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 information. The relatives’ impairment on the executive functioning WM task does not appear to be attributable to psychometric properties (i.e., discriminating power) of the LNS conditions or the presence of schizophrenia spectrum disorders, and persisted after accounting for the effects of lifetime mood and substance use disorder histories. In conjunction with evidence that WM abilities are substantially heritable (Greenwood et al 2007
), the current results support the validity and usefulness of executive functioning WM as an endophenotype for schizophrenia in large-scale genetic studies of quantitative endophenotypes.
In this report, there were no significant correlations between sub-clinical schizotypal features and WM within the relative or CCS groups. Prior studies of the relationship between WM and schizotypal features among unaffected relatives of schizophrenia probands have shown generally mixed results (e.g., (Conklin et al 2005
; Delawalla 2006
; Johnson et al 2003
; Saperstein et al 2006
), possibly reflecting differences in the schizotypy assessment instruments and WM tasks employed across studies. The current results suggest that the LNS Reordered impairments in the relatives reflect vulnerability to schizophrenia rather than the clinical or subclinical features of schizophrenia spectrum disorders assessed in this study.
Although verbal WM with an executive component clearly demonstrated some of the expected characteristics of an endophenotype for schizophrenia (Gottesman and Gould 2003
), the magnitudes of the separations between probands and family members, compared to CCS, were somewhat smaller than those found in previous studies using the same or comparable WM tasks (e.g., an effect size between probands and CCS on LNS Reordered of d = .94 in this study compared with effect sizes of 1.4 or greater in other studies (Conklin et al 2005
; Gold et al 1997
; Perry et al 2001
)). The medium patient versus CCS effect size for LNS forward (d = .54) was also somewhat smaller than previous studies of conventional digit span forward tasks (Aleman et al 1999
). Similarly, the magnitude of the relatives’ impairment on LNS Reordered (d= .36) was somewhat lower than that reported in a recent study (d = .56 (Conklin et al 2005
), and the magnitude of the non-significant difference between relatives and CCS on LNS Forward fell at the low end of the range for effect sizes for digit span forward tasks (Snitz et al 2006
; Trandafir et al 2006
The somewhat smaller but still significant separations among groups in the current study could be associated with two key methodological features of the COGS. First, the central aim of the COGS is to investigate the genetic determinants of quantitative endophenotypic traits, which requires sufficient “contrast” among affected and unaffected relatives to obtain statistical power. Enrolled families included at least two unaffected first-degree relatives of schizophrenia probands, a minimum family structure that resulted in somewhat larger pedigrees than those of most previous family studies. These rigorous selection criteria might have led to the inclusion of relatively intact patients and family members who were willing to complete the lengthy clinical and endophenotype assessments. Thus, the less marked group separations might reflect the possibility that these families are unusually intact with less severe manifestations of the illness compared to other studies. The normal-range WRAT-3 scores in the probands and the low proportion of relatives with lifetime histories of schizophrenia spectrum disorders appear consistent with this possibility.
Second, to parallel lifetime psychiatric comorbidity in relatives of probands, the COGS project includes CCS with disorders outside of the schizophrenia spectrum, whereas previous studies often excluded such participants (see (Snitz et al 2006
). This inclusion criterion enabled us to meaningfully examine the impact of comorbid diagnoses on LNS performance in the relatives and CCS, and minimizes potential confounds associated with the use of “super controls” (Kendler 1990
). However, the inclusion of comparison subjects with non-spectrum psychiatric disorders might create additional “noise” in the control sample and could have reduced the between-group separations on the WM tasks in the current study.
Another issue that deserves consideration is the task demands of the LNS-Forward task, which did not significantly differentiate the relative and CCS groups. This task emphasizes one aspect of WM maintenance, namely the “load” or number of items to be recalled. Tasks that assess other maintenance-related functions, such as the delay interval over which information must be maintained before recall, may show larger separations between relatives of schizophrenia probands and controls (e.g., (Park et al 1995
Genetic studies of complex quantitative endophenotypes require the use of large numbers of family cohorts, which are often only possible through multi-site collaborative efforts that use standardized recruitment and assessment procedures. The current findings demonstrate that the rigorous data collection and quality assurance procedures employed by the COGS can be successfully implemented for WM assessments across seven geographically diverse research sites, as we detected no significant site effects. Confidence in these methods is bolstered by initial heritability analyses of the primary endophenotypic measures from the COGS project, including the LNS Reordered (Greenwood et al 2007
). Based on a sample that largely overlaps with the current one, the observed heritability for LNS-Reordered was .39, which was among the highest of the candidate endophenotypes. This figure closely approximates previous heritability estimates for verbal and visual working memory (36-42%) in families of schizophrenia probands from a Finnish isolate with a different pedigree structure (Tuulio-Henriksson et al 2002
) and in non-clinical samples (Ando et al 2001
; Hansell et al 2005
These heritability figures, like those from other endophenotypes, are lower than the typical heritability estimates for schizophrenia (.80; (Owen et al 2002
). However, the COGS project recognizes a key distinction between heritability and “mapability” in genetics. Though highly heritable, the clinical diagnosis of schizophrenia comprises a diverse range of signs and symptoms that likely reflect a complex genetic architecture that impacts multiple, largely unspecified, neurobiological systems. The LNS and other COGS endophenotypes were carefully selected in an effort to increase mapability. Although the genetic architecture of these endophenotypes may also be somewhat complex (Flint and Munafo 2007
), the expectation is that they more directly reflect the activities of neuronal mechanisms than the illness itself. Several promising polymorphisms in candidate genes associated with WM performance have already been identified in both healthy subjects and in schizophrenia patients (e.g., (Cannon 2005
; Goldberg and Weinberger 2004
; Greenwood and Parasuraman 2003
; Parasuraman et al 2005
; Wedenoja et al in press
). The endophenotype strategy adopted by COGS is complementary to 20 years of genetic linkage and association studies using the clinical diagnosis of schizophrenia that have had modest success in identifying disease-related genes.
It should be noted that this report describes only part of a larger research project that involved an extensive assessment battery. Therefore, the possibility of error associated with multiple comparisons must be kept in mind in this type of large-scale project. The COGS continues to collect WM and other neurocognitive and neurophysiological performance data, as well as DNA on all proband and family member participants. In future reports, associations between WM task performance, performance on other COGS candidate endophenotypes, and DNA will ultimately be evaluated in accordance with our mission to identify genes that contribute to vulnerability for schizophrenia.