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PubMed2005

Face recognition memory deficits and visual object memory performance in patients with schizophrenia and their relatives.

OBJECTIVE: Face recognition memory deficits in schizophrenia are attributed to frontotemporal dysfunction. Biological relatives of patients have similar deficits, suggesting genetic susceptibility. Because the impairment may reflect generalized object memory deficits, the authors evaluated both face and visual object recognition. METHOD: The Penn Face Memory Test and Visual Object Learning Test were given to 102 patients with schizophrenia, 60 of their biological relatives, and 135 healthy comparison subjects. RESULTS: Significant immediate and delayed face recognition deficits were observed in patients and their relatives. Although patients were more impaired in visual object memory than comparison subjects, relatives were not. CONCLUSIONS: Face recognition deficits in patients with schizophrenia and their families are not secondary to generalized object memory deficits and may be an endophenotype reflecting frontotemporal impairment.

Adult↗

PubMed2005

Impairment of executive function but not memory in first-degree relatives of patients with bipolar I disorder and in euthymic patients with unipolar depression.

OBJECTIVE: The authors' goal was to characterize cognitive flexibility and verbal learning in relatives of patients with bipolar disorder and in euthymic patients with recurrent major depression. METHOD: The intradimensional/extradimensional shift task and California Verbal Learning Test were administered to 27 first-degree relatives of probands with bipolar I disorder, 15 euthymic outpatients with recurrent unipolar depression, and 47 healthy comparison subjects. RESULTS: The relatives of patients with bipolar I disorder and the euthymic patients with unipolar depression were more likely to fail the intradimensional/extradimensional shift task than the healthy comparison subjects. The impairments at the extradimensional shift stage were pronounced. Verbal learning, delayed recall, and recognition were unimpaired in all groups. CONCLUSIONS: Attentional set shifting may represent an endophenotype in mood disorder, related to underlying vulnerability rather than the actual disease phenotype.

Adolescent↗

PubMed2005

A multidimensional model of obsessive-compulsive disorder.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a clinically heterogeneous condition. This heterogeneity can reduce the power and obscure the findings from natural history studies to genome scans, neuroimaging, and clinical trials. The authors review the evidence supporting a multidimensional model of OCD. METHOD: Computerized and manual literature searches were performed to identify factor-analytic studies of obsessive-compulsive symptoms before data from disciplines that bear on the potential usefulness of these dimensions were considered. Selection criteria included the novelty and importance of studies and their relevance to outcomes of interest to well-informed mental health professionals. RESULTS: Twelve factor-analytic studies involving more than 2,000 patients were identified that consistently extracted at least four symptom dimensions: symmetry/ordering, hoarding, contamination/cleaning, and obsessions/checking. These dimensions were associated with distinct patterns of comorbidity, genetic transmission, neural substrates, and treatment response. The evidence supporting the hoarding dimension is particularly robust. CONCLUSIONS: The complex clinical presentation of OCD can be summarized with a few consistent, temporally stable symptom dimensions. These can be understood as a spectrum of potentially overlapping syndromes that may 1) coexist in any patient, 2) be continuous with normal obsessive-compulsive phenomena, and 3) extend beyond the traditional nosological boundaries of OCD. Although the dimensional structure of obsessive-compulsive symptoms is imperfect, this quantitative approach to phenotypic traits has the potential to advance our understanding of OCD and may aid in the identification of more robust endophenotypes. The need for a dimensional rating scale and suggestions for future research aimed at reducing the burden of this disorder are discussed.

Brain↗

PubMed2005

A concordance study of three electrophysiological measures in schizophrenia.

OBJECTIVE: The authors evaluated concordance rates among three electrophysiological measures in patients with schizophrenia, nonschizophrenic first-degree relatives of schizophrenia patients, and healthy comparison subjects. The purpose of the study was to provide data for defining a common endophenotype for genetic studies of schizophrenia and for improving the criteria for diagnosis. METHOD: P50 event-related potential inhibition, antisaccade, and smooth pursuit eye tracking paradigms were measured. Data for all three paradigms were available for 81 patients with schizophrenia, 25 parents of patients with schizophrenia, and 60 healthy comparison subjects. RESULTS: The schizophrenia patients and the patients' parents showed a high rate of inhibitory deficits measured by the P50 inhibition and antisaccade paradigms. Both groups had a high prevalence of eye tracking dysfunction. Smooth pursuit gain and the error rate in the antisaccade paradigm were significantly correlated in the schizophrenia patients and the parents, whereas P50 inhibition showed no correlation with smooth pursuit gain or antisaccade paradigm measurements. CONCLUSIONS: Despite superficial similarities, two paradigms designed to measure central inhibition processes (antisaccade and P50 inhibition) do not appear to reflect the same neurobiological substrates. In contrast, the convergence in performance data for the antisaccade and eye tracking paradigms suggests that the neural circuitry underlying these tasks may overlap. P50 inhibition and antisaccade errors were the optimal paradigms for discrimination between comparison subjects, patients with schizophrenia, and the parents of patients with schizophrenia.

Adult↗

PubMed2006

Regional brain morphometry in patients with schizophrenia or bipolar disorder and their unaffected relatives.

OBJECTIVE: Schizophrenia and psychotic bipolar disorder have a number of overlapping symptoms and risk factors, but it is not yet clear if the disorders are characterized by similar deviations in brain morphometry or whether any such deviations reflect the impact of shared susceptibility genes on brain structure. The authors used region-of-interest morphometry to volumetrically assess brain structures frequently implicated in psychotic illness in families affected with schizophrenia or psychotic bipolar disorder. METHOD: Magnetic resonance imaging brain scans were obtained from 243 subjects, comprising 42 patients with schizophrenia or schizoaffective disorder, 57 of their unaffected first-degree relatives, 38 patients with psychotic bipolar disorder, 52 of their unaffected first-degree relatives, and 54 healthy comparison subjects. Most of the families affected with schizophrenia and all of the families affected with bipolar disorder were multiply affected with the illness. Volumetric measurements of the cerebrum, lateral ventricles, third ventricle, and hippocampus were completed with stereological methods. RESULTS: Patients with schizophrenia had increased volume of the lateral and third ventricles and reduced hippocampal volume. None of these volumetric abnormalities was present in psychotic bipolar disorder. Unaffected relatives of patients with schizophrenia from multiply affected families had enlarged lateral ventricles but no other volumetric deviations. Unaffected relatives of patients with bipolar disorder showed preservation of ventricular and hippocampal volume. CONCLUSIONS: Schizophrenia and psychotic bipolar disorder are characterized by morphometric distinctions in ventricular and hippocampal regions. Lateral ventricular enlargement represents a potential morphometric endophenotype for schizophrenia.

Adolescent↗

PubMed2006

Antisaccade performance in monozygotic twins discordant for schizophrenia: the Maudsley twin study.

OBJECTIVE: Deficiency in antisaccade performance has been proposed as a schizophrenia endophenotype. METHOD: The authors assessed performance on an antisaccade task (and a prosaccade control condition) by 10 monozygotic twin pairs discordant for DSM-IV schizophrenia and 10 monozygotic healthy twin pairs matched for age, sex, and parental socioeconomic status. The authors computed antisaccade gain, latency, and error rate, as well as prosaccade gain and latency. RESULTS: The schizophrenic twins made more antisaccade reflexive errors than the nonschizophrenic co-twins and comparison twins, who did not significantly differ from each other. The nonschizophrenic members of discordant pairs performed worse than the comparison twins on antisaccade gain and latency but did not differ from their schizophrenic co-twins on these variables. There were no differences on prosaccade performance. Antisaccade errors were correlated with negative symptoms in the patients. CONCLUSIONS: Antisaccade spatial accuracy and latency deficits may serve as markers of genetic liability for schizophrenia.

Adult↗

PubMed2006

Unirhinal olfactory function in schizophrenia patients and first-degree relatives.

Previous studies report birhinal impairments in odor identification in patients with schizophrenia and their family members. The authors employed unirhinal odor identification and detection threshold sensitivity tests in schizophrenia patients, healthy first-degree family members, and healthy comparison subjects. Patients and family members showed deficits in odor identification performance in both nostrils. Odor detection thresholds differed only between patients and healthy comparison subjects. Comparable odor identification deficits in both patients and healthy family members suggest that odor identification measures may serve as a sensitive endophenotypic vulnerability marker and that unirhinal olfactory measures are as precise, if not more so, than birhinal performance measures.

Adult↗

PubMed2006

Mid-latency auditory-evoked responses and sensory gating in focal epilepsy: a preliminary exploration.

The relationship between epilepsy and psychosis is not well defined. Sensory gating is a possible endophenotype for psychosis, and has not been fully examined in epileptic patients. The authors examined 29 patients with focal epilepsy who were on antiepileptic medications, and 29 age-matched healthy comparison subjects, using a paired-stimulus (S1-S2) paradigm. P50 and N100 amplitudes or gating did not differ between the groups. The P200 was significantly smaller and did not gate as well in epileptic patients. Though alteration of sensory gating can be demonstrated in epileptic patients, it seems to be qualitatively different from alterations reported in association with schizophrenia.

Acoustic Stimulation↗

PubMed2026

Imaging and genomics in stroke.

Imaging after ischemic and hemorrhagic stroke may allow measurement of key phenotypes of injury and recovery for which targeted therapies are still lacking. Such imaging endophenotypes provide quantifiable and heritable biomarkers that can represent mechanistic aspects of disease processes better than clinical measures. Artificial intelligence is allowing extraction of these imaging biomarkers in large cohorts, which can be paired with genomic and other omics data. This will allow the evaluation of what genetic and other biologic variations impact stroke injury and recovery. Integration of these analyses with bioinformatics tools (such as Mendelian randomization and multi-trait analysis) could further dissect how stroke complications overlap with other biologic processes and how they may be causally linked to risk factors. Further work is required to confirm the translational impact of these methods in elucidating mechanisms and drug targets for stroke. However, global collaborations are accelerating analyses on large multi-ethnic stroke cohorts, with availability of imaging data facilitated by federally-funded repositories such as the Imaging Repository for the Cerebrovascular Disease Knowledge Portal (iCDKP).

Humans↗

PubMed2003

Similarity by state/descent and genetic vector spaces: analysis of a longitudinal family study.

Using the genome-wide screening data of the Framingham Heart Study (394 nuclear families, 1328 genotyped subjects, 397 marker loci) we have quantified the underlying genetic diversity through high-dimensional genetic feature vectors and constructed a genetic vector space for the analysis of population substructure. Adaptive clustering procedures led to three major subgroups that were regarded as being related to "biological" ethnicity and that included more than 70% of the subjects. Based on these subgroups we addressed the question of ethnicity-related and ethnicity-independent risk factors for coronary heart disease (CHD). To this end, we relied upon hypertension as an endophenotype of CHD and applied a multivariate sib-pair method in order to search for oligogenic marker configurations for which the sib-sib similarities deviated from the parent-offspring similarities. Indeed, the latter similarities are always "0.5" irrespective of the affection status of parents and offspring. Loci with significant contributions to the oligogenic marker configuration constituted a CHD-specific genetic vector space. We found several ethnicity-independent signals. One signal on chromosome 8 may relate to the CYP11B1/CYP11B2 genes.

Adult Children↗

PubMed2005

Data mining of the GAW14 simulated data using rough set theory and tree-based methods.

Rough set theory and decision trees are data mining methods used for dealing with vagueness and uncertainty. They have been utilized to unearth hidden patterns in complicated datasets collected for industrial processes. The Genetic Analysis Workshop 14 simulated data were generated using a system that implemented multiple correlations among four consequential layers of genetic data (disease-related loci, endophenotypes, phenotypes, and one disease trait). When information of one layer was blocked and uncertainty was created in the correlations among these layers, the correlation between the first and last layers (susceptibility genes and the disease trait in this case), was not easily directly detected. In this study, we proposed a two-stage process that applied rough set theory and decision trees to identify genes susceptible to the disease trait. During the first stage, based on phenotypes of subjects and their parents, decision trees were built to predict trait values. Phenotypes retained in the decision trees were then advanced to the second stage, where rough set theory was applied to discover the minimal subsets of genes associated with the disease trait. For comparison, decision trees were also constructed to map susceptible genes during the second stage. Our results showed that the decision trees of the first stage had accuracy rates of about 99% in predicting the disease trait. The decision trees and rough set theory failed to identify the true disease-related loci.

Computer Simulation↗

PubMed2001

Assessing the heritability of attentional networks.

BACKGROUND: Current efforts to study the genetics of higher functions have been lacking appropriate phenotypes to describe cognition. One of the problems is that many cognitive concepts for which there is a single word (e.g. attention) have been shown to be related to several anatomical networks. Recently we have developed an Attention Network Test (ANT) that provides a separate measure for each of three anatomically defined attention networks. In this small scale study, we ran 26 pairs of MZ and DZ twins in an effort to determine if any of these networks show sufficient evidence of heritability to warrant further exploration of their genetic basis. RESULTS: The efficiency of the executive attention network, that mediates stimulus and response conflict, shows sufficient heritability to warrant further study. Alerting and overall reaction time show some evidence for heritability and in our study the orienting network shows no evidence of heritability. CONCLUSIONS: These results suggest that genetic variation contributes to normal individual differences in higher order executive attention involving dopamine rich frontal areas including the anterior cingulate. At least the executive portion of the ANT may serve as a valid endophenotype for larger twin studies and subsequent molecular genetic analysis in normal subject populations.

Adolescent↗

PubMed2002

Assessing the molecular genetics of attention networks.

BACKGROUND: Current efforts to study the genetic underpinnings of higher brain functions have been lacking appropriate phenotypes to describe cognition. One of the problems is that many cognitive concepts for which there is a single word (e.g. attention) have been shown to be related to several anatomical networks. Recently, we have developed an Attention Network Test (ANT) that provides a separate measure for each of three anatomically defined attention networks. RESULTS: In this study we have measured the efficiency of neural networks related to aspects of attention using the ANT in a population of 200 adult subjects. We then examined genetic polymorphisms in four candidate genes (DRD4, DAT, COMT and MAOA) that have been shown to contribute to the risk of developing various psychiatric disorders where attention is disrupted. We find modest associations of several polymorphisms with the efficiency of executive attention but not with overall performance measures such as reaction time. CONCLUSIONS: These results suggest that genetic variation may underlie inter-subject variation in the efficiency of executive attention. This study also shows that genetic influences on executive attention may be specific to certain anatomical networks rather than affecting performance in a global or non-specific manner. Lastly, this study further validates the ANT as an endophenotypic assay suitable for assessing how genes influence certain anatomical networks that may be disrupted in various psychiatric disorders.

Adolescent↗

PubMed2004

Heritability of Stroop and flanker performance in 12-year old children.

BACKGROUND: There is great interest in appropriate phenotypes that serve as indicator of genetically transmitted frontal (dys)function, such as ADHD. Here we investigate the ability to deal with response conflict, and we ask to what extent performance variation on response interference tasks is caused by genetic variation. We tested a large sample of 12-year old monozygotic and dizygotic twins on two well-known and closely related response interference tasks; the color Stroop task and the Eriksen flanker task. Using structural equation modelling we assessed the heritability of several performance indices derived from those tasks. RESULTS: In the Stroop task we found high heritabilities of overall reaction time and - more important - Stroop interference (h2 = nearly 50 %). In contrast, we found little evidence of heritability on flanker performance. For both tasks no effects of sex on performance variation were found. CONCLUSIONS: These results suggest that normal variation in Stroop performance is influenced by underlying genetic variation. Given that Stroop performance is often hampered not only in people suffering from frontal dysfunction, but also in their unaffected relatives, we conclude that this variable may constitute a suitable endophenotype for future genetic studies. We discuss several reasons for the absence of genetic effects on the flanker task.

Attention↗

PubMed2004

Family-based clusters of cognitive test performance in familial schizophrenia.

BACKGROUND: Cognitive traits derived from neuropsychological test data are considered to be potential endophenotypes of schizophrenia. Previously, these traits have been found to form a valid basis for clustering samples of schizophrenia patients into homogeneous subgroups. We set out to identify such clusters, but apart from previous studies, we included both schizophrenia patients and family members into the cluster analysis. The aim of the study was to detect family clusters with similar cognitive test performance. METHODS: Test scores from 54 randomly selected families comprising at least two siblings with schizophrenia spectrum disorders, and at least two unaffected family members were included in a complete-linkage cluster analysis with interactive data visualization. RESULTS: A well-performing, an impaired, and an intermediate family cluster emerged from the analysis. While the neuropsychological test scores differed significantly between the clusters, only minor differences were observed in the clinical variables. CONCLUSIONS: The visually aided clustering algorithm was successful in identifying family clusters comprising both schizophrenia patients and their relatives. The present classification method may serve as a basis for selecting phenotypically more homogeneous groups of families in subsequent genetic analyses.

Adult↗

PubMed2006

Schizophrenia proteomics: biomarkers on the path to laboratory medicine?

Over two million Americans are afflicted with schizophrenia, a debilitating mental health disorder with a unique symptomatic and epidemiological profile. Genomics studies have hinted towards candidate schizophrenia susceptibility chromosomal loci and genes. Modern proteomic tools, particularly mass spectrometry and expression scanning, aim to identify both pathogenic-revealing and diagnostically significant biomarkers. Only a few studies on basic proteomics have been conducted for psychiatric disorders relative to the plethora of cancer specific experiments. One such proteomic utility enables the discovery of proteins and biological marker fingerprinting profiling techniques (SELDI-TOF-MS), and then subjects them to tandem mass spectrometric fragmentation and de novo protein sequencing (MALDI-TOF/TOF-MS) for the accurate identification and characterization of the proteins. Such utilities can explain the pathogenesis of neuro-psychiatric disease, provide more objective testing methods, and further demonstrate a biological basis to mental illness. Although clinical proteomics in schizophrenia have yet to reveal a biomarker with diagnostic specificity, methods that better characterize the disorder using endophenotypes can advance findings. Schizophrenia biomarkers could potentially revolutionize its psychopharmacology, changing it into a more hypothesis and genomic/proteomic-driven science.

Journal Article↗

PubMed1987

Is there really a split in schizophrenia? The genetic evidence.

Although the clinical presentation and course of schizophrenia is highly variable, it is unclear whether this reflects heterogeneity at an aetiological level. The genetic evidence is reviewed concerning 'traditional' clinical subtypes as more novel categories derived from multivariate statistical methods and Crow's type I-type II classification. Recent data based on a twin series and re-analysis of older published family material suggest that attempts to divide up schizophrenia have resulted in splits between two or more categories of disorder which occupy different positions on the same continuum of liability. Thus, apparent heterogeneity is more likely to be due to quantitative difference in familial-genetic loading rather than qualitative differences. Similarly, the hypothesis that schizophrenia can be broadly divided into two groups, one genetic and the other non-genetic has little to support it. It seems improbable that any further useful and genetically relevant subdivision of schizophrenia can be effected on purely clinical grounds. Further progress awaits developments in the discovery of endophenotypes and the application of molecular genetic marker strategies.

Adult↗

PubMed2006

Intellectual asymmetry and genetic liability in first-degree relatives of probands with schizophrenia.

Intellectual asymmetry with superiority of verbal skills to spatial skills frequently characterises patients with schizophrenia, but it is unclear whether this pattern also reflects genetic susceptibility to the disorder. We examined the association of a continuous measure of genetic liability to schizophrenia with Verbal-Spatial Contrast IQ (an index of intellectual asymmetry) in 108 first-degree relatives without psychosis of probands with schizophrenia. Higher genetic liability was significantly associated with greater intellectual asymmetry in favour of verbal skills. Intellectual asymmetry with a relative superiority of verbal skills to spatial skills represents a putative endophenotype of schizophrenia.

Adolescent↗