Verbal working memory impairments in individuals with schizophrenia and their first-degree relatives: Findings from the Consortium on the Genetics of Schizophrenia

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Abstract

Working memory (WM) impairment is a promising candidate endophenotype for schizophrenia that could facilitate the identification of susceptibility genes for this disorder. The validity of this putative endophenotype was assessed by determining whether 149 probands with schizophrenia and 337 of their first-degree relatives demonstrated WM impairment as compared to 190 unaffected community comparison subjects. Subjects were participants in the Consortium on the Genetics of Schizophrenia (COGS) project, a seven-site research network that was established to investigate the genetic architecture of endophenotypes for schizophrenia. Participants received comprehensive clinical assessments and completed two verbal WM tasks, one requiring transient on-line storage and another requiring maintenance plus complex manipulation of information by reordering the stimuli. Schizophrenia probands performed worse than the other groups on both tasks, with larger deficits found for the more challenging reordering WM task. The probands' relatives performed more poorly than community comparison subjects on both tasks, but the difference was significant only for the more challenging maintenance plus complex manipulation WM task. This WM impairment was not attributable to diagnoses of schizophrenia spectrum disorder, mood disorders, or substance use disorders in the relatives. In conjunction with evidence that WM abilities are substantially heritable, the current results support the validity and usefulness of verbal WM impairments in manipulation of information as endophenotypes for schizophrenia in large-scale genetic linkage and association studies.

Introduction

While there is strong evidence for genetic transmission of vulnerability to schizophrenia (Harrison and Weinberger, 2005, Tsuang et al., 2001), the heterogeneity and complexity of this “group” of clinical phenotypes pose great obstacles for research aimed at understanding the molecular genetic basis of liability to this disorder. A powerful alternative for identifying susceptibility genes is to study the transmission of endophenotypes that are presumed to be more closely linked to the underlying genes that mediate schizophrenia and are likely to have a simpler genetic architecture than the clinical phenotype (Braff and Freedman, 2002, Braff et al., 2007, Gottesman and Gould, 2003). Furthermore, endophenotypes are presumed to vary quantitatively among individuals at risk for schizophrenia, making clinically unaffected relatives of schizophrenia patients informative for linkage and association studies.

The Consortium on the Genetics of Schizophrenia (COGS) was established across seven sites to investigate the genetic architecture of six carefully selected candidate neurocognitive and neurophysiological endophenotypes for schizophrenia (Calkins et al., 2007). In this report, we evaluate whether one of the COGS candidate neurocognitive endophenotypes, verbal working memory (WM) impairment, characterizes schizophrenia probands and their relatives. WM is typically defined as a limited-capacity storage system used for the temporary on-line maintenance and manipulation of information (Baddeley, 1986). The validity of WM deficits as endophenotypes for schizophrenia is supported by four main lines of evidence.

First, schizophrenia patients consistently demonstrate WM deficits across a diverse range of tasks (Lee and Park, 2005). Two broad types of WM paradigms have typically been studied in schizophrenia (Perry et al., 2001). The first type assesses transient, on-line maintenance functions that do not involve manipulation of the stored information, whereas the second type involves maintenance plus manipulation of information (sometimes called “executive functioning” WM). Schizophrenia patients often show more severe impairment on WM tasks that involve maintenance plus complex manipulation (Barch, 2005). In the verbal domain, patients and healthy controls show average separations of about of 0.71–0.82 standard deviations on both digit span forward and backward repetition tasks (Aleman et al., 1999). However, group differences can exceed 1.4 standard deviations on more complex letter–number sequencing tasks (e.g., Conklin et al., 2005, Gold et al., 1997, Perry et al., 2001).

Second, WM impairment appears to be a core feature of schizophrenia that is not attributable to other aspects of the illness. WM deficits show minimal cross-sectional correlations with severity of delusions and hallucinations, are detectable in clinically stabilized outpatients, and appear to be relatively stable across both time and fluctuations in clinical status, suggesting that they are not merely secondary manifestations of psychotic symptoms (Heaton et al., 2001, Hill et al., 2004, Park et al., 1999). They are also not secondary to antipsychotic medication side effects or factors associated with chronicity, as deficits of comparable magnitude are present in neuroleptic-free patients (Barch et al., 2001, Carter et al., 1996) and during the immediate post-onset period (Hutton et al., 1998, Lussier and Stip, 2001).

Third, WM abilities appear to be genetically mediated. Heritability estimates for verbal and spatial WM tasks are moderately high in both healthy individuals (.43–.49; Ando et al., 2001, Hansell et al., 2005) and schizophrenia patients (.36–.42; Tuulio-Henriksson et al., 2002). In addition, WM impairments in healthy siblings of schizophrenia probands scale in severity with genetic loading for this disorder in singleton versus multiplex families (Tuulio-Henriksson et al., 2003) and in discordant dizygotic versus monozygotic twin pairs (Cannon et al., 2000, Glahn et al., 2003).

Fourth, similar, though attenuated, WM disturbances are also present in clinically unaffected biological relatives of schizophrenia patients. First-degree relatives of schizophrenia probands score about .25 to .50 standard deviations below healthy controls across verbal and spatial WM tasks (Snitz et al., 2006, Trandafir et al., 2006). Some, though not all, studies suggest that relatives may perform more poorly on tasks that require more demanding executive functions. For example, a recent study found that effect sizes between relatives of schizophrenia probands and controls increased as one moved from digit span forward (d = .43) to digit span backward (d = .56) and to letter–number sequencing (d = .66) (Conklin et al. 2005).

These converging lines of evidence suggest that WM deficits, particularly those involving executive functions, reflect genetically-mediated susceptibility to schizophrenia. This study evaluated the performance of large number of well characterized schizophrenia patients, their first-degree relatives, and community comparison subjects on the Letter–Number Span (LNS) task (Gold et al., 1997, Wechsler, 1997), which included a forward span repetition condition and a reordering condition.

Although other studies have considered WM performance in first-degree relatives of schizophrenia patients, this study had several advantageous features. First, this is the largest study to date. Second, this study included comprehensive clinical assessments which, in combination with the good statistical power, enabled us to evaluate a variety of factors that may contribute to performance. Third, the COGS uses a highly rigorous data collection quality assurance program (described in (Calkins et al., 2007)) that ensures the cross-site reliability of the dependent measures. Fourth, the recruitment scheme of COGS is somewhat unusual. As described below and elsewhere (Calkins et al., 2007), the COGS employs a distinctive ascertainment strategy designed to optimize genetic analyses of quantitative endophenotypes. The minimal requirement for pedigree ascertainment includes a schizophrenia proband, both parents (at least one unaffected), and at least one unaffected sibling. Sampling both affected and unaffected individuals increases variation or “contrast” in the proposed endophenotypes (see (Braff et al., 2007, Schork et al., 2007) for reviews). This contrast-based approach differs from alternate recruitment strategies (e.g., affected sibling pairs and multiplex families) that are commonly used for studying qualitatively-defined disease phenotypes. Hence, the current study carefully evaluated whether working memory displays the expected patterns of performance in families using this contrast-based family recruitment method.

The primary variable for working memory for COGS was defined a priori as the Reordered condition of the LNS, which has a mental manipulation component. The secondary measure was the simple repetition condition was included to examine the genetics of WM maintenance. In line with expectations for an endophenotype (Gottesman and Gould, 2003), the primary hypothesis was that schizophrenia patients would perform worse than their relatives, who would in turn perform worse than comparison subjects, on the LNS Reordered condition.

Section snippets

Overview

The COGS is a 7-site National Institute of Mental Health (NIMH) funded project designed to collect neurocognitive and neurophysiological endophenotypes and to perform genetic analyses on schizophrenia subjects, their first-degree relatives, and community comparison subjects (CCS). The COGS includes the University of California San Diego, University of California Los Angeles, University of Colorado, Harvard University, Mount Sinai School of Medicine, University of Pennsylvania, and University of

Statistical methods

Data analysis was conducted in four phases. First, group differences in demographics were evaluated with one-way ANOVA's for continuous variables and chi-square tests for categorical variables. Second, group differences on LNS Reordered and Forward were evaluated using separate mixed effects regression analyses (SAS Proc MIXED, specifying an unstructured covariance structure and Satterthwaite degrees of freedom). These models used LNS scores as the dependent variables, family as a random effect

Demographic and clinical characteristics

As shown in Table 1, probands had a higher proportion of males, fewer years of completed education (as expected), lower estimated pre-morbid intellectual functioning on the WRAT-3, and higher parental education than both other groups. The relatives were significantly older than the proband and CCS groups. Probands had a typical age of onset and demonstrated low to moderate levels of symptoms.

Within the proband group, there were several significant and trend-level correlations between symptoms

Discussion

This study evaluated verbal WM in what we believe to be the largest samples of schizophrenia probands, first-degree relatives, and CCS studied to date. Consistent with our hypotheses, probands performed worse than both other groups on both WM tasks, with larger effect sizes found for the WM task that required executive functions. Probands' relatives also performed worse than CCS on the more demanding maintenance plus manipulation task but not on the WM task that required only maintenance of

Role of funding source

None.

Contributors

William P. Horan, Ph.D.1, David L. Braff, M.D.2, Keith H. Nuechterlein, Ph.D.1, Catherine A. Sugar, Ph.D.1, Kristin S. Cadenhead, M.D.2, Monica E. Calkins, Ph.D.3, Dorcas J. Dobie, M.D.4 Robert Freedman, M.D.5, Tiffany A. Greenwood, Ph.D.2, Raquel E. Gur, M.D., Ph.D.3, Ruben C. Gur, Ph.D.3, Gregory A. Light, Ph.D.2, James Mintz, Ph.D.1, Ann Olincy, M.D.5, Allan D. Radant, M.D.4, Nicholas J. Schork, Ph.D.2, Larry J. Seidman, Ph.D. 6, Larry J. Siever, M.D.7,8, Jeremy M. Silverman, Ph.D.7 William

Conflicts of interest

There are no conflicts of interest.

Acknowledgements

None.

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