John R. Pepple

NIMH genetics initiative millennium 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.

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.

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 Alzheimers 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).

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.

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.

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.

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.

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.

WAIS-R validation of the Wonderlic Personnel Test as a brief intelligence measure in a psychiatric sample

Although there have been several reports of high correlations between Wonderlic Personnel Test scores and Wechsler Adult Intelligence Scale (WAIS) Full Scale IQ, findings have been inconsistent in psychiatric samples. Sample differences and differences between the WAIS and the revised WAIS (WAIS-R) were considered likely reasons. In this study of relatively nonagitated but chronically ill psychiatric patients (N = 18), Wonderlic IQ estimation accuracy and Wonderlic/WAIS-R correlations were consistent with data previously reported for the WAIS, and generally support the value of the Wonderlic as a highly economical measure of general intelligence. However, the inability of 1 subject to manage the Wonderlic format suggests that severe visuospatial impairment can invalidate this test

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; SNP2 1 and haplotypes SNP2‐(CTG)n and SNP1 2 ‐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.