls on most measures, some aspects of language complexity were reduced. A familial effect was observed for tests of reading ability, attention, some syntactic measures, and short-term memory, although these were not the measures that distinguished patients from controls in this cohort, the scores were not correlated among the ill sibling pairs, and poorer scores did not segregate with schizophrenia within these families. Thus, while some measures of language, memory and attention are deviant in patients with schizophrenia, they may not be heritable and directly related to the genetics of the disorder. Instead, they may be a manifestation of, rather than a vulnerability to, the illness.

Diagnostic accuracy and confusability analyses: an application to the Diagnostic Interview for Genetic Studies.

The dominant, contemporary paradigm for developing and refining diagnoses relies heavily on assessing reliability with kappa coefficients and virtually ignores a core component of psychometric practice: the theory of latent structures. This article describes a psychometric approach to psychiatric nosology that emphasizes the diagnostic accuracy and confusability of diagnostic categories. We apply these methods to the Diagnostic Interview for Genetic Studies (DIGS), a structured psychiatric interview designed by the NIMH Genetics Initiative for genetic studies of schizophrenia and bipolar disorder. Our results show that sensitivity and specificity were excellent for both DSM-III-R and RDC diagnoses of major depression, bipolar disorder, and schizophrenia. In contrast, diagnostic accuracy was substantially lower for subtypes of schizoaffective disorder-especially for the DSM-III-R definitions. Both the bipolar and depressed subtypes of DSM-III-R schizoaffective disorder had excellent specificity but poor sensitivity. The RDC definitions also had excellent specificity but were more sensitive than the DSM-III-R schizoaffective diagnoses. The source of low sensitivity for schizoaffective subtypes differed for the two diagnostic systems. For RDC criteria, the schizoaffective subtypes were frequently confused with one another; they were less frequently confused with other diagnoses. In contrast, the DSM-III-R subtypes were often confused with schizophrenia, but not with each other.

Diagnostic accuracy and linkage analysis: how useful are schizophrenia spectrum phenotypes?

OBJECTIVE: Numerous studies suggest that the nonschizophrenic relatives of schizophrenic patients exhibit psychiatric and other features that discriminate them from normal comparison subjects. These features have been put forth as "spectrum" phenotypes that may be variant manifestations of the schizophrenia genotype. However, most of these studies do not address a key measurement question: does the diagnostic accuracy of these spectrum classifications warrant their use in genetic linkage studies of schizophrenia? METHOD: The authors reviewed 30 studies of putative indicators of the schizophrenic genotype: schizotypal personality disorder, eye tracking dysfunction, attentional impairment, auditory evoked potentials, neurological signs, neuropsychological impairment, and allusive thinking. RESULTS: Although each of 42 measures of these indicators discriminated the relatives of schizophrenic patients from the normal comparison subjects, a diagnostic accuracy analysis suggested that only six of these would improve the informativeness of genetic linkage data. CONCLUSIONS: Many proposed spectrum phenotypes for schizophrenia may not be useful for linkage analysis because of high false positive rates (poor specificity). Future work aimed at describing and developing phenotypes for linkage analysis should assess the diagnostic accuracy of proposed measures.

Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: a diagnostic efficiency analysis.

Numerous studies suggest that the relatives of schizophrenic patients exhibit neuropsychological impairments that are milder yet similar to those seen among schizophrenic patients. The authors assessed 35 nonpsychotic relatives of schizophrenic patients and 72 normal controls using a clinical and experimental neuropsychological test battery. Three neuropsychological functions met criteria for risk indicators of the schizophrenia genotype: abstraction, verbal memory, and auditory attention. These findings could not be attributed to parental socioeconomic status, education, general visual-spatial ability, or psychopathology. Furthermore, exploratory analyses were performed to determine whether the diagnostic efficiency of the indicators could be adjusted to meet the needs of genetic linkage analyses. These analyses suggest that psychometric considerations may help to create measures for genetic linkage studies.

The '3 Rs' and neuropsychological function in schizophrenia: a test of the matching fallacy in biological relatives.

The 'matching fallacy' suggests that matching schizophrenic patients and normal control subjects on education or IQ may cause systematic mismatching of theoretically expected ability. This study supports a modest version of the matching fallacy effect in nonpsychotic biological relatives of schizophrenic patients. At equivalent levels of education, relatives and control subjects had similar Reading and Spelling scores on the Wide Range Achievement Test-Revised--measures that are largely unimpaired by schizophrenia-related processes. However, relatives showed a deficit in IQ (primarily verbal IQ) compared with what would be predicted from their Reading scores. A similar deficit in Arithmetic scores was found in non-college-educated relatives, but college-educated relatives showed an advantage. We discuss possible implications of the findings with regard to genetic and environmental factors.

Neuropsychological risk indicators for schizophrenia: a review of family studies.

We reviewed potential neuropsychological risk indicators for schizophrenia by addressing two broad questions about neuropsychological performance in biological relatives of schizophrenia patients: (1) Is there evidence of deficits, and, if so, (2) are those deficits similar to deficits found in schizophrenia patients themselves? There has not yet been adequate validation of most neuropsychological risk indicators, but promising leads have emerged from studies of relatives of persons with schizophrenia. The strongest evidence of impairment in relatives was in sustained attention, perceptual-motor speed, and concept formation and abstraction; to a slightly lesser extent, mental control/encoding (primarily with distraction) was implicated as well. Impairments in verbal memory and verbal fluency were also found, although these have been less well studied. The pattern of deficits paralleled that found in schizophrenia patients, thus suggesting dysfunction in prefrontal, temporal-limbic, and attentional systems. Findings were similar for children and adult relatives of schizophrenia patients. It is suggested that future studies (1) emphasize comprehensive test batteries, (2) develop composite neuropsychological measures, (3) use profile and deviant-responder analyses, (4) include psychiatric comparison groups, and (5) integrate neuropsychological assessments with brain imaging techniques.

Neuropsychological performance in chronic schizophrenia in response to neuroleptic dose reduction.

The effect of 80%-90% neuroleptic dose reductions on neuropsychological function in schizophrenic and schizoaffective patients was examined in a prospective study. A neuropsychological battery was administered in the week prior to neuroleptic reduction followed by retesting at least 6 weeks postreduction. Patients were retested only if they did not relapse after reduction. The design allowed neuropsychological changes due to neuroleptic medications to be assessed independently of general clinical change. Neuropsychological performance was generally stable and unchanging. However, there was a trend toward significant improvement on a dichotic digits task based in improvement in left ear accuracy. Negative symptoms diminished after reduction. Compared with a normal control group, schizophrenics' initial laterality index showed a significantly exaggerated right ear advantage (REA); after reduction, the REA was no longer different from controls. The findings indicate that neuropsychological changes in a small sample of older nonrelapsing chronic schizophrenics are modest. The data suggest that neuroleptics may impair right hemisphere functions in some patients.

Attention/information-processing factors in psychotic disorders. Replication and extension of recent neuropsychological findings.

The scores of attention/information-processing measures derived from neuropsychological testing of 34 chronic psychotic, primarily schizophrenic patients were subjected to a principal components analysis. Measures were chosen a priori on the basis of a previous factor-analytic study by A.F. Mirsky (1987, Behavioral and psychophysiological markers of disordered attention, Environmental Health Perspectives 74:191-199). The factor pattern in the present study was strikingly similar to that reported by Mirsky on a largely nonpsychotic sample. In both studies, four factors emerged that may be identified as: a) perceptual motor speed; b) mental control (numerical-mnemonic); c) flexibility; and d) vigilance. This replication provides support for previously postulated types of attention and suggests that schizophrenic and other psychotic disorders are not associated with atypical organization of attention/information-processing dimensions. The authors discuss questions raised by Mirsky's previous results in light of the present findings. In particular, it was concluded that the flexibility factor requires further clarification. Implications of the findings for clinical evaluation and research in schizophrenia are discussed as well.

Neuropsychological probes of fronto-limbic system dysfunction in schizophrenia. Olfactory identification and Wisconsin Card Sorting performance.

Schizophrenic patients and normal control subjects took the University of Pennsylvania Smell Identification Test (UPSIT) and Wisconsin Card Sorting Test (WCST) as dual neuropsychological 'probes' of orbitofrontal (OF) and dorsolateral (DL) prefrontal function respectively. Patients were significantly impaired on both tasks compared to controls. UPSIT and WCST performance were uncorrelated in patients but were positively correlated in controls. The lack of correlation found in the patients suggests that the tasks may be tapping independent dysfunctions in schizophrenia reflecting differential impairment in fronto-limbic brain systems. Individual profiles of preserved and impaired performance on the UPSIT and WCST suggested that three schizophrenic patients had OF dysfunction, five had DL dysfunction and seven had a generalized (OF and DL) frontal system dysfunction. The reduced ability of schizophrenic patients to identify odors was largely independent of many deficits or confounds typically associated with schizophrenia and did not appear to be simply a function of generalized deficit. These data are preliminary and require replication with larger samples and validation with other measures of fronto-limbic system dysfunction.

Wisconsin Card Sorting Test performance over time in schizophrenia. Preliminary evidence from clinical follow-up and neuroleptic reduction studies.

Two groups of schizophrenic patients took the Wisconsin Card Sorting Test (WCST) in separate follow-up studies; a naturalistic clinical follow-up (n = 12, study 1) and a neuroleptic reduction study (n = 10, study 2). 11 of 22 subjects (50%) performed well on the task at one or both time points. In each study no group differences were found between time 1 and time 2 performance on three WCST variables. However, correlational analyses revealed considerable within-subject variation on the WCST in the study 1 sample, which was composed of younger and more acute patients than those in study 2. This variation was present despite within-subject stability on the WAIS-R Vocabulary and Block Design subtests. For the sample combined, a trend was found (p = 0.12) linking better WCST performance at either time period with higher WAIS-R Vocabulary scores. This intra-subject variability may reflect fluctuations in neuropsychological performance in schizophrenics who maintain the residual capacity to do the task. These findings highlight the importance of longitudinal studies of neuropsychological functioning in schizophrenia. Studies of larger samples are needed to confirm these initial results.