Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Heritability and polygenic predictionIn the EUR sample, the SNP-based heritability (h 2 SNP ) (that is, the proportion of variance in liability attributable to all measured SNPs)

In an effort to reveal susceptibility genes, schizophrenia research has turned to the endophenotype strategy. Endophenotypes are characteristics that reflect the actions of genes predisposing an individual to a disorder, even in the absence of diagnosable pathology. Individual endophenotypes are presumably determined by fewer genes than the more complex phenotype of schizophrenia and would, therefore, reduce the complexity of genetic analyses. Unfortunately, despite there being rational criteria to define a viable endophenotype, the term is sometimes applied indiscriminately to characteristics that are deviant in affected individuals. Schizophrenia patients exhibit deficits in several neurophysiological measures of information processing that have been proposed as candidate endophenotypes. Successful processing of sensory inputs requires the ability to inhibit intrinsic responses to redundant stimuli and, reciprocally, to facilitate responses to less frequent salient stimuli. There is evidence to suggest that both these processes are "impaired" in schizophrenia. Measures of inhibitory failure include prepulse inhibition of the startle reflex, P50 auditory evoked potential suppression, and antisaccade eye movements. Measures of impaired deviance detection include mismatch negativity and the P300 event-related potential. The purpose of this review is to systematically evaluate the endophenotype candidacy of these key neurophysiological abilities. For each candidate, we describe typical experimental procedures, the current understanding of the underlying neurobiology, the nature of the abnormality in schizophrenia, the reliability, stability and heritability of the measure, and any reported gene associations. We conclude with a discussion of the few studies thus far that have employed a multivariate approach with these candidates.

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.

These data support the efficacy of prazosin for nightmares, sleep disturbance, and other PTSD symptoms.

Objective We have used a custom 1,536-SNP array to interrogate 94 functionally relevant candidate genes for schizophrenia and identify associations with 12 heritable neurophysiological and neurocognitive endophenotypes collected as part of the Consortium on the Genetics of Schizophrenia (COGS). Method Variance-component association analyses of 534 genotyped subjects from 130 families were conducted using Merlin. A novel bootstrap Total Significance Test was also developed to overcome the limitations of existing genomic multiple testing methods and robustly demonstrate the presence of significant associations in the context of complex family data and possible population stratification effects. Results Associations were observed for 46 genes of potential functional significance with 3 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 (p=0.001) 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 displayed evidence for pleiotropy (e.g., NRG1 and ERBB4), revealing associations with four or more endophenotypes. Our results collectively support a strong role for genes related to glutamate signaling in mediating schizophrenia susceptibility. Conclusions This study supports the use of relevant endophenotypes and the bootstrap Total Significance Test for the identification of genetic variation underlying the etiology of schizophrenia. In addition, the observation of extensive pleiotropy for some genes and singular associations for others in our data suggests alternative, independent pathways mediating pathogenesis in the “group of schizophrenias”.

BackgroundEndophenotypes are quantitative, laboratory-based measures representing intermediate links in the pathways between genetic variation and the clinical expression of a disorder. Ideal endophenotypes exhibit deficits in patients, are stable over time and across shifts in psychopathology, and are suitable for repeat testing. Unfortunately, many leading candidate endophenotypes in schizophrenia have not been fully characterized simultaneously in large cohorts of patients and controls across these properties. The objectives of this study were to characterize the extent to which widely-used neurophysiological and neurocognitive endophenotypes are: 1) associated with schizophrenia, 2) stable over time, independent of state-related changes, and 3) free of potential practice/maturation or differential attrition effects in schizophrenia patients (SZ) and nonpsychiatric comparison subjects (NCS). Stability of clinical and functional measures was also assessed.MethodsParticipants (SZ n = 341; NCS n = 205) completed a battery of neurophysiological (MMN, P3a, P50 and N100 indices, PPI, startle habituation, antisaccade), neurocognitive (WRAT-3 Reading, LNS-forward, LNS-reorder, WCST-64, CVLT-II). In addition, patients were rated on clinical symptom severity as well as functional capacity and status measures (GAF, UPSA, SOF). 223 subjects (SZ n = 163; NCS n = 58) returned for retesting after 1 year.ResultsMost neurophysiological and neurocognitive measures exhibited medium-to-large deficits in schizophrenia, moderate-to-substantial stability across the retest interval, and were independent of fluctuations in clinical status. Clinical symptoms and functional measures also exhibited substantial stability. A Longitudinal Endophenotype Ranking System (LERS) was created to rank neurophysiological and neurocognitive biomarkers according to their effect sizes across endophenotype criteria.ConclusionsThe majority of neurophysiological and neurocognitive measures exhibited deficits in patients, stability over a 1-year interval and did not demonstrate practice or time effects supporting their use as endophenotypes in neural substrate and genomic studies. These measures hold promise for informing the “gene-to-phene gap” in schizophrenia research.

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.

Importance Neurophysiological measures of early auditory information processing (EAP) are used as endophenotypes in genomic studies and biomarkers in clinical intervention studies. Research in schizophrenia has established correlations among measures of EAP, cognition, clinical symptoms, and functional outcome. Clarifying these relationships by determining the pathways through which deficits in EAP affect functioning would suggest when and where to therapeutically intervene. Objective We sought to characterize the pathways from EAP to outcome and to estimate the extent to which enhancement of basic information processing might improve both cognition and psychosocial functioning in schizophrenia. Design Cross-sectional data were analyzed using structural equation modeling to examine the associations between EAP, cognition, negative symptoms, and functional outcome. Setting Participants were recruited from the community at five geographically distributed laboratories as part of the Consortium on the Genetics of Schizophrenia-2 (COGS-2). Participants This well-characterized cohort of schizophrenia patients (N = 1,415) underwent EAP and cognitive testing as well as thorough clinical and functional assessment. Main Outcome and Measures EAP was measured by mismatch negativity, P3a, and reorienting negativity. Cognition was measured by the Letter Number Span test and scales from the California Verbal Learning Test - Second Edition, the Wechsler Memory Scale Third Edition, and the Penn Computerized Neurocognitive Battery. Negative symptoms were measured by the Scale for the Assessment of Negative Symptoms. Functional outcome was measured by the Role Functioning Scale. Results EAP had a direct effect on cognition (β = 0.37, p < .001), cognition had a direct effect on negative symptoms (β = −0.16, p < .001), and both cognition (β = 0.26, p < .001) and experiential negative symptoms (β = −0.75, p < .001) had direct effects on functional outcome. Overall, EAP had a fully mediated effect on functional outcome, engaging general rather than modality-specific cognition, with separate pathways that either involved or bypassed negative symptoms. Conclusions and Relevance The data support a model where EAP deficits lead to poor functional outcome via impaired cognition and increased negative symptoms. Results can be used to help guide mechanistically informed, personalized treatments, and support the strategy of using EAP measures as surrogate endpoints in early stage pro-cognitive intervention studies.