Electrophysiological Endophenotypes for Schizophrenia.
Ontology highlight
ABSTRACT:
SUBMITTER: Owens EM
PROVIDER: S-EPMC4785844 | biostudies-literature | 2016 Mar-Apr
REPOSITORIES: biostudies-literature
Publications
Electrophysiological Endophenotypes for Schizophrenia.
Owens Emily M EM Bachman Peter P Glahn David C DC Bearden Carrie E CE
Harvard review of psychiatry 20160301 2
Endophenotypes are quantitative, heritable traits that may help to elucidate the pathophysiologic mechanisms underlying complex disease syndromes, such as schizophrenia. They can be assessed at numerous levels of analysis; here, we review electrophysiological endophenotypes that have shown promise in helping us understand schizophrenia from a more mechanistic point of view. For each endophenotype, we describe typical experimental procedures, reliability, heritability, and reported gene and neuro ...[more]
Similar Datasets
Project description:Several event-related potentials (ERP), including P3, sensory gating (P50), and gamma oscillation, are robustly impaired in patients with schizophrenia (SCZ) and bipolar disorder (BIP). Although these ERPs are known to be heritable, little is known about the specific genetic loci involved and the degree to which they overlap with loci influencing mood and psychotic disorders. In the present study, we conducted GWAS to a) identify common variants associated with ERP endophenotypes, and b) construct polygenic risk scores (PRS) to examine overlap between genetic components of ERPs and mood and psychotic disorders. The sample consisted of 271 patients with SCZ or psychotic BIP diagnosis and 128 controls for whom ERP and genomewide data were available. GWAS were conducted using the full sample. PRS, derived from the Psychiatric Genomics Consortium (PGC) analyses of SCZ, BIP, and major depressive disorder were applied to each ERP phenotype. We identified a region on chromosome 14 that was significantly associated with sensory gating (peak SNP rs10132223, P?=?1.27?×?10(-9) ). This locus has not been previously associated with psychotic illness in PGC-GWAS. In the PRS analyses, patients with a higher load of SCZ risk alleles had reduced gamma response whereas patients with a higher load of BIP risk alleles had smaller P3 amplitude. We observed a genomewide significant locus on chromosome 14 for P50. This locus may influence P50 but not psychotic illness. Among patients with psychotic illness, PRS results indicated genetic overlap between SCZ loci and gamma oscillation and between BIP loci and P3 amplitude.
| S-EPMC4458348 | biostudies-literature
Project description:BackgroundAlthough case-control approaches are beginning to disentangle schizophrenia's complex polygenic burden, other methods will likely be necessary to fully identify and characterize risk genes. Endophenotypes, traits genetically correlated with an illness, can help characterize the impact of risk genes by providing genetically relevant traits that are more tractable than the behavioral symptoms that classify mental illness. Here, we present an analytic approach for discovering and empirically validating endophenotypes in extended pedigrees with very few affected individuals. Our approach indexes each family member's risk as a function of shared genetic kinship with an affected individual, often referred to as the coefficient of relatedness. To demonstrate the utility of this approach, we search for neurocognitive and neuroanatomic endophenotypes for schizophrenia in large unselected multigenerational pedigrees.MethodsA fixed-effects test within the variance component framework was performed on neurocognitive and cortical surface area traits in 1606 Mexican-American individuals from large, randomly ascertained extended pedigrees who participated in the Genetics of Brain Structure and Function study. As affecteds were excluded from analyses, results were not influenced by disease state or medication usage.ResultsDespite having sampled just 6 individuals with schizophrenia, our sample provided 233 individuals at various levels of genetic risk for the disorder. We identified three neurocognitive measures (digit-symbol substitution, facial memory, and emotion recognition) and six medial temporal and prefrontal cortical surfaces associated with liability for schizophrenia.ConclusionsWith our novel analytic approach, one can discover and rank endophenotypes for schizophrenia, or any heritable disease, in randomly ascertained pedigrees.
| S-EPMC4261014 | biostudies-literature
Project description:Endophenotypes represent intermediate phenotypes on the putative causal pathway from the genotype to the phenotype. They offer a potentially valuable strategy to examine the molecular etiopathology of complex behavioral phenotypes such as schizophrenia. Neurocognitive and neurophysiological impairments that suggest functional impairments associated with schizophrenia have been proposed as endophenotypes. However, few studies have examined the structural variations in the brain that might underlie the functional impairments as useful endophenotypes for schizophrenia. Over the past three decades, there has been an impressive body of literature supporting brain structural alterations in schizophrenia. We critically reviewed the extant literature on the neuroanatomical variations in schizophrenia in this paper to evaluate their candidacy as endophenotypes and how useful they are in furthering the understanding of etiology and pathophysiology of schizophrenia. Brain morphometric measures meet many of the criteria set by different investigators, such as being robustly associated with schizophrenia, heritable, quantifiable, and present in unaffected family members more frequently than in the general population. We conclude that the brain morphometric alterations appear largely to meet the criteria for endophenotypes in psychotic disorders. Some caveats for the utility of endophenotypes are discussed. A proposal to combine more than one endophenotype ("extended endophenotype") is suggested. Further work is needed to examine how specific genes and their interactions with the environment may produce alterations in brain structure and function that accompany psychotic disorders.
| S-EPMC2632444 | biostudies-literature
Project description:ObjectiveWe performed a whole-genome expression study to clarify the nature of the biological processes mediating between inherited genetic variations and cognitive dysfunction in schizophrenia.MethodGene expression was assayed from peripheral blood mononuclear cells using Illumina Human WG6 v3.0 chips in twins discordant for schizophrenia or bipolar disorder and control twins. After quality control, expression levels of 18,559 genes were screened for association with the California Verbal Learning Test (CVLT) performance, and any memory-related probes were then evaluated for variation by diagnostic status in the discovery sample (N = 190), and in an independent replication sample (N = 73). Heritability of gene expression using the twin design was also assessed.ResultsAfter Bonferroni correction (p < 2.69 × 10-6), CVLT performance was significantly related to expression levels for 76 genes, 43 of which were differentially expressed in schizophrenia patients, with comparable effect sizes in the same direction in the replication sample. For 41 of these 43 transcripts, expression levels were heritable. Nearly all identified genes contain common or de novo mutations associated with schizophrenia in prior studies.ConclusionGenes increasing risk for schizophrenia appear to do so in part via effects on signaling cascades influencing memory. The genes implicated in these processes are enriched for those related to RNA processing and DNA replication and include genes influencing G-protein coupled signal transduction, cytokine signaling, and oligodendrocyte function.
| S-EPMC4693618 | biostudies-literature
Project description:While it is clear that schizophrenia is highly heritable, the genetic basis of this heritability is complex. Human genetic, brain imaging, and model organism studies have met with only modest gains. A complementary research tactic is to evaluate the genetic substrates of quantitative endophenotypes with demonstrated deficits in schizophrenia patients. We used an Illumina custom 1,536-SNP array to interrogate 94 functionally relevant candidate genes for schizophrenia and evaluate association with both the qualitative diagnosis of schizophrenia and quantitative endophenotypes for schizophrenia. Subjects included 219 schizophrenia patients and normal comparison subjects of European ancestry and 76 schizophrenia patients and normal comparison subjects of African ancestry, all ascertained by the UCSD Schizophrenia Research Program. Six neurophysiological and neurocognitive endophenotype test paradigms were assessed: prepulse inhibition (PPI), P50 suppression, the antisaccade oculomotor task, the Letter-Number Span Test, the California Verbal Learning Test-II, and the Wisconsin Card Sorting Test-64 Card Version. These endophenotype test paradigms yielded six primary endophenotypes with prior evidence of heritability and demonstrated schizophrenia-related impairments, as well as eight secondary measures investigated as candidate endophenotypes. Schizophrenia patients showed significant deficits on ten of the endophenotypic measures, replicating prior studies and facilitating genetic analyses of these phenotypes. A total of 38 genes were found to be associated with at least one endophenotypic measure or schizophrenia with an empirical p-value<0.01. Many of these genes have been shown to interact on a molecular level, and eleven genes displayed evidence for pleiotropy, revealing associations with three or more endophenotypic measures. Among these genes were ERBB4 and NRG1, providing further support for a role of these genes in schizophrenia susceptibility. The observation of extensive pleiotropy for some genes and singular associations for others in our data may suggest both converging and independent genetic (and neural) pathways mediating schizophrenia risk and pathogenesis.
| S-EPMC3258248 | biostudies-literature
Project description:BackgroundThe utility of an endophenotype depends on its ability to reduce complex disorders into stable, genetically linked phenotypes. P50 and P300 event-related potential (ERP) measures are endophenotype candidates for schizophrenia; however, their abnormalities are broadly observed across neuropsychiatric disorders. This study examined the diagnostic efficiency of P50 and P300 in schizophrenia as compared with healthy and bipolar disorder samples. Supplemental ERP measures and a multivariate classification approach were evaluated as methods to improve specificity.MethodsDiagnostic classification was first modeled in schizophrenia (SZ = 50) and healthy normal (HN = 50) samples using hierarchical logistic regression with predictors blocked by 4 levels of analysis: (1) P50 suppression, P300 amplitude, and P300 latency; (2) N100 amplitude; (3) evoked spectral power; and (4) P50 and P300 hemispheric asymmetry. The optimal model was cross-validated in a holdout sample (SZ = 34, HN = 31) and tested against a bipolar (BP = 50) sample.ResultsP50 and P300 endophenotypes classified SZ from HN with 71% accuracy (sensitivity = .70, specificity = .72) but did not differentiate SZ from BP above chance level. N100 and spectral power measures improved classification accuracy of SZ vs HN to 79% (sensitivity = .78, specificity = .80) and SZ vs BP to 72% (sensitivity = .74, specificity = .70). Cross validation analyses supported the stability of these models.ConclusionsAlthough traditional P50 and P300 measures failed to differentiate schizophrenia from bipolar participants, N100 and evoked spectral power measures added unique variance to classification models and improved accuracy to nearly the same level achieved in comparison of schizophrenia to healthy individuals.
| S-EPMC3796068 | biostudies-literature
Project description:Endophenotypes are disease-associated phenotypes that are thought to reflect the neurobiological or other mechanisms that underlie the more overt symptoms of a psychiatric illness. Endophenotypes have been critical in understanding the genetics, neurobiology, and treatment of schizophrenia. Because psychiatric illnesses have multiple causes, including both genetic and nongenetic risk factors, an endophenotype linked to one of the mechanisms may be expressed more frequently than the disease itself. However, in schizophrenia research, endophenotypes have almost exclusively been studied in older adolescents or adults who have entered or passed through the age of risk for the disorder. Yet, schizophrenia is a neurodevelopmental disorder where prenatal development starts a cascade of brain changes across the lifespan. Endophenotypes have only minimally been utilized to explore the perinatal development of vulnerability. One major impediment to the development of perinatally-useful endophenotypes has been the established validity criteria. For example, the criterion that the endophenotype be more frequently present in those with disease than those without is difficult to demonstrate when there can be a decades-long period between endophenotype measurement and the age of greatest risk for onset of the disorder. This article proposes changes to the endophenotype validity criteria appropriate to perinatal research and reviews how application of these modified criteria helped identify a perinatally-usable phenotype of risk for schizophrenia, P50 sensory gating, which was then used to propose a novel perinatal primary prevention intervention.
| S-EPMC4466194 | biostudies-literature
Project description:BackgroundEndophenotypes are laboratory-based measures hypothesized to lie in the causal chain between genes and clinical disorder, and to serve as a more powerful way to identify genes associated with the disorder. One promise of endophenotypes is that they may assist in elucidating the neurobehavioral mechanisms by which an associated genetic polymorphism affects disorder risk in complex traits. We evaluated this promise by testing the extent to which variants discovered to be associated with schizophrenia through large-scale meta-analysis show associations with psychophysiological endophenotypes.MethodWe genome-wide genotyped and imputed 4905 individuals. Of these, 1837 were whole-genome-sequenced at 11× depth. In a community-based sample, we conducted targeted tests of variants within schizophrenia-associated loci, as well as genome-wide polygenic tests of association, with 17 psychophysiological endophenotypes including acoustic startle response and affective startle modulation, antisaccade, multiple frequencies of resting electroencephalogram (EEG), electrodermal activity and P300 event-related potential.ResultsUsing single variant tests and gene-based tests we found suggestive evidence for an association between contactin 4 (CNTN4) and antisaccade and P300. We were unable to find any other variant or gene within the 108 schizophrenia loci significantly associated with any of our 17 endophenotypes. Polygenic risk scores indexing genetic vulnerability to schizophrenia were not related to any of the psychophysiological endophenotypes after correction for multiple testing.ConclusionsThe results indicate significant difficulty in using psychophysiological endophenotypes to characterize the genetically influenced neurobehavioral mechanisms by which risk loci identified in genome-wide association studies affect disorder risk.
| S-EPMC5352523 | biostudies-literature
Project description:BACKGROUND:Quantitative endophenotypes are needed to better understand the pathogenesis of schizophrenia. The psychobiological model of temperament and character suggests that personality traits are heritable and regulated by brain systems influencing schizophrenia susceptibility. Thus, measures of temperament and character may serve as schizophrenia-related endophenotypes in individuals with schizophrenia and their non-psychotic siblings. METHODS:Individuals with schizophrenia (n=35), their non-psychotic siblings (n=34), controls (n=63), and their siblings (n=56) participated in a study of the clinical, neurocognitive and neuromorphological characteristics of schizophrenia. A mixed-model approach assessed group differences on the Temperament and Character Inventory (TCI). Neurocognitive deficits and psychopathology were correlated with the TCI. Configurations of TCI domains were examined using a generalized linear model. RESULTS:Individuals with schizophrenia and their non-psychotic siblings had higher harm avoidance than controls and their siblings. Individuals with schizophrenia had lower self-directedness and cooperativeness, and higher self-transcendence than their non-psychotic siblings, controls, and the siblings of controls. Neurocognition was not related to temperament and character in individuals with schizophrenia or either control group. In non-psychotic siblings, self-directedness and cooperativeness were correlated with working memory and crystallized IQ. CONCLUSION:Evidence supports harm avoidance as a schizophrenia-related endophenotype. An increased risk of schizophrenia may be associated with asociality (configured as high harm avoidance and low reward dependence), schizotypy (configured as low self-directedness, low cooperativeness, and high self-transcendence), and neurocognitive deficits (poor executive functioning, working/episodic memory, attention, and low IQ). The non-psychotic siblings demonstrated features of a mature character profile including strong crystallized IQ, which may confer protection against psychopathology.
| S-EPMC2565802 | biostudies-literature
Project description:Reelin has been implicated in the development of schizophrenia but the mechanisms involved in this interaction remain unclear. Chronic methamphetamine (Meth) use may cause dopaminergic sensitisation and psychosis and has been proposed to affect brain dopamine systems similarly to changes seen in schizophrenia. We compared the long-term effect of chronic Meth treatment between heterozygous reelin mice (HRM) and wildtype controls (WT) with the aim of better understanding the role of reelin in schizophrenia. Meth pretreatment induced sensitisation to the effect of an acute Meth challenge on locomotor activity, but it had no effect on baseline PPI or sociability and social preference. In all behavioural models, HRM did not significantly differ from WT at baseline, except spontaneous exploratory locomotor activity which was higher in HRM than WT, and sociability which was enhanced in HRM. Locomotor hyperactivity sensitisation was not significantly different between HRM and WT. Chronic Meth treatment reduced spontaneous locomotor activity to the level of WT. No deficits in PPI or social behaviour were induced by chronic Meth pretreatment in either strain. In conclusion, these data do not support a role of reelin in schizophrenia, at least not in HRM and in the methamphetamine sensitisation model.
| S-EPMC7355789 | biostudies-literature