Robust differences in antisaccade performance exist between COGS schizophrenia cases and controls regardless of recruitment strategies

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Abstract

The impaired ability to make correct antisaccades (i.e., antisaccade performance) is well documented among schizophrenia subjects, and researchers have successfully demonstrated that antisaccade performance is a valid schizophrenia endophenotype that is useful for genetic studies. However, it is unclear how the ascertainment biases that unavoidably result from recruitment differences in schizophrenia subjects identified in family versus case–control studies may influence patient–control differences in antisaccade performance. To assess the impact of ascertainment bias, researchers from the Consortium on the Genetics of Schizophrenia (COGS) compared antisaccade performance and antisaccade metrics (latency and gain) in schizophrenia and control subjects from COGS-1, a family-based schizophrenia study, to schizophrenia and control subjects from COGS-2, a corresponding case–control study. COGS-2 schizophrenia subjects were substantially older; had lower education status, worse psychosocial function, and more severe symptoms; and were three times more likely to be a member of a multiplex family than COGS-1 schizophrenia subjects. Despite these variations, which were likely the result of ascertainment differences (as described in the introduction to this special issue), the effect sizes of the control–schizophrenia differences in antisaccade performance were similar in both studies (Cohen's d effect size of 1.06 and 1.01 in COGS-1 and COGS-2, respectively). This suggests that, in addition to the robust, state-independent schizophrenia-related deficits described in endophenotype studies, group differences in antisaccade performance do not vary based on subject ascertainment and recruitment factors.

Introduction

Past studies have demonstrated that schizophrenia (SZ) subjects are impaired in their ability to make correct antisaccades, especially in contrast to healthy control subjects (HCS). Evidence also suggests that antisaccade error rate (i.e., antisaccade performance) is specifically related to a biological diathesis toward SZ (Smyrnis et al., 2003, Nieman et al., 2007), whereas in mood disorders, antisaccade performance is likely associated with illness exacerbation but not with the illnesses themselves (Garcia-Blanco et al., 2013). The multisite NIMH-funded Consortium on the Genetics of Schizophrenia (COGS) has successfully built upon these well-demonstrated findings by using the antisaccade endophenotype in genetic association and linkage analyses of SZ (Greenwood et al., 2007, Greenwood et al., 2013). The first COGS study (COGS-1), for example, used family-based methods to examine the heritability and genetics of antisaccade performance and other SZ-related endophenotypes (Calkins et al., 2007). In this study, which enrolled a proband, at least one unaffected sibling, and in most cases, both parents, we found that antisaccade performance was significantly heritable (h2 = 0.42) (Greenwood et al., 2007). This finding parallels the work of Ettinger and colleagues (Ettinger et al., 2006), who found that oculomotor function was concordant in monozygotic twins. We also found robust differences between SZ subjects and HCS in antisaccade performance, highly significant differences between SZ subjects and HCS in the latency and gain of correct antisaccades (i.e., antisaccade metrics) (Radant et al., 2007, Radant et al., 2010), and suggestive evidence of antisaccade-related susceptibility regions (e.g., a linkage to 1q) (Greenwood et al., 2007, Greenwood et al., 2013) and genes (e.g., RELN, GRIK4, and HTR2A) (Greenwood et al., 2011). COGS-2 sought to extend these investigations via larger case–control genetic association studies.

Determining the effect of ascertainment strategy differences on endophenotypes is crucial for understanding genetic studies employing endophenotypes, as these studies tend to require specific recruitment procedures that, a priori, would be expected to result in ascertainment biases. For instance, familial studies such as COGS-1 require the participation of both a proband and at least one family member, and it is possible that affected subjects from these intact families may differ demographically, symptomatically, or in other ways from affected subjects in case–control genetic association studies who may not necessarily be in contact with other family members.

Given the increasing recognition of the utility of endophenotypes in genetics research (see Braff, this issue), it is particularly important to address these ascertainment-related issues. Yet to our knowledge, no study has examined the effects of ascertainment bias on the antisaccade endophenotype in SZ. Therefore, the COGS-1 and COGS-2 studies, which used identical oculomotor methods, provide an excellent opportunity to explore the effects that ascertainment bias may play in antisaccade performance and antisaccade metrics among SZ subjects and, ultimately, to extend our knowledge of the genomic substrates of these antisaccade deficits and their relationship to SZ.

Section snippets

Methods

Previous reports have described in detail the general study design of COGS-1 (Calkins et al., 2007) and COGS-2 (Swerdlow et al., 2014), as well as the specific oculomotor methods that were employed in both studies (Radant et al., 2007, Radant et al., 2010). In the COGS-1 and COGS-2 studies, we administered the antisaccade task to SZ subjects and HCS who spoke English, provided signed informed consent, and were between the ages of 18 and 65. COGS-1 subjects were recruited and tested at seven

Results

In the COGS-1 study, we obtained valid antisaccade data from 284 out of 345 (82%) SZ subjects who had at least one non-missing endophenotype, and 495 out of 517 (96%) HCS who had at least one non-missing endophenotype. In the COGS-2 study, we obtained valid antisaccade data from 997 out of 1039 (96%) SZ subjects who had at least one non-missing endophenotype, and 906 out of 917 (99%) HCS who had at least one non-missing endophenotype. Invalid data resulted from those rare instances in which the

Discussion

The COGS-1 and COGS-2 studies employed two different ascertainment strategies to successfully collect benchmark, large, cohort-based antisaccade data on SZ subjects and HCS for behavioral and subsequent genomic analyses. After adjusting for important covariates, there was no statistically significant difference between the antisaccade performance or metrics of subjects in COGS-1 and COGS-2.

Our discovery that SZ subjects from COGS-2 were three times more likely to belong to multiplex families

Funding

This material is based upon work supported (or supported in part) by the Office of Research and Development Medical Research Service (or) Health Services R&D Service, Department of Veterans Affairs. This study was supported by NIMH grants R01 MH65571, R01 MH65588, R01 MH65562, R01 MH65707, R01 MH65554, R01 MH65578, and R01 MH65558.

Contributors

Dr. Radant composed the manuscript and provided training and ongoing quality assurance for the antisaccade task at the COGS-1 and COGS-2 sites. Dr. Millard led the statistical analyses for the manuscript. All other authors participated in aspects of study design, including subject recruitment, antisaccade testing, and validation of the clinical and endophenotype data. All authors were responsible for reviewing, editing, and approving the final version of the manuscript.

Conflicts of interest

Dr. Green has been a consultant to AbbVie, Biogen, DSP, EnVivo/Forum and Roche, and he is on the scientific advisory board of Mnemosyne. He has received research funds from Amgen. Dr. Lazzeroni is an inventor on a patent application filed by Stanford University on genetic polymorphisms associated with depression. Dr. Light has been a consultant to EnVivo/Forum and Astellas and serves on an advisory board for Neuroverse. Dr. Nuechterlein has received unrelated research support from Janssen

Acknowledgment

The authors wish to thank all of the subjects and their family members for participating in this study. We also thank Andrew David for his editorial assistance.

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