Genome-wide study identifies PTPRO and WDR72 and FOXQ1-SUMO1P1 interaction associated with neurocognitive function
ABSTRACT Several aspects of neurocognitive function have high heritability, but the molecular genetic mechanisms underlying neurocognition are not known. We performed a genome-wide association study (GWAS) to identify genes associated with neurocognition.
700 Subjects (schizophrenia spectrum disorder, n=190, bipolar disorder n=157 and healthy individuals n=353) were tested with an extensive neuropsychological test battery, and genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0. After quality control, linear regression analysis of each of the 24 cognitive tests on the SNP dosage was performed, including age, gender, education and disease group as covariates. Additionally, 9 SNPs trending toward genome-wide significance were considered for epistatic interactions.
Four SNPs and 2 independent association signals achieving genome-wide significance were identified. Three intronic SNPs in PTPRO were associated with learning and memory (CVLT-II LDFR) (rs17222089, p=1.55×10(-8); rs11056571, p=1.68×10(-8); and rs2300290, p=1.09×10(-8)). rs719714 downstream of WDR72 was associated with executive functioning (CW-3: Inhibition, D-KEFS) (p=4.32×10(-8)). A highly significant epistatic interaction was found between rs9378605 upstream of FOXQ1 and rs11699311 downstream of SUMO1P1 for the Grooved Pegboard test (p=7.6×10(-14)).
We identified four novel loci associated with neurocognitive function and one novel epistatic interaction. The findings should be replicated in independent samples, but indicate a role of PTPRO in learning and memory, WDR72 with executive functioning, and an interaction between FOXQ1 and SUMO1P1 for psychomotor speed.
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ABSTRACT: Deficits in metacognitive capacity in schizophrenia can be conceptualized as existing along a spectrum from more discrete to more synthetic activities. These capacities may be of great importance in schizophrenia research given their potential to mediate and moderate the impact of illness-related factors on outcome. To explore this possibility this review summarizes research on synthetic metacognition using a paradigm in which metacognitive capacity is rated on the basis of spontaneously produced personal narratives. Evidence from a review of the literature shows that these deficits are detectable in patients with schizophrenia and are related to, but not reducible to, symptom severity and poorer neurocognitive function. Independent of symptoms and neurocognition, deficits in synthetic metacognition, which are likely linked to the brain's ability to integrate information, are related to a range of outcomes including functional competence, learning potential, and insight. These deficits may also play a role in long term psychosocial functioning via their impact on the ability to sustain social functions.Translational Neuroscience 09/2013; 4(3). DOI:10.2478/s13380-013-0131-4 · 0.72 Impact Factor
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ABSTRACT: Episodic memory is one of the most affected cognitive domains in schizophrenia. First-degree biological relatives of individuals with schizophrenia also have been found to exhibit a similar, but milder, episodic memory deficit. Unlike most studies that focus on the percent of previously presented items recognized, the current investigation sought to further elucidate the nature of memory dysfunction associated with schizophrenia by examining the discrimination of old and new material during recognition (measured by d') to consider false recognition of new items. Using the Recurring Figures Test and the California Verbal Learning Test (CVLT), we studied a sample of schizophrenia probands and the first-degree biological relatives of patients with schizophrenia, as well as probands with bipolar disorder and first-degree biological relatives to assess the specificity of recognition memory dysfunction to schizophrenia. The schizophrenia sample had poorer recognition discrimination in both nonverbal and verbal modalities; no such deficits were identified in first-degree biological relatives or bipolar disorder probands. Discrimination in schizophrenia and bipolar probands failed to benefit from the geometric structure in the designs in the manner that controls did on the nonverbal test. Females performed better than males in recognition of geometric designs. Episodic memory dysfunction in schizophrenia is present for a variety of stimulus domains and reflects poor use of item content to increase discrimination of old and new items.
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ABSTRACT: Cardiovascular disease (CVD) is a well-described complication of schizophrenia, however, mechanisms connecting CVD with other facets of psychotic disorders, such as neurocognition, are not understood. The current study examined folate metabolism as a potential mechanism of CVD and neurocognitive deficits by: 1) using endothelial dysfunction as a biomarker of CVD, and 2) comparing enzymes associated with neurocognition, CVD, and critical to folate metabolism, methylenetetrahydrofolate reductase (MTHFR) and catechol-o-methyl transferase (COMT). Endothelial function was assessed in 147 participants with schizophrenia, schizoaffective disorder, and psychotic disorder not otherwise specified grouped by MTHFR and COMT allele status. Regression models were used to compare neurocognitive performance based on the Brief Assessment of Cognition in Schizophrenia (BACS). Overall, endothelial function predicted BACS composite z-scores after controlling for age, race, level of education, serum folate levels, and MTHFR/COMT risk allele status. Participants with at least one or more MTHFR and/or COMT risk alleles had lower BACS Composite and BACS Symbol Coding adjusted mean z-scores than those with both MTHFR CC and COMT Met/Met genotypes. Thus, endothelial dysfunction may contribute to the neurocognitive deficits seen in psychotic disorders. CVD interventions may not only reduce CVD-related morbidity, but also lessen progressive neurocognitive deficits reported in psychotic disorders. Copyright © 2015 Elsevier B.V. All rights reserved.Schizophrenia Research 02/2015; DOI:10.1016/j.schres.2015.02.006 · 4.43 Impact Factor