Genome-wide association study in 404,302 individuals identifies 7 significant loci for reaction time variability.

Reaction time variability (RTV), reflecting fluctuations in response time on cognitive tasks, has been proposed as an endophenotype for many neuropsychiatric disorders. There have been no large-scale genome-wide association studies (GWAS) of RTV and little is known about its genetic underpinnings. Here, we used data from the UK Biobank to conduct a GWAS of RTV in participants of white British ancestry (n = 404,302) as well as a trans-ancestry GWAS meta-analysis (n = 44,873) to assess replication. We found 161 genome-wide significant single nucleotide polymorphisms (SNPs) distributed across 7 genomic loci in our discovery GWAS. Functional annotation of the variants implicated genes involved in synaptic function and neural development. The SNP-based heritability (h2SNP) estimate for RTV was 3%. We investigated genetic correlations between RTV and selected neuropsychological traits using linkage disequilibrium score regression, and found significant correlations with several traits, including a positive correlation with mean reaction time and schizophrenia. Despite the high genetic correlation between RTV and mean reaction time, we demonstrate distinctions in the genetic underpinnings of these traits. Lastly, we assessed the predictive ability of a polygenic score (PGS) for RTV, calculated using PRSice and PRS-CS, and found that the RTV-PGS significantly predicted RTV in independent cohorts, but that the generalisability to other ancestry groups was poor. These results identify genetic underpinnings of RTV, and support the use of RTV as an endophenotype for neurological and psychiatric disorders.

Adverse childhood experiences and cognition: A cross-sectional study in Xhosa people living with schizophrenia and matched medical controls.

BACKGROUND: Adverse childhood experiences (ACEs) are associated with impaired cognitive function in adult life in the general population as well as in people living with schizophrenia (PLS). Research on cognitive function in PLS in low- and middle-income countries (LMIC) is, however, limited. The objectives of this study were to investigate the association between ACE types and various cognitive domains in a sample of PLS and matched medical controls, and to determine the moderating effect of group membership (PLS vs. medical controls) on these associations, in the South African setting. METHODS: Participants (n PLS = 520; n medical controls = 832) completed the Childhood Trauma Questionnaire-Short Form, the Structured Clinical Interview for DSM-IV (SCID-I), and the University of Pennsylvania Computerized Neurocognitive Battery (PennCNB). An efficiency or speed score was used to assess performance across 9 cognitive domains. The association between exposure to different ACE types and 9 cognitive domains was examined using partial correlations and multiple linear regression models, adjusting for sex, age and education years. Finally, potential moderating effects of group membership (PLS vs. medical controls) on the association between ACEs and cognitive domains were tested. RESULTS: In the entire sample, emotional and physical abuse predicted worse performance on sensorimotor and emotion identification domains. Also, emotional abuse was negatively associated with motor function, physical abuse was negatively associated with spatial processing, and physical neglect was negatively associated with face memory and emotion identification. In contrast, emotional neglect was related to better performance on abstraction and mental flexibility. No moderating effect of group membership was found on any of these associations. CONCLUSION: Exposure to ACEs was associated with social and non-social cognition in adulthood, although the magnitude of these relationships was small and similar between PLS and matched medical controls. The nature of these associations differed across ACE subtype, suggesting the need for a nuanced approach to studying a range of mechanisms that may underlie different associations. However, a number of ACE subtypes were associated with worse performance on emotional identification, indicating that some underlying mechanisms may have more transversal impact. These findings contribute to the sparse body of literature on ACEs and cognition in PLS in LMIC.

Disability benefits protect against lost income for South Africans living with Schizophrenia.

Little is known about the economic impact of disability grants for people living with schizophrenia in low- and middle- income countries. In this brief report, we show that receipt of disability benefits is significantly associated (ß = 0.105, p < 0.0001) with increased household and personal wealth in large sample of people living with schizophrenia in South Africa (n = 1154). This study provides further support for the use of disability grants as a mechanism to protect people living with schizophrenia and their families against the economic costs associated with schizophrenia.

Predictors of within-individual variability in cognitive performance in schizophrenia in a South African case-control study.

INTRODUCTION: Cognitive dysfunction in schizophrenia may be assessed by measuring within-individual variability (WIV) in performance across a range of cognitive tests. Previous studies have found increased WIV in people with schizophrenia, but no studies have been conducted in low- to middle-income countries where the different sociocultural context may affect WIV. We sought to address this gap by exploring the relationship between WIV and a range of clinical and demographic variables in a large study of people with schizophrenia and matched controls in South Africa. METHODS: 544 people with schizophrenia and 861 matched controls completed an adapted version of The University of Pennsylvania Computerized Neurocognitive Battery (PennCNB). Demographic and clinical information was collected using the Structured Clinical Interview for DSM-IV Diagnoses. Across-task WIV for performance speed and accuracy on the PennCNB was calculated. Multivariate linear regression was used to assess the relationship between WIV and a diagnosis of schizophrenia in the whole sample, and WIV and selected demographic and clinical variables in people with schizophrenia. RESULTS: Increased WIV of performance speed across cognitive tests was significantly associated with a diagnosis of schizophrenia. In people with schizophrenia, increased speed WIV was associated with older age, a lower level of education and a lower score on the Global Assessment of Functioning scale. Increased accuracy WIV was significantly associated with a younger age in people with schizophrenia. CONCLUSIONS: Measurements of WIV of performance speed can add to the knowledge gained from studies of cognitive dysfunction in schizophrenia in resource-limited settings.

Genomic insights into the shared and distinct genetic architecture of cognitive function and schizophrenia.

Cognitive impairment is a major determinant of functional outcomes in schizophrenia, however, understanding of the biological mechanisms underpinning cognitive dysfunction in the disorder remains incomplete. Here, we apply Genomic Structural Equation Modelling to identify latent cognitive factors capturing genetic liabilities to 12 cognitive traits measured in the UK Biobank. We identified three broad factors that underly the genetic correlations between the cognitive tests. We explore the overlap between latent cognitive factors, schizophrenia, and schizophrenia symptom dimensions using a complementary set of statistical approaches, applied to data from the latest schizophrenia genome-wide association study (Ncase = 53,386, Ncontrol = 77,258) and the Thematically Organised Psychosis study (Ncase = 306, Ncontrol = 1060). Global genetic correlations showed a significant moderate negative genetic correlation between each cognitive factor and schizophrenia. Local genetic correlations implicated unique genomic regions underlying the overlap between schizophrenia and each cognitive factor. We found substantial polygenic overlap between each cognitive factor and schizophrenia and biological annotation of the shared loci implicated gene-sets related to neurodevelopment and neuronal function. Lastly, we show that the common genetic determinants of the latent cognitive factors are not predictive of schizophrenia symptoms in the Norwegian Thematically Organized Psychosis cohort. Overall, these findings inform our understanding of cognitive function in schizophrenia by demonstrating important differences in the shared genetic architecture of schizophrenia and cognitive abilities.

An evolutionary perspective on complex neuropsychiatric disease.

The forces of evolution-mutation, selection, migration, and genetic drift-shape the genetic architecture of human traits, including the genetic architecture of complex neuropsychiatric illnesses. Studying these illnesses in populations that are diverse in genetic ancestry, historical demography, and cultural history can reveal how evolutionary forces have guided adaptation over time and place. A fundamental truth of shared human biology is that an allele responsible for a disease in anyone, anywhere, reveals a gene critical to the normal biology underlying that condition in everyone, everywhere. Understanding the genetic causes of neuropsychiatric disease in the widest possible range of human populations thus yields the greatest possible range of insight into genes critical to human brain development. In this perspective, we explore some of the relationships between genes, adaptation, and history that can be illuminated by an evolutionary perspective on studies of complex neuropsychiatric disease in diverse populations.

Within-individual variability in cognitive performance in schizophrenia: A narrative review of the key literature and proposed research agenda.

Schizophrenia is a neurodevelopmental disorder and a leading cause of disability worldwide. Deficits in cognitive function are characteristic of schizophrenia and are predictors of functional outcomes in the disorder. Within-individual variability (WIV) in cognitive performance is elevated in schizophrenia and has been suggested to provide additional insight into cognitive function over and above mean performance measures. Despite growing interest in WIV in schizophrenia, research on the clinical significance and neural correlates of WIV in the disorder remains sparse. The present narrative review summarizes the key literature linking WIV in schizophrenia to clinical, neural, and genetic correlates. Here, we aim to highlight key knowledge gaps and provide directions for future research into WIV in schizophrenia.

Genome-wide association study in 404,302 individuals identifies 7 significant loci for reaction time variability.

Reaction time variability (RTV), reflecting fluctuations in response time on cognitive tasks, has been proposed as an endophenotype for many neuropsychiatric disorders. There have been no large-scale genome wide association studies (GWAS) of RTV and little is known about its genetic underpinnings. Here, we used data from the UK Biobank to conduct a GWAS of RTV in participants of white British ancestry (n = 404,302) as well as a trans-ancestry GWAS meta-analysis (n = 44,873) to assess replication. We found 161 genome-wide significant single nucleotide polymorphisms (SNPs) distributed across 7 genomic loci in our discovery GWAS. Functional annotation of the variants implicated genes involved in synaptic function and neural development. The SNP-based heritability (h2SNP) estimate for RTV was 3%. We investigated genetic correlations between RTV and selected neuropsychological traits using linkage disequilibrium score regression, and found significant correlations with several traits, including a positive correlation with schizophrenia. We assessed the predictive ability of a polygenic score (PGS) for RTV, calculated using PRSice and PRS-CS, and found that the RTV-PGS significantly predicted RTV in independent cohorts, but that the generalizability to other ancestry groups was poor. These results identify genetic underpinnings of RTV, and support the use of RTV as an endophenotype for neurological and psychiatric disorders.

Genomic Insights into the Shared and Distinct Genetic Architecture of Cognitive Function and Schizophrenia.

Cognitive impairment is a major determinant of functional outcomes in schizophrenia, and efforts to understand the biological basis of cognitive dysfunction in the disorder are ongoing. Previous studies have suggested genetic overlap between global cognitive ability and schizophrenia, but further work is needed to delineate the shared genetic architecture. Here, we apply genomic structural equation modelling to identify latent cognitive factors capturing genetic liabilities to 12 cognitive traits measured in the UK Biobank (UKB). We explore the overlap between latent cognitive factors, schizophrenia, and schizophrenia symptom dimensions using a complementary set of statistical approaches, applied to data from the latest schizophrenia genome-wide association study (Ncase = 53,386, Ncontrol = 77,258) and the Thematically Organised Psychosis study (Ncase = 306, Ncontrol = 1060). We identified three broad factors (visuo-spatial, verbal analytic and decision/reaction time) that underly the genetic correlations between the UKB cognitive tests. Global genetic correlations showed a significant but moderate negative genetic correlation between each cognitive factor and schizophrenia. Local genetic correlations implicated unique genomic regions underlying the overlap between schizophrenia and each cognitive factor. We found evidence of substantial polygenic overlap between each cognitive factor and schizophrenia but show that most loci shared between the latent cognitive factors and schizophrenia have unique patterns of association with the cognitive factors. Biological annotation of the shared loci implicated gene-sets related to neurodevelopment and neuronal function. Lastly, we find that the common genetic determinants of the latent cognitive factors are not predictive of schizophrenia symptom dimensions. Overall, these findings inform our understanding of cognitive function in schizophrenia by demonstrating important differences in the shared genetic architecture of schizophrenia and cognitive abilities.