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.

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Available from: Ruben Gur, Jan 27, 2014
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    • "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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    • "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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    • "GWAS has had many successes. Many common polymorphisms have now been found that increase genetic risk for AD (Harold et al. 2009; Lambert et al. 2009; Naj et al. 2011), age-related cognitive decline (Davies et al. 2012), schizophrenia (Almasy et al. 2008; Stefansson et al. 2009; Ripke et al. 2011; Rietschel et al. 2012), bipolar disorder (Sklar et al. 2011; Cichon et al. 2011) as well as obesity (Yang et al. 2012), alcohol drinking (Schumann et al. 2011), tobacco smoking (Thorgeirsson et al. 2008), cardiovascular disease (CARDIoGRAMplusC4D Consortium et al. 2013), osteoporosis (Estrada et al. 2012), prevalent psychiatric disorders (Cross-Disorder Group of the Psychiatric Genomics Consortium et al. 2013) and for many other traits and diseases. "
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