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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., (Published by Elsevier B.V.)

Background: Neurocognitive deficits in schizophrenia (SZ) are established and the Consortium on the Genetics of Schizophrenia (COGS) investigated such measures as endophenotypes in family-based (COGS-1) and case-control (COGS-2) studies. By requiring family participation, family-based sampling may result in samples that vary demographically and perform better on neurocognitive measures., Methods: The Penn computerized neurocognitive battery (CNB) evaluates accuracy and speed of performance for several domains and was administered across sites in COGS-1 and COGS-2. Most tests were included in both studies. COGS-1 included 328 patients with SZ and 497 healthy comparison subjects (HCS) and COGS-2 included 1195 patients and 1009 HCS., Results: Demographically, COGS-1 participants were younger, more educated, with more educated parents and higher estimated IQ compared to COGS-2 participants. After controlling for demographics, the two samples produced very similar performance profiles compared to their respective controls. As expected, performance was better and with smaller effect sizes compared to controls in COGS-1 relative to COGS-2. Better performance was most pronounced for spatial processing while emotion identification had large effect sizes for both accuracy and speed in both samples. Performance was positively correlated with functioning and negatively with negative and positive symptoms in both samples, but correlations were attenuated in COGS-2, especially with positive symptoms., Conclusions: Patients ascertained through family-based design have more favorable demographics and better performance on some neurocognitive domains. Thus, studies that use case-control ascertainment may tap into populations with more severe forms of illness that are exposed to less favorable factors compared to those ascertained with family-based designs.

Objective: The Consortium on the Genetics of Schizophrenia has undertaken a large multisite study to characterize 12 neurophysiological and neurocognitive endophenotypic measures as a step toward understanding the complex genetic basis of schizophrenia. The authors previously demonstrated the heritability of these endophenotypes; in the present study, genetic linkage was evaluated., Method: Each family consisted of a proband with schizophrenia, at least one unaffected sibling, and both parents. A total of 1,286 participants from 296 families were genotyped in two phases, and 1,004 individuals were also assessed for the endophenotypes. Linkage analyses of the 6,055 single-nucleotide polymorphisms that were successfully assayed, 5,760 of which were common to both phases, were conducted using both variance components and pedigree-wide regression methods., Results: Linkage analyses of the 12 endophenotypes collectively identified one region meeting genome-wide significance criteria, with a LOD (log of odds) score of 4.0 on chromosome 3p14 for the antisaccade task, and another region on 1p36 nearly meeting genome-wide significance, with a LOD score of 3.5 for emotion recognition. Chromosomal regions meeting genome-wide suggestive criteria with LOD scores >2.2 were identified for spatial processing (2p25 and 16q23), sensorimotor dexterity (2q24 and 2q32), prepulse inhibition (5p15), the California Verbal Learning Test (8q24), the degraded-stimulus Continuous Performance Test (10q26), face memory (10q26 and 12p12), and the Letter-Number Span (14q23)., Conclusions: Twelve regions meeting genome-wide significant and suggestive criteria for previously identified heritable, schizophrenia-related endophenotypes were observed, and several genes of potential neurobiological interest were identified. Replication and further genomic studies are needed to assess the biological significance of these results.

Objective: The authors used a custom array of 1,536 single-nucleotide polymorphisms (SNPs) to interrogate 94 functionally relevant candidate genes for schizophrenia and identify associations with 12 heritable neurophysiological and neurocognitive endophenotypes in data collected by the Consortium on the Genetics of Schizophrenia., Method: Variance-component association analyses of 534 genotyped subjects from 130 families were conducted by using Merlin software. A novel bootstrap total significance test was also developed to overcome the limitations of existing genomic multiple testing methods and robustly demonstrate significant associations in the context of complex family data and possible population stratification effects., Results: Associations with endophenotypes were observed for 46 genes of potential functional significance, with three SNPs at p<10(-4), 27 SNPs at p<10(-3), and 147 SNPs at p<0.01. The bootstrap analyses confirmed that the 47 SNP-endophenotype combinations with the strongest evidence of association significantly exceeded that expected by chance alone, with 93% of these findings expected to be true. Many of the genes interact on a molecular level, and eight genes (e.g., NRG1 and ERBB4) displayed evidence for pleiotropy, revealing associations with four or more endophenotypes. The results collectively support a strong role for genes related to glutamate signaling in mediating schizophrenia susceptibility., Conclusions: This study supports use of relevant endophenotypes and the bootstrap total significance test for identifying genetic variation underlying the etiology of schizophrenia. In addition, the observation of extensive pleiotropy for some genes and singular associations for others suggests alternative, independent pathways mediating pathogenesis in the "group of schizophrenias."

Genetic studies of schizophrenia focus increasingly on putative endophenotypes because their genetic etiology may be simpler than clinical diagnosis. The Consortium on the Genetics of Schizophrenia (COGS), a multisite family study, aims to identify the genetic basis of several endophenotypes including verbal declarative memory (VDM), a neurocognitive function that shows robust impairment in schizophrenia. We present data on one type of measure of VDM, the California Verbal Learning Test, Second Edition (CVLT-II), in schizophrenia probands (n=305), their full biological siblings (n=449) and parents (n=232), and in community comparison subjects (CCS; n=509) across seven sites. Probands performed more poorly on each of five CVLT-II measures compared to related sibling and parent groups and CCS. Siblings and parents performed significantly worse than CCS on one measure (Discriminability), but with smaller effect sizes and less impairment than observed previously. The results raise questions about the homogeneity of VDM as an endophenotype, about methodological issues related to sampling, and about psychometric issues that impact the utility of the CVLT for detecting VDM deficits in nonpsychotic relatives of persons with schizophrenia., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The antisaccade task is a widely used technique to measure failure of inhibition, an important cause of cognitive and clinical abnormalities found in schizophrenia. Although antisaccade performance, which reflects the ability to inhibit prepotent responses, is a putative schizophrenia endophenotype, researchers have not consistently reported the expected differences between first-degree relatives and comparison groups. Schizophrenia participants (n=219) from the large Consortium on the Genetics of Schizophrenia (COGS) sample (n=1078) demonstrated significant deficits on an overlap version of the antisaccade task compared to their first-degree relatives (n=443) and community comparison subjects (CCS; n=416). Although mean antisaccade performance of first-degree relatives was intermediate between schizophrenia participants and CCS, a linear mixed-effects model adjusting for group, site, age, and gender found no significant performance differences between the first-degree relatives and CCS. However, admixture analyses showed that two components best explained the distributions in all three groups, suggesting two distinct doses of an etiological factor. Given the significant heritability of antisaccade performance, the effects of a genetic polymorphism is one possible explanation of our results.

Inhibition of the P50 evoked electroencephalographic response to the second of paired auditory stimuli has been frequently examined as a neurophysiological deficit in schizophrenia. The Consortium on the Genetics of Schizophrenia (COGS), a 7-site study funded by the National Institute of Mental Health, examined this endophenotype in recordings from 181 probands with schizophrenia, 429 of their first degree relatives, and 333 community comparison control subjects. Most probands were treated with second generation antipsychotic medications. Highly significant differences in P50 inhibition, measured as either the ratio of amplitudes or their difference in response to the two stimuli, were found between the probands and the community comparison sample. There were no differences between the COGS sites for these findings. For the ratio parameter, an admixture analysis found that nearly 40% of the relatives demonstrated deficiencies in P50 inhibition that are comparable to the deficit found in the probands. These results indicate that P50 auditory evoked potentials can be recorded across multiple sites and reliably demonstrate a physiological abnormality in schizophrenia. The appearance of the physiological abnormality in a substantial proportion of clinically unaffected first degree relatives is consistent with the hypothesis that deficits in cerebral inhibition are a familial neurobiological risk factor for the illness., (Published by Elsevier B.V.)

Background: N100 evoked potential amplitude and gating abnormalities have been widely observed in schizophrenia patients. However, previous studies have been inconclusive as to whether similar deficits are present in unaffected family members. The Consortium on the Genetics of Schizophrenia (COGS) is a multisite National Institute of Mental Health (NIMH) initiative examining neurocognitive and neurophysiological measures as endophenotypes for genetic studies of schizophrenia. We report initial results from the COGS dataset of auditory N100 amplitude and gating as candidate endophenotypes., Methods: Evoked potential data were acquired from 142 schizophrenia probands, 373 unaffected first-degree relatives, and 221 community comparison subjects (CCS), using an auditory paired-click stimulation paradigm. Amplitude of the N100 response to each click and the click 2/click 1 ratio were dependent variables. Heritability was estimated based on kinships using Solar v.2.1.2. Group differences were examined after subjects were categorized as either "broad" or "narrow," based on the presence (broad) or absence (narrow) of nonpsychotic psychiatric comorbidity., Results: Heritability estimates were .40 and .29 for click1 and click2 amplitudes and .22 for the ratio. Broad and narrow patients both had impaired click 1 amplitudes. Broad relatives, but not narrow relatives, exhibited similar impairments. There were no group differences for either click 2 amplitude or the gating ratio., Conclusions: N100 amplitude is a heritable measure that is abnormal in patients and a subset of relatives for whom psychiatric comorbidity may be a genetically associated phenotype. Auditory N100 gating, although heritable, is less viable as a schizophrenia endophenotype.

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.

Context: Exploration of the genetic architecture of specific endophenotypes may be a powerful strategy for understanding the genetic basis of schizophrenia., Objective: To characterize the genetic architecture of some key endophenotypic measures selected for their reported heritabilities in schizophrenia., Design: Family-based heritability study., Setting: Seven sites across the United States., Participants: At the time of these initial data analyses, the members of 183 nuclear families ascertained through probands with schizophrenia had been assessed for these endophenotypes., Main Outcome Measures: Variance component models were used to assess the heritability of and the environmental and genetic correlations among the endophenotypes. The Consortium on the Genetics of Schizophrenia assesses the neurophysiologic measures of prepulse inhibition of acoustic startle, P50 event-related potential suppression, and the antisaccade task for eye movements and the neurocognitive measures of the Continuous Performance Test (Degraded Stimulus version), the California Verbal Learning Test, the Letter-Number Sequencing test, and 6 measures from the University of Pennsylvania Computerized Neurocognitive Battery. The heritabilities of these 12 measures are the focus of this article., Results: All of the endophenotypes and the University of Pennsylvania Computerized Neurocognitive Battery measures were found to be significantly heritable (P < or = .005), with heritabilities ranging from 24% to 55%. Significant environmental and genetic correlations were also observed between many of the endophenotypic measures., Conclusion: This is the first large-scale, multisite, family-based heritability study of a collection of endophenotypes for schizophrenia and suggests that endophenotypes are important measures to consider in characterizing the genetic basis of schizophrenia.

Background: Startle and its inhibition by weak lead stimuli ("prepulse inhibition": PPI) are studied to understand the neurobiology of information processing in patients and community comparison subjects (CCS). PPI has a strong genetic basis in infrahumans, and there is evidence for its heritability, stability and reliability in humans. PPI has gained increasing use as an endophenotype to identify vulnerability genes for brain disorders, including schizophrenia. Genetic studies now often employ multiple, geographically dispersed test sites to accommodate the need for large and complex study samples. Here, we assessed the feasibility of using PPI in multi-site studies., Methods: Within a 7-site investigation with multiple measures, the Consortium on the Genetics of Schizophrenia conducted a methodological study of acoustic startle and PPI in CCS. Methods were manualized, videotaped and standardized across sites with intensive in-person training sessions. Equipment was acquired and programmed at the "PPI site" (UCSD), and stringent quality assurance (QA) procedures were used. Testing was completed on 196 CCS over 2.5 years, with 5 primary startle dependent measures: eyeblink startle magnitude, habituation, peak latency, latency facilitation and PPI., Results: Analyses identified significant variability across sites in some but not all primary measures, and determined factors both within the testing process and subject characteristics that influenced a number of test measures. QA procedures also identified non-standardized practices with respect to testing methods and procedural "drift", which may be particularly relevant to multi-site studies using these measures., Conclusion: With thorough oversight and QA procedures, measures of acoustic startle PPI can be acquired reliably across multiple testing sites. Nonetheless, even among sites with substantial expertise in utilizing psychophysiological measures, multi-site studies using startle and PPI as dependent measures require careful attention to methodological procedures.

The antisaccade task is a promising schizophrenia endophenotype; it is stable over time and reflects neurophysiological deficits present in both schizophrenia subjects and their first-degree relatives. Meaningful genetic research requires large sample sizes that are best ascertained using multi-site study designs. To establish the criterion validity of the antisaccade task in a multi-site design, the Consortium on the Genetics of Schizophrenia (COGS) examined whether seven sites could detect previously reported antisaccade deficits in schizophrenia subjects. Investigators presented 3 blocks of 20 antisaccade stimuli to 143 schizophrenia subjects and 195 comparison subjects. Frequent collaborator communication, standardized training, and ongoing quality assurance optimized testing uniformity. Data were discarded from only 1.2% of subjects due to poor quality, reflecting the high fidelity of data collection and scoring methods. All sites detected a significant difference in the proportion of correct antisaccades between schizophrenia and comparison subjects (p<.02 at all sites); group differences in gain and latency were less robust. Regression analyses to adjust for the effects of group, site, age, gender, smoking, and parental education on the proportion of correct antisaccades revealed a significant effect of group, site, and age but no effect of gender, smoking, or parental education, and no group-by-site interactions. Intraclass correlations between proportion of correct antisaccades across the blocks of stimuli ranged from 0.87 to 0.93, demonstrating good within-session reliability at sites. These results confirm previous findings of antisaccade deficits in schizophrenia subjects and support the use of the antisaccade task as a potential schizophrenia endophenotype in multi-site genetic studies.

Background: The Consortium on the Genetics of Schizophrenia (COGS) is an ongoing, National Institute of Mental Health-funded, 7-site collaboration investigating the occurrence and genetic architecture of quantitative endophenotypes related to schizophrenia. The purpose of this article is to provide a description of the COGS structure and methods, including participant recruitment and assessment., Methods: The hypothesis-driven recruitment strategy ascertains families that include a proband with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia, and at least one unaffected full sibling available for genotyping and endophenotyping, along with parents available for genotyping and (optional depending on age) endophenotyping. The family structure is selected to provide contrast in quantitative endophenotypic traits and thus to maximize the power of the planned genetic analyses. Probands are recruited from many sources including clinician referrals, local National Alliance for the Mentally Ill chapters, and advertising via the media. All participants undergo a standardized protocol that includes clinical characterization, a blood draw for genotyping, and endophenotype assessments (P50 suppression, prepulse inhibition, antisaccade performance, continuous performance tasks, letter-number span, verbal memory, and a computerized neurocognitive battery). Investigators participate in weekly teleconferences to coordinate and evaluate recruitment, clinical assessment, endophenotyping, and continuous quality control of data gathering and analyses. Data integrity is maintained through use of a highly quality-assured, centralized web-based database., Results: As of February 2006, 355 families have been enrolled and 688 participants have been endophenotyped, including schizophrenia probands (n = 154, M:F = 110:44), first-degree biological relatives (n = 343, M:F = 151:192), and community comparison subjects (n = 191, M:F = 81:110)., Discussion: Successful multisite genetics collaborations must institute standardized methodological criteria for assessment and recruitment that are clearly defined, well communicated, and uniformly applied. In parallel, studies utilizing endophenotypes require strict adherence to criteria for cross-site data acquisition, equipment calibration and testing and software equivalence, and continuous quality assurance for many measures obtained across sites. This report describes methods and presents the structure of the COGS as a model of multisite endophenotype genetic studies. It also provides demographic information after the first 2 years of data collection on a sample for whom the behavioral data and genetics of endophenotype performance will be fully characterized in future articles. Some issues discussed in the reviews that follow reflect the challenges of evaluating endophenotypes in studies of the genetic architecture of endophenotypes in schizophrenia.