Gary Donohoe
National University of Ireland, Galway, Psychology, Faculty Member
Cognitive deficits are core to the disability associated with many psychiatric disorders. Both variation in cognition and psychiatric risk show substantial heritability, with overlapping genetic variants contributing to both.... more
Cognitive deficits are core to the disability associated with many psychiatric disorders. Both variation in cognition and psychiatric risk show substantial heritability, with overlapping genetic variants contributing to both. Unsurprisingly, therefore, these fields have been mutually beneficial: just as cognitive studies of psychiatric risk variants may identify genes involved in cognition, so too can genome-wide studies based on cognitive phenotypes lead to genes relevant to psychiatric aetiology. The purpose of this review is to consider the main issues involved in the phenotypic characterization of cognition, and to describe the challenges associated with the transition to genome-wide approaches. We conclude by describing the approaches currently being taken by the international consortia involving many investigators in the field internationally (e.g. Cognitive Genomics Consortium; COGENT) to overcome these challenges.(Received May 18 2012)(Revised September 20 2012)(Accepted October 11 2012)(Online publication November 30 2012)
Research Interests:
Classification in psychiatry is heavily dependent on clinical symptoms and illness course. This ignores the critical role that cognitive problems play in neuropsychiatric disorders affecting different domains across the lifespan, from... more
Classification in psychiatry is heavily dependent on clinical symptoms and illness course. This ignores the critical role that cognitive problems play in neuropsychiatric disorders affecting different domains across the lifespan, from ADHD and autism to schizophrenia and Alzheimers disease. At this point, it is unclear whether cognitive mechanisms are specific to disorders, whether multiple processes can contribute to the same disorder, or whether aberrant neural processing can result in many different phenotypic outcomes. Understanding this would allow us to better grasp normal as well as pathological brain function. This could inform diagnostics based on understanding of neurophysiological processes and the consequent development of new therapeutics. Genetics, and the development of genomic research, offers real opportunities to understand the molecular mechanisms relevant to cognition. This chapter defines and describes the main cognitive phenotypes, which are investigated in psychiatric disorders. We review evidence for their heritability and early progress in the field using cytogenetic, linkage and candidate gene-based research methodologies. With high-throughput genomics it is now possible to explore novel common and rare risk variants for psychiatric disorders and their role in cognitive function at a genome-wide level. We review the results of early genomic studies and discuss the novel insights that they are starting to provide. Finally, we review the analysis of whole-genome DNA sequence data and the challenges that this will bring for cognitive genomics research.
Research Interests:
Objectives. SNP rs2473277 upstream of the cell division cycle 42 (CDC42) gene was associated with schizophrenia in a recent genome-wide association study (GWAS). Reduced expression of CDC42 in schizophrenia has previously been reported.... more
Objectives. SNP rs2473277 upstream of the cell division cycle 42 (CDC42) gene was associated with schizophrenia in a recent genome-wide association study (GWAS). Reduced expression of CDC42 in schizophrenia has previously been reported. Our objective was to test whether the associated SNP affected CDC42 expression. Methods. Two available SNP × gene expression datasets were accessed to test the effect of rs2473277 on CDC42 expression: (i) the mRNA by SNP Browser, which presents results of a genome-wide linkage study of gene expression, and (ii) the Genevar HapMap expression dataset. rs2473277 is in strong linkage disequilibrium (LD) with the SNP rs2473307 (r(2) = 0.96), which is predicted to affect transcription factor binding. rs2473307 was directly tested for allelic effects on gene expression using a gene reporter assay in a human neuronal cell line. Results. In both datasets, the schizophrenia risk allele at rs2473277 was associated with a reduction in CDC42 mRNA levels. In the reporter gene assay the risk allele at rs2473307 similarly reduced gene expression. Conclusions. We found evidence that rs2473307, in strong LD with the schizophrenia associated SNP rs2473277, is a functional variant at CDC42 that may increase risk for schizophrenia by reducing expression of CDC42.
Research Interests:
Research Interests:
Research Interests:
Background: The nitric oxide synthasase-1 gene (NOS1) has been implicated in mental disorders including schizophrenia and variation in cognition. The NOS1 variant rs6490121 identified in a genome wide association study of schizophrenia... more
Background: The nitric oxide synthasase-1 gene (NOS1) has been implicated in mental disorders including schizophrenia and variation in cognition. The NOS1 variant rs6490121 identified in a genome wide association study of schizophrenia has recently been associated with variation in general intelligence and working memory in both patients and healthy participants. Whether this variant is also associated with variation in early sensory processing remains unclear. Methods: We investigated differences in the P1 visual evoked potential in a high density EEG study of 54 healthy participants. Given both NOS1's association with cognition and recent evidence that cognitive performance and P1 response are correlated, we investigated whether NOS1's effect on P1 response was independent of its effects on cognition using CANTAB's spatial working memory (SWM) task. Results: We found that carriers of the previously identified risk “G” allele showed significantly lower P1 responses than non-carriers. We also found that while P1 response and SWM performance were correlated, NOS1 continued to explain a significant proportion of variation in P1 response even when its effects on cognition were accounted for. Conclusion: The schizophrenia implicated NOS1 variants rs6490121 influences visual sensory processing as measured by the P1 response, either as part of the gene's pleiotropic effects on multiple aspects of brain function, or because of a primary influence on sensory processing that mediates the effects already seen in higher cognitive processes. Hum Brain Mapp, 2011. © 2011 Wiley-Liss, Inc.
Research Interests:
Research Interests: Psychology, Cognitive Science, Emotion, Psychopharmacology, Schizophrenia, and 69 moreIndividuality, Polymorphism, Motor Learning, Skeletal muscle biology, Transcranial Magnetic Stimulation, Attention, China, Treatment Outcome, Health, Neurophysiology, Adolescent, Anxiety, Emotions, Learning, Italy, CAD, SAP, Thinking, Pregnancy, Humans, Personality Assessment Inventory, Major Depressive Disorder, Aggression, Female, Alcohol Drinking, Male, Nature Neuroscience, Reaction Time, Regression Analysis, Young Adult, Psychoneuroendocrinology, Motor Cortex, Depressive Disorder, Body Mass Index, Embryo Transfer, Clinical Sciences, UAP, Aged, Middle Aged, Body mass index (BMI), Genotype, Adult, Single Nucleotide Polymorphism, Endometriosis, Sex Factors, Analysis of Variance, Time Factors, Methionine, Hand, Eating Disorder, Chi Square Distribution, Fertilization in Vitro, ANXIETY, Citalopram, Genetic Association, Amino Acid Substitution Rates, Female Infertility, Task Performance and Analysis, Neurosciences, Follicular Fluid, Life Change Events, Parkinson Disease, Cognition disorders, Serotonin Uptake Inhibitors, Motor Skills, Case Control Studies, Functional Laterality, Severity of Illness Index, and Neuropsychological Tests
Research Interests:
1. Schizophr Res. 2011 Feb;125(2-3):304-6. Epub 2010 Nov 26. A neuropsychological investigation of the genome wide associated schizophrenia risk variant NRGN rs12807809. Donohoe G, Walters J, Morris DW, Da Costa A, Rose E, Hargreaves A,... more
1. Schizophr Res. 2011 Feb;125(2-3):304-6. Epub 2010 Nov 26. A neuropsychological investigation of the genome wide associated schizophrenia risk variant NRGN rs12807809. Donohoe G, Walters J, Morris DW, Da Costa A, Rose E, Hargreaves A, Maher K, Hayes E, Giegling I, Hartmann AM, Möller HJ, Muglia P, Moskvina V, Owen MJ, O'Donovan MC, Gill M, Corvin A, Rujescu D. PMID: 21112188 [PubMed - indexed for MEDLINE]. Publication Types: Letter; Research Support, Non-US Gov't. MeSH Terms. ...
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests: Sustained Attention, Psychometrics, Schizophrenia, Attention, Working Memory, and 13 moreHumans, Female, Male, Reaction Time, Middle Aged, Adult, Short Term Memory, Psychotic Disorders, Cognition disorders, Disorganized Schizophrenia, Psychomotor Performance, Psychiatric Status Rating Scales, and Neuropsychological Tests
Poor insight is associated with impaired cognitive function in psychosis. Whether poor clinical insight overlaps with other aspects of self-awareness in schizophrenia, such as cognitive self-awareness, is unclear. We investigated whether... more
Poor insight is associated with impaired cognitive function in psychosis. Whether poor clinical insight overlaps with other aspects of self-awareness in schizophrenia, such as cognitive self-awareness, is unclear. We investigated whether awareness of clinical state (“clinical insight”) and awareness of cognitive deficits (“cognitive insight”) overlap in schizophrenia in a sample of 51 stabilized patients with chronic schizophrenia. Cognitive insight was assessed in terms of the agreement between subjective self-report and neuropsychological assessment. Patients who show good cognitive insight did not necessarily show good clinical insight. By contrast, self-report and objective neuropsychological assessment only correlated for patients in the intact clinical insight group and not for those in the impairment clinical insight group. We conclude that while good cognitive insight may not be necessary for good clinical insight, good cognitive awareness is at least partly reliant on the processes involved in clinical insight. (JINS, 2009, 15, 471–475.)(Received August 20 2008)(Reviewed January 19 2009)(Accepted January 19 2009)
Research Interests:
... Dr. Aiden Corvin, Professor Michael Gill and Dr Derek Morris conceived the study. ... Esslinger, C., Walter, H., Kirsch, P., Erk, S., Schnell, K., Arnold, C., Haddad, L., Mier, D., Opitz von Boberfeld, C., Raab, K., Witt, SH,... more
... Dr. Aiden Corvin, Professor Michael Gill and Dr Derek Morris conceived the study. ... Esslinger, C., Walter, H., Kirsch, P., Erk, S., Schnell, K., Arnold, C., Haddad, L., Mier, D., Opitz von Boberfeld, C., Raab, K., Witt, SH, Rietschel, M., Cichon, S., Meyer-Lindenberg, A., 2009. ...
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
The single nucleotide polymorphism rs10503253 within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2 has been identified as genome-wide significant for schizophrenia (SZ). This gene is of unknown function but has been... more
The single nucleotide polymorphism rs10503253 within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2 has been identified as genome-wide significant for schizophrenia (SZ). This gene is of unknown function but has been implicated in multiple neurodevelopmental disorders that impact upon cognition, leading us to hypothesize that an effect on brain structure and function underlying cognitive processes may be part of the mechanism by which CMSD1 increases illness risk. To test this hypothesis, we investigated this CSMD1 variant in vivo in healthy participants in a magnetic resonance imaging (MRI) study comprised of both fMRI of spatial working memory (N = 50) and a voxel-based morphometry investigation of grey and white matter (WM) volume (N = 150). Analyses of these data indicated that the risk “A” allele was associated with comparatively reduced cortical activations in BA18, that is, middle occipital gyrus and cuneus; posterior brain regions that support maintenance processes during performance of a spatial working memory task. Conversely, there was an absence of significant structural differences in brain volume (i.e., grey or WM). In accordance with previous evidence, these data suggest that CSMD1 may mediate brain function related to cognitive processes (i.e., executive function); with the relatively deleterious effects of the identified “A” risk allele on brain activity possibly constituting part of the mechanism by which CSMD1 increases schizophrenia risk. © 2013 Wiley Periodicals, Inc.The single nucleotide polymorphism rs10503253 within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2 has been identified as genome-wide significant for schizophrenia (SZ). This gene is of unknown function but has been implicated in multiple neurodevelopmental disorders that impact upon cognition, leading us to hypothesize that an effect on brain structure and function underlying cognitive processes may be part of the mechanism by which CMSD1 increases illness risk. To test this hypothesis, we investigated this CSMD1 variant in vivo in healthy participants in a magnetic resonance imaging (MRI) study comprised of both fMRI of spatial working memory (N = 50) and a voxel-based morphometry investigation of grey and white matter (WM) volume (N = 150). Analyses of these data indicated that the risk “A” allele was associated with comparatively reduced cortical activations in BA18, that is, middle occipital gyrus and cuneus; posterior brain regions that support maintenance processes during performance of a spatial working memory task. Conversely, there was an absence of significant structural differences in brain volume (i.e., grey or WM). In accordance with previous evidence, these data suggest that CSMD1 may mediate brain function related to cognitive processes (i.e., executive function); with the relatively deleterious effects of the identified “A” risk allele on brain activity possibly constituting part of the mechanism by which CSMD1 increases schizophrenia risk. © 2013 Wiley Periodicals, Inc.
Research Interests:
Donohoe G, Duignan A, Hargreaves A, Morris DW, Rose E, Robertson D, Cummings E, Moore S, Gill M, Corvin A. Social cognition in bipolar disorder versus schizophrenia: comparability in mental state decoding deficits. Bipolar Disord 2012:... more
Donohoe G, Duignan A, Hargreaves A, Morris DW, Rose E, Robertson D, Cummings E, Moore S, Gill M, Corvin A. Social cognition in bipolar disorder versus schizophrenia: comparability in mental state decoding deficits. Bipolar Disord 2012: 14: 743–748. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S.Objectives: Neuropsychological studies comparing patients with bipolar disorder (BD) to patients with schizophrenia (SZ) suggest milder cognitive deficits in BD patients and across a smaller range of functions. The present study investigated whether this pattern is also true for social cognition – a range of socially relevant abilities, including emotion perception and recognition, theory of mind, and social attributions – by comparing performance on measures of social cognition in patients with BD, SZ, and healthy participants.Methods: One hundred and two patients with BD, 208 patients with SZ, and 132 healthy participants were assessed using a battery of tasks measuring basic neuropsychological and social cognition.Results: We observed significant differences between patients with BD and healthy participants in a test of mental state decoding (‘eyes task’) that was at a level comparable to deficits seen in patients with SZ. By comparison, BD patients showed more subtle deficits in mental state reasoning (‘hinting task’) than those shown by patients with SZ.Conclusions: Mental state decoding difficulties are significant in BD. An important direction for further research will be to establish to what extent these deficits affect social and occupational functioning as a potential target for therapeutic intervention.
Research Interests:
ObjectivePsychotic symptoms are common in the population and index risk for a range of severe psychopathological outcomes. We wished to investigate functional connectivity in a community sample of adolescents who reported psychotic... more
ObjectivePsychotic symptoms are common in the population and index risk for a range of severe psychopathological outcomes. We wished to investigate functional connectivity in a community sample of adolescents who reported psychotic symptoms (the extended psychosis phenotype).Psychotic symptoms are common in the population and index risk for a range of severe psychopathological outcomes. We wished to investigate functional connectivity in a community sample of adolescents who reported psychotic symptoms (the extended psychosis phenotype).MethodThis study investigated intrinsic functional connectivity (iFC) during resting-state functional magnetic resonance imaging (fMRI; rs-fMRI). Following screening in schools, 11 non-treatment seeking, youth with psychotic symptoms (aged 11–13) and 14 community controls participated in the study. Seed regions of interest comprised brain regions previously shown to exhibit aberrant activation during inhibitory control in adolescents with psychotic symptoms.This study investigated intrinsic functional connectivity (iFC) during resting-state functional magnetic resonance imaging (fMRI; rs-fMRI). Following screening in schools, 11 non-treatment seeking, youth with psychotic symptoms (aged 11–13) and 14 community controls participated in the study. Seed regions of interest comprised brain regions previously shown to exhibit aberrant activation during inhibitory control in adolescents with psychotic symptoms.ResultsRelative to controls, adolescents with psychotic symptoms exhibited reduced iFC between regions supporting inhibitory control. Specifically, they showed weaker iFC between the right inferior frontal gyrus (IFG) and the cingulate, IFG and the striatum, anterior cingulate and claustrum, and precuneus and supramarginal gyrus. Conversely, the psychotic symptoms group exhibited stronger iFC between the superior frontal gyrus and claustrum and IFG and lingual gyrus.Relative to controls, adolescents with psychotic symptoms exhibited reduced iFC between regions supporting inhibitory control. Specifically, they showed weaker iFC between the right inferior frontal gyrus (IFG) and the cingulate, IFG and the striatum, anterior cingulate and claustrum, and precuneus and supramarginal gyrus. Conversely, the psychotic symptoms group exhibited stronger iFC between the superior frontal gyrus and claustrum and IFG and lingual gyrus.ConclusionThe present findings are the first to reveal aberrant functional connectivity in resting-state networks in a community sample of adolescents with psychotic symptoms and suggest that disruption in integration between distributed neural networks (particularly between prefrontal, cingulate and striatal brain regions) may be a key neurobiological feature of the extended psychosis phenotype.The present findings are the first to reveal aberrant functional connectivity in resting-state networks in a community sample of adolescents with psychotic symptoms and suggest that disruption in integration between distributed neural networks (particularly between prefrontal, cingulate and striatal brain regions) may be a key neurobiological feature of the extended psychosis phenotype.
Research Interests:
Schizophrenia is accompanied by significant impairment in psychosocial functioning, which is only partially explained by clinical symptom severity. Recently, these impairments have been strongly associated with deficits in neurocognition... more
Schizophrenia is accompanied by significant impairment in psychosocial functioning, which is only partially explained by clinical symptom severity. Recently, these impairments have been strongly associated with deficits in neurocognition and social cognition. Although the Global Assessment of Function (GAF) scale remains the most widely used measure of psychosocial function in clinical practice, it is unclear whether this instrument is sensitive to changes in cognition, or merely provides a snapshot of symptom severity. To investigate this, we assessed whether variation in GAF score was explained by performance on measures of neurocognitive and social cognition, particularly after variation associated with symptom severity had been accounted for. 216 patients with schizophrenia were assessed using the GAF scale, two theory of mind tasks (the 'Hinting' task and 'Reading the Eyes in the Mind' task), and a neuropsychological battery sensitive to the areas of deficit typically seen in schizophrenia - IQ, episodic memory, working memory and attentional control. Using linear regression analysis, symptom severity explained 24% of the variance in GAF scores (F(3, 188) = 21.14, p<.001). While neuropsychological performance explained a further 4.7% of variation (r(2)change = .047, Fchange (1, 187) = 12.63, p<.001), social cognition did not explain any further variance in functioning (r(2)change = .006, Fchange (1, 186) = 1.63, p = .20). These data indicate that GAF scores are primarily sensitive to variation in clinical symptoms severity and not at all sensitive to variation in social cognition, an important determinant of real world outcome. Doing so highlights the need to supplement the measurement of psychosocial function using the GAF in clinical practice with functional measures that are more sensitive to deficits in social cognition.
Research Interests:
A single nucleotide polymorphism rs12807809 located upstream of the neurogranin (NRGN) gene has been identified as a risk variant for schizophrenia in recent genome-wide association studies. To date, there has been little investigation of... more
A single nucleotide polymorphism rs12807809 located upstream of the neurogranin (NRGN) gene has been identified as a risk variant for schizophrenia in recent genome-wide association studies. To date, there has been little investigation of the endophenotypic consequences of this variant, and our own investigations have suggested that the effects of this gene are not apparent at the level of cognitive function in patients or controls. Because the impact of risk variants may be more apparent at the level of brain, the aim of this investigation was to delineate whether NRGN genotype predicted variability in brain structure and/or function. Healthy individuals participated in structural (N = 140) and/or functional (N = 36) magnetic resonance imaging (s/fMRI). Voxel-based morphometry was used to compare gray and white matter volumes between carriers of the non-risk C allele (i.e., CC/CT) and those who were homozygous for the risk T allele. Functional imaging data were acquired during the performance of a spatial working memory task, and were also analyzed with respect to the difference between C carriers and T homozygotes. There was no effect of the NRGN variant rs12807809 on behavioral performance or brain structure. However, there was a main effect of genotype on brain activity during performance of the working memory task, such that while C carriers exhibited a load-independent decrease in left superior frontal gyrus/BA10, TT individuals failed to show a similar decrease in activity. The failure to disengage this ventromedial prefrontal region, despite preserved performance, may be indicative of a reduction in processing efficiency in healthy TT carriers. Although it remains to be established whether this holds true in larger samples and in patient cohorts, if valid, this suggests a potential mechanism by which NRGN variability might contribute to schizophrenia risk.(Received November 02 2011)(Accepted November 22 2011)
Research Interests:
OBJECTIVE The authors investigated the effects of recently identified genome-wide significant schizophrenia genetic risk variants on cognition and brain structure. METHOD A panel of six single-nucleotide polymorphisms (SNPs) was selected... more
OBJECTIVE The authors investigated the effects of recently identified genome-wide significant schizophrenia genetic risk variants on cognition and brain structure. METHOD A panel of six single-nucleotide polymorphisms (SNPs) was selected to represent genome-wide significant loci from three recent genome-wide association studies (GWAS) for schizophrenia and was tested for association with cognitive measures in 346 patients with schizophrenia and 2,342 healthy comparison subjects. Nominally significant results were evaluated for replication in an independent case-control sample. For SNPs showing evidence of association with cognition, associations with brain structural volumes were investigated in a large independent healthy comparison sample. RESULTS Five of the six SNPs showed no significant association with any cognitive measure. One marker in the major histocompatibility complex (MHC) region, rs6904071, showed independent, replicated evidence of association with delayed episodic memory and was significant when both samples were combined. In the combined sample of up to 3,100 individuals, this SNP was associated with widespread effects across cognitive domains, although these additional associations were no longer significant after adjusting for delayed episodic memory. In the large independent structural imaging sample, the same SNP was also associated with decreased hippocampal volume. CONCLUSIONS The authors identified a SNP in the MHC region that was associated with cognitive performance in patients with schizophrenia and healthy comparison subjects. This SNP, rs6904071, showed a replicated association with episodic memory and hippocampal volume. These findings implicate the MHC region in hippocampal structure and functioning, consistent with the role of MHC proteins in synaptic development and function. Follow-up of these results has the potential to provide insights into the pathophysiology of schizophrenia and cognition.
Research Interests: Schizophrenia, Magnetic Resonance Imaging, Adolescent, Ireland, Episodic Memory, and 15 moreGermany, Cross-Cultural Comparison, Hippocampus, Brain, Humans, Young Adult, Follow-up studies, Aged, Middle Aged, Genotype, Adult, Major histocompatibility complex, Cognition disorders, Case Control Studies, and Neuropsychological Tests
Suicide is the leading cause of death in schizophrenia. An association between suicidal behavior and both higher and lower cognitive ability in schizophrenia has been reported. To clarify this relationship, we investigated whether the... more
Suicide is the leading cause of death in schizophrenia. An association between suicidal behavior and both higher and lower cognitive ability in schizophrenia has been reported. To clarify this relationship, we investigated whether the relationship between suicidality and neurocognition varied according to differences in suicidal ideation and behavior. Three hundred and ten patients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder were categorized based on patient and staff interviews as either non-suicide attempters, non-attempters expressing suicidal ideation, single suicide attempters, or multiple suicide attempters. These groups were compared on a neuropsychological battery examining current general cognitive ability, episodic and working memory, and attentional control. Neuropsychological performance in those with a history of suicidal ideation (n=63), and those who had made one suicide attempt (n=48) was comparable. Together, these groups outperformed patients with no history of either suicidal behavior or ideation (n=172) on measures of IQ, episodic memory and working memory. Only differences in global cognition remained significant after controlling for between-group differences in depressive symptoms. Those who had either expressed suicidal ideation and/or made a single suicide attempt demonstrated trend level advantages in neuropsychological tests over those that had made multiple suicide attempts. These findings support earlier evidence of an association between suicidality and neurocognitive ability in schizophrenia. Specifically, these data suggest that patients who have contemplated suicide or made a single suicide attempt have better cognitive functioning than those who have not. Suicidality in multiple attempters, who do not perform better in neurocognitive tests than those who have neither contemplated nor attempted suicide, is likely to be influenced by factors other than neurocognitive ability.
Research Interests:
Research Interests:
The Zinc Finger Protein 804A gene (ZNF804A) has been implicated in schizophrenia susceptibility by several genome-wide association studies. ZNF804A is brain expressed but of unknown function. To investigate whether the identified risk... more
The Zinc Finger Protein 804A gene (ZNF804A) has been implicated in schizophrenia susceptibility by several genome-wide association studies. ZNF804A is brain expressed but of unknown function. To investigate whether the identified risk allele at the disease-associated single nucleotide polymorphism rs1344706 is associated with variation in neuropsychological performance in patients and controls. Comparison of cases and controls grouped according to ZNF804A genotype (AA vs AC vs CC) on selected measures of cognition in 2 independent samples. Unrelated patients from general adult psychiatric inpatient and outpatient services and unrelated healthy participants from the general population were ascertained. Patients with DSM-IV-diagnosed schizophrenia and healthy participants from independent samples of Irish (297 cases and 165 controls) and German (251 cases and 1472 controls) nationality. In this 2-stage study, we tested for an association between ZNF804A rs1344706 and cognitive functions known to be impaired in schizophrenia (IQ, episodic memory, working memory, and attention) in an Irish discovery sample. We then tested significant results in a German replication sample. In the Irish samples, the ZNF804A genotype was associated with differences in episodic and working memory in patients but not in controls. These findings replicated in the same direction in the German samples. Furthermore, in both samples, when patients with a lower IQ were excluded, the association between ZNF804A and schizophrenia strengthened. In a disorder characterized by heterogeneity, a risk variant at ZNF804A seems to delineate a patient subgroup characterized by relatively spared cognitive ability. Further work is required to establish whether this represents a discrete molecular pathogenesis that differs from that of other patient groups and whether this also has consequences for nosologic classification, illness course, or treatment.
Research Interests: Schizophrenia, Ireland, Germany, Humans, Female, and 13 moreC2H2 zinc fingers, Male, Cognitive Performance, Genotype, Adult, European Continental Ancestry Group, Genetic variation, Psychotic Disorders, Memory Disorders, Archives General Psychiatry, Cognition disorders, Case Control Studies, and Neuropsychological Tests
Research Interests: Genetics, Schizophrenia, Bipolar Disorder, Population Genetics, Prostate Cancer, and 28 moreNature, Biological Sciences, Humans, Mutation, Glioma, Perimetry and Visual Fields, Haplotypes, Female, Male, Intraocular Pressure, Gene Dosage, Glaucoma Surgery, microRNAs, Human Genome, Carcinoma, Genotype, Linkage Disequilibrium, Reproducibility of Results, PLoS Genetics, European Continental Ancestry Group, Asian Continental Ancestry Group, Glaucoma Progression Analysis, Logistic Models, Gene Expression Regulation, Case Control Studies, Pediatric Glaucoma, Perimetric Devices, and Glaucoma Diagnosis
Relapse of schizophrenia due to poor medication adherence is a major preventable source of psychiatric morbidity. This has led to a burgeoning of interest in improving compliance based on a wide range of psychological approaches. One of... more
Relapse of schizophrenia due to poor medication adherence is a major preventable source of psychiatric morbidity. This has led to a burgeoning of interest in improving compliance based on a wide range of psychological approaches. One of the difficulties for health service providers is to establish the utility of such interventions, particularly when the economic costs of these programs are unclear. This review examines the evidence for one leading approach to improving adherence - the cognitive behavioral approach adopted in the `compliance therapy' of Kemp et al. A context for this review is provided by way of a brief overview of both traditional medical and psychoeducational approaches to treatment adherence, along with more cognitively based formulations of nonadherence. The aims and rationale of compliance therapy are presented along with a brief description of the therapy sessions. The empirical support for the efficacy of this treatment is discussed based on the few published studies available. The review concludes that while compliance therapy may be of value, this intervention will require further empirical study before reaching definite conclusions about its utility for responding to poor adherence to medications.
Research Interests:
This paper outlines a methodology to measure the ability of a schizophrenic patient to saccade against a presented stimulus by tracking the patient's electro- oculographic (EOG) activity. The overall goal... more
This paper outlines a methodology to measure the ability of a schizophrenic patient to saccade against a presented stimulus by tracking the patient's electro- oculographic (EOG) activity. The overall goal is to investigate a deficit in this anti-saccade task as a cognitive endophenotype for schizophrenia. A portable system for performing this test and a novel biopotential amplifier are presented along
Research Interests:
Research Interests:
Research Interests:
Delineating relationships between susceptibility genes and clinical symptoms may be an important step in understanding the genetics of psychosis. Recent data suggests that the gene dysbindin (DTNBP1) may confer susceptibility across... more
Delineating relationships between susceptibility genes and clinical symptoms may be an important step in understanding the genetics of psychosis. Recent data suggests that the gene dysbindin (DTNBP1) may confer susceptibility across psychotic disorders and may particularly be associated with negative symptoms, i.e. affective flattening, alogia and avolition. We have previously published evidence of association with a dysbindin risk haplotype derived from alleles C-A-T at SNPs P1655 (rs2619539), P1635 (rs3213207) and SNP66961 (rs2619538) in two independent schizophrenia (SZ) case-control samples. The C-A-T haplotype impacts at the level of gene function and phenotype: the haplotype indexes lower cortical expression of the dysbindin gene in post-mortem SZ brain samples and haplotype carriers show greater deficits in spatial working memory and early visual processing than non-carrier SZ patients. The aim of this study was to establish if the C-A-T dysbindin risk haplotype is associated with a specific clinical symptom profile. We investigated the relationship between the haplotype and PANSS-derived symptom factors in 262 individuals with schizophrenia/schizoaffective disorder using principal components analysis (PCA) and analysis of variance (ANOVA). Dysbindin risk carriers scored significantly less than non-carriers on the ‘hostility/excitability’ factor (F1,196 = 8.468; p = .004), with a trend for higher negative symptom scores. This suggests that risk variation at the dysbindin gene may contribute to a more prototypical SZ presentation with less severe excitement/manic symptoms and more negative symptoms.
Research Interests: Genetics, Neuroscience, Psychology, Cognitive Science, Schizophrenia, and 16 moreBipolar Disorder, Principal Component Analysis, Visual Processing, Humans, Haplotypes, Female, Male, Psychotic Disorder, Spatial Working Memory, Middle Aged, Adult, Analysis of Variance, Gene Function, Indexation, Neurosciences, and Psychiatric Status Rating Scales
Research Interests: Psychology, Cognitive Science, Schizophrenia, Spatial Memory, Cognition, and 19 moreAttention, Working Memory, Adolescent, Attentional Control, Humans, Haplotypes, Female, Male, Spatial Working Memory, Cognitive Performance, Middle Aged, Genotype, Adult, Neuropsychologia, Short Term Memory, Automated Testing, Neurosciences, Psychomotor Performance, and Psychiatric Status Rating Scales
Although deficits in executive functioning in schizophrenia have been consistently reported, their precise relationship to symptomatology remains unclear. Recent approaches to executive functioning in nonschizophrenia studies have aimed... more
Although deficits in executive functioning in schizophrenia have been consistently reported, their precise relationship to symptomatology remains unclear. Recent approaches to executive functioning in nonschizophrenia studies have aimed to "fractionate" the individual cognitive processes involved. In this study, we hypothesised that if these processes are fractionable, then particular symptom syndromes may be selectively related to executive deficits. In particular, it was hoped that this approach could clarify whether negative and positive symptoms of schizophrenia are differentially related to particular aspects of executive/attentional functions. A total of 32 patients with schizophrenia and 16 matched controls were assessed on a series of tasks designed to tap the theoretically derived executive functions of Inhibition, Shifting set, Working memory, and Sustained attention. Negative symptoms were significantly predicted by performance on an "Inhibition" task (Stroop), and not by performance on any other task. Furthermore, for a subgroup of patients with predominantly negative symptoms variance in positive symptoms was only significantly predicted by performance on a set-shifting task (Visual Elevator), and not by performance on other tasks, including inhibition. Our results support the contention that negative symptoms can, at least partly, be conceived of as cognitive behaviours expressing specific executive deficits. Specifically, we discuss the possibility that negative symptoms may, in part, express a failure in response monitoring. We further suggest that the disordered metacognition resulting in positive symptoms may be mediated by cognitive flexibility in patients with a predominantly negative symptom profile.
Research Interests: Sustained Attention, Cognition, Attention, Working Memory, Cognitive Neuropsychiatry, and 13 moreExecutive Function, Cognitive Flexibility, Humans, Female, Male, Cognitive Process, Middle Aged, Adult, Predictive value of tests, Cognition disorders, Psychomotor Performance, Psychiatric Status Rating Scales, and Neuropsychological Tests
Research Interests:
Although a relationship between insight and symptomatology in schizophrenia has been repeatedly demonstrated, the influence of psychological variables such as coping mechanisms and attributional style is less clear. We evaluated health... more
Although a relationship between insight and symptomatology in schizophrenia has been repeatedly demonstrated, the influence of psychological variables such as coping mechanisms and attributional style is less clear. We evaluated health attributions, subjective resources for coping, symptomatology, general cognitive functioning, and insight among 38 consecutive admissions with DSM-III-R schizophrenia from a geographically defined catchment area. Health attributions accounted for a significant amount of insight even after symptom severity was accounted for and together predicted 32% of variation in insight scores. This study emphasizes the multifactorial nature of insight and the importance of psychological variables in addition to symptomatology.
Research Interests: Psychology, Cognitive Science, Schizophrenia, Cognition, Probability, and 13 moreHumans, Personality Assessment Inventory, Female, Male, Regression Analysis, Health Status, Clinical Sciences, Questionnaires, Adult, Severity of Illness Index, Psychiatric Status Rating Scales, Neuropsychological Tests, and attitude to health
Research Interests: Genetics, Psychopharmacology, Depression, Schizophrenia, Polymorphism, and 32 moreMagnetic Resonance Imaging, Neuropsychopharmacology, Adolescent, Prefrontal Cortex, Serotonin, Hippocampus, Brain, Humans, Child, Genetic Testing, Major Depressive Disorder, Female, Serotonin Transporter, Voxel Based Morphometry, Male, Young Adult, Risk factors, Aged, Middle Aged, High Resolution, Major Depression, White matter, Genotype, Adult, Brain Structure, Risk Factors, Brain Chemistry, Healthy Subjects, Genetic Susceptibility, Region of Interest, Magnetic resonance image, and DNA mutational analysis
Despite the substantial heritability of the psychoses and their genuine public health burden, the applicability of the genomic approach in psychiatry has been strongly questioned or prematurely dismissed. selective review of the recent... more
Despite the substantial heritability of the psychoses and their genuine public health burden, the applicability of the genomic approach in psychiatry has been strongly questioned or prematurely dismissed. selective review of the recent literature on molecular genetic and genomic approaches to the psychoses including the early output from genome-wide association studies and the genomic analysis of DNA structural variation. Susceptibility variants at strong candidate genes have been identified including neuregulin, dysbindin, DISC1 and neurexin 1. Rare but highly penetrant copy number variants and new mutations affecting genes involved in neurodevelopment, cell signalling and synaptic function have been described showing some overlapping genetic architecture with other developmental disorders including autism. The de-novo mutations described offer an explanation for the familial sporadic divide and the persistence of schizophrenia in the population. The functional effects of risk variants at the level of cognition and connectivity has been described and recently, ZNF804A has been identified, and the MHC re-identified as risk loci, and it has been shown that at least a third of the variation in liability is due to multiple common risk variants of small effect with a substantial shared genetic liability between schizophrenia and bipolar affective disorder. The genomics have done much for the psychoses to date and more is anticipated.
Research Interests:
The D-amino acid oxidase (DAO) signaling pathway has been implicated in schizophrenia pathogenesis. This may be mediated through modulation of NMDA function by DAO, which is in turn activated by DAO activator (DAOA, formerly G72).... more
The D-amino acid oxidase (DAO) signaling pathway has been implicated in schizophrenia pathogenesis. This may be mediated through modulation of NMDA function by DAO, which is in turn activated by DAO activator (DAOA, formerly G72). Chumakov et al. (2002); PNAS 99: 13675–13680, identifying the novel schizophrenia susceptibility gene DAOA/G30 and a number of independent studies have since reported evidence of association between the DAOA and DAO genes and schizophrenia. However, at least two studies have failed to replicate the epistatic interaction between these loci described in the original report and there have been differences in the associated alleles/haplotypes reported at each locus. In this study, we performed association and epistasis analyses of the DAOA/G30 and DAO loci in a sample of 373 cases with DSM-IV schizophrenia/schizoaffective disorder and 812 controls from the Republic of Ireland. Corrected for the number of tests performed, we found evidence for association between markers at both genes and schizophrenia: DAOA/G30 (P = 0.005, OR = 1.34 (1.09, 1.65)) and DAO (P = 0.003, OR = 1.43 (1.12, 1.84). The data suggest that evidence for association at DAO (marker rs2111902) is more consistent than previously realized, particularly in Caucasian schizophrenia populations. We identified evidence for epistatic interaction between the associated SNPs at DAOA and DAO genes in contributing to schizophrenia risk (OR = 9.3 (1.4, 60.5). Based on these data, more systematic investigation of genes involved in DAO signaling is required. © 2007 Wiley-Liss, Inc.
Research Interests:
Research Interests: Genetics, Neuroscience, Psychology, Cognitive Science, Schizophrenia, and 16 morePrincipal Component Analysis, Glutamate, Humans, Female, Male, Psychotic Disorder, Mood Disorders, Middle Aged, Spectrum, Genotype, Adult, Chi Square Distribution, Depressive Symptoms, Neurosciences, Affective Disorder, and NMDA receptor
Research Interests: Selective Attention, Schizophrenia, Attention, Working Memory, Space perception, and 16 moreResponse Inhibition, Humans, Female, Saccades, Male, Verbal behavior, Verbal working memory, The, Task Performance, Inhibitory Control, Middle Aged, Adult, Multiple regression analysis, Short Term Memory, Choice Behavior, and Neuropsychological Tests
The relationship between clinical symptoms and neurocognitive impairment has been a growing interest in the field of schizophrenia research. We review the empirical evidence for whether some schizophrenia symptoms can be viewed as... more
The relationship between clinical symptoms and neurocognitive impairment has been a growing interest in the field of schizophrenia research. We review the empirical evidence for whether some schizophrenia symptoms can be viewed as expressions of disordered executive functioning. A specific focus of our review is Frith's (1992) neurocognitive theory of negative symptoms, and whether this theory is supported by studies of executive functioning in schizophrenia. The current trend towards viewing executive functioning in terms of fractionable cognitive processes is discussed. Difficulties with traditional clinical measures (e.g. the Wisconsin Card Sorting Test; WCST) in separating these processes are highlighted. Neurocognitive studies of schizophrenia are then reviewed in terms of this fractionated view of executive processes. We conclude that a more specific approach to executive functioning deficits in schizophrenia using more selective measures is needed before stronger conclusions can be drawn about their relationship to clinical symptoms.