A Genome Screen for Quantitative Trait Loci Influencing Schizophrenia and Neurocognitive Phenotypes

Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
American Journal of Psychiatry (Impact Factor: 12.3). 09/2008; 165(9):1185-92. DOI: 10.1176/appi.ajp.2008.07121869
Source: PubMed


Deficits in neurocognitive function have been demonstrated in individuals with schizophrenia and in the unaffected family members of these individuals. Genetic studies of such complementary traits, along with traditional analyses of diagnosis, may help to elucidate the biological pathways underlying familial liability to schizophrenia and related disorders. The authors conducted a multiplex, multigenerational family study using a genome-wide screen for schizophrenia and related neurocognitive phenotypes.
Participants were 1) 676 European American individuals from 43 families, ascertained through an individual with schizophrenia, and 2) 236 healthy comparison subjects. Participants were evaluated clinically and examined through the use of a computerized neurocognitive test battery that provided measures of accuracy and speed on the cognitive domains of abstraction and mental flexibility; attention; verbal, face, and spatial memory; language and reasoning; spatial and emotion processing; and sensorimotor dexterity. A genome-wide linkage screen was also performed. Healthy comparison subjects were included in order to obtain normative phenotypic data but were not genotyped.
Significant evidence for linkage of schizophrenia to chromosome 19q was observed. Analysis of cognitive traits revealed significant linkage to chromosome 5q for the domains of abstraction and mental flexibility. A variety of other neurocognitive traits also showed nominal evidence of linkage to the 5q region. Joint analyses with diagnosis suggested that this quantitative trait locus may also influence schizophrenia.
Although chromosome 5 has been implicated in previous linkage studies of schizophrenia, the identification of the chromosome 19 quantitative trait locus is a novel finding. The identification of the chromosome 5 quantitative trait locus through linkage to neurocognitive phenotypes in the present study may inform functional hypotheses pertaining to how genotypes are connected to disease.

    • "The attractiveness of endophenotypes stems from the observation that these traits are heritable, segregate in SZ families and likely possess a less complex genetic architecture [Gottesman II and Gould TD 2003; Cannon TD and Keller MC 2006]. Over the past few years, genome-wide association and linkage studies have identified genetic loci associated with SZ candidate neurocognitive endophenotypes [Almasy L et al., 2008; Greenwood TA et al., 2013; Papassotiropoulos A et al., 2013; Lencz T et al., 2014; Vaidyanathan U et al., 2014]. "
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    ABSTRACT: Neurocognitive abilities constitute complex traits with considerable heritability. Impaired neurocognition is typically observed in schizophrenia (SZ), whereas convergent evidence has shown shared genetic determinants between neurocognition and SZ. Here, we report a genome-wide association study (GWAS) on neuropsychological and oculomotor traits, linked to SZ, in a general population sample of healthy young males (n = 1079). Follow-up genotyping was performed in an identically phenotyped internal sample (n = 738) and an independent cohort of young males with comparable neuropsychological measures (n = 825). Heritability estimates were determined based on genome-wide single-nucleotide polymorphisms (SNPs) and potential regulatory effects on gene expression were assessed in human brain. Correlations with general cognitive ability and SZ risk polygenic scores were tested utilizing meta-analysis GWAS results by the Cognitive Genomics Consortium (COGENT) and the Psychiatric Genomics Consortium (PGC-SZ). The GWAS results implicated biologically relevant genetic loci encoding protein targets involved in synaptic neurotransmission, although no robust individual replication was detected and thus additional validation is required. Secondary permutation-based analysis revealed an excess of strongly associated loci among GWAS top-ranked signals for verbal working memory (WM) and antisaccade intra-subject reaction time variability (empirical P < 0.001), suggesting multiple true-positive single-SNP associations. Substantial heritability was observed for WM performance. Further, sustained attention/vigilance and WM were suggestively correlated with both COGENT and PGC-SZ derived polygenic scores. Overall, these results imply that common genetic variation explains some of the variability in neurocognitive functioning among young adults, particularly WM, and provide supportive evidence that increased SZ genetic risk predicts neurocognitive fluctuations in the general population. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    No preview · Article · May 2015 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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    • "The battery we used, the web-based Computerized Neurocognitive Battery (CNB), consists of 17 cognitive tests, and provides measures of accuracy as well as speed in the following cognitive domains: abstraction and mental flexibility, attention, working memory, memory (verbal , face, and spatial), language and nonverbal reasoning, spatial ability, emotion identification, emotion-and age differentiation, sensorimotor speed, and motor speed. Individual differences in these domains are substantially heritable and demonstrate genetic linkage (Almasy et al., 2008). Scores on the CNB are reliable and compare well to scores on traditional pen-and-paper tests in healthy samples as well as in clinical samples (e.g. "
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    ABSTRACT: Regular exercise has often been suggested to have beneficial effects on cognition, but empirical findings are mixed because of heterogeneity in sample composition (age and sex); the cognitive domain being investigated; the definition and reliability of exercise behavior measures; and study design (e.g., observational versus experimental). Our aim was to scrutinize the domain specificity of exercise effects on cognition, while controlling for the other sources of heterogeneity. In a population based sample consisting of 472 males and 668 females (aged 10-86years old) we administered the Computerized Neurocognitive Battery (CNB), which provided accuracy and speed measures of abstraction and mental flexibility, attention, working memory, memory (verbal, face, and spatial), language and nonverbal reasoning, spatial ability, emotion identification, emotion- and age differentiation, sensorimotor speed, and motor speed. Using univariate and multivariate regression models, CNB scores were associated with participants' average energy expenditure per week (weekly METhours), which were derived from a questionnaire on voluntary regular leisure time exercise behavior. Univariate models yielded generally positive associations between weekly METhours and cognitive accuracy and speed, but multivariate modeling demonstrated that direct relations were small and centered around zero. The largest and only significant effect size (β=0.11, p<0.001) was on the continuous performance test, which measures attention. Our results suggest that in the base population, any chronic effects of voluntary regular leisure time exercise on cognition are limited. Only a relation between exercise and attention inspires confidence. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · May 2015 · Brain and Cognition
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    • "Although the tests that compose the CNB were often adapted from traditional neuropsychological assessments, they also have the advantage of being validated with functional neuroimaging as reflecting the recruitment of specific brain systems (e.g., Gur et al., 2000; Roalf et al., 2013, 2014; Satterthwaite et al., 2013), making them particularly useful as biomarkers of brain dysfunction (Gur et al., 2012). To this end, the CNB has been deployed in multiple large-scale genomic, neurobehavioral, and treatment studies (Aliyu et al., 2006; Almasy et al., 2008; Grant, Huh, Perivoliotis, Stolar, & Beck, 2012; Greenwood et al., 2007; Gur et al., 2001, 2012; R. E. Gur, Calkins, et al., 2007; Gur, Nimgaonkar, et al., 2007; Thomas et al., 2013). The Penn Line Orientation Test (PLOT) is included in the CNB to assess visuospatial processing with minimal motor or language demands. "
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