A genome-wide study of common SNPs and CNVs in cognitive performance in the CANTAB

Center for Human Genome Variation, Institute for Genome Sciences and Policy, Duke University, 450 Research Drive, Box 91009, Durham, NC 27708, USA.
Human Molecular Genetics (Impact Factor: 6.39). 10/2009; 18(23):4650-61. DOI: 10.1093/hmg/ddp413
Source: PubMed

ABSTRACT Psychiatric disorders such as schizophrenia are commonly accompanied by cognitive impairments that are treatment resistant and crucial to functional outcome. There has been great interest in studying cognitive measures as endophenotypes for psychiatric disorders, with the hope that their genetic basis will be clearer. To investigate this, we performed a genome-wide association study involving 11 cognitive phenotypes from the Cambridge Neuropsychological Test Automated Battery. We showed these measures to be heritable by comparing the correlation in 100 monozygotic and 100 dizygotic twin pairs. The full battery was tested in approximately 750 subjects, and for spatial and verbal recognition memory, we investigated a further 500 individuals to search for smaller genetic effects. We were unable to find any genome-wide significant associations with either SNPs or common copy number variants. Nor could we formally replicate any polymorphism that has been previously associated with cognition, although we found a weak signal of lower than expected P-values for variants in a set of 10 candidate genes. We additionally investigated SNPs in genomic loci that have been shown to harbor rare variants that associate with neuropsychiatric disorders, to see if they showed any suggestion of association when considered as a separate set. Only NRXN1 showed evidence of significant association with cognition. These results suggest that common genetic variation does not strongly influence cognition in healthy subjects and that cognitive measures do not represent a more tractable genetic trait than clinical endpoints such as schizophrenia. We discuss a possible role for rare variation in cognitive genomics.

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    • "Total Errors is a sum of the errors made across all stages, whereas the adjusted score includes an adjustment made for any stages not reached, allowing it to be comparable to all subjects even if the task was ended prematurely due to cognitive limitation. The Verbal Recognition Memory test assesses immediate and delayed verbal memory and learning under immediate and delayed free-recall and forced-choice recognition conditions [24] [25]. The subject is instructed to immediately recall as many words as possible after being presented with a list of stimuli (on the basis of frequency, word length, and imageability). "
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    ABSTRACT: Background: The macula (central retina) contains a yellow pigment, comprising the dietary carotenoids lutein (L), zeaxanthin (Z), and meso-zeaxanthin, known as macular pigment (MP). The concentrations of MP's constituent carotenoids in retina and brain tissue correlate, and there is a biologically-plausible rationale, supported by emerging evidence, that MP's constituent carotenoids are also important for cognitive function. Objective: To investigate if patients with Alzheimer's disease (AD) are comparable to controls in terms of MP and visual function. Methods: 36 patients with moderate AD and 33 controls with the same age range participated. MP was measured using dual-wavelength autofluorescence (Heidelberg Spectralis®); cognitive function was assessed using a battery of cognition tests (including Cambridge Neuropsychological Test Automated Battery). Visual function was recorded by measuring best corrected visual acuity (BCVA) and contrast sensitivity (CS). Serum L and Z concentrations (by HPLC) and age-related macular degeneration (AMD, by retinal examination) status were also assessed. Results: In the AD group, central MP (i.e., at 0.23°) and MP volume were significantly lower than the control group (p < 0.001 for both), as were measures of BCVA, CS, and serum L and Z concentrations (p < 0.05, for all). Conclusion: AD patients were observed to exhibit significantly less MP, lower serum concentrations of L and Z, poorer vision, and a higher occurrence of AMD when compared to control subjects. A clinical trial in AD patients designed to investigate the impact of macular carotenoid supplementation with respect to MP, visual function, and cognitive function is merited.
    Journal of Alzheimer's disease: JAD 07/2014; 42(4). DOI:10.3233/JAD-140507 · 4.15 Impact Factor
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    • "Because each of the five scales measures risky propensity in different ways, principle component analysis (PCA) was used to extract an index reflecting GRP. PCA is a general technique used to extract common or shared variance from a set of measures (Costello and Osborne, 2005) and has been previously used in similar contexts (Need et al., 2009). "
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    ABSTRACT: Men are more risk prone than women, but the underlying basis remains unclear. To investigate this question, we developed a trait-like measure of risk propensity which we correlated with resting-state functional connectivity to identify sex differences. Specifically, we used short- and long-range functional connectivity densities to identify associated brain regions and examined their functional connectivities in resting-state functional magnetic resonance imaging (fMRI) data collected from a large sample of healthy young volunteers. We found that men had a higher level of general risk propensity (GRP) than women. At the neural level, although they shared a common neural correlate of GRP in a network centered at the right inferior frontal gyrus, men and women differed in a network centered at the right secondary somatosensory cortex, which included the bilateral dorsal anterior/middle insular cortices and the dorsal anterior cingulate cortex. In addition, men and women differed in a local network centered at the left inferior orbitofrontal cortex. Most of the regions identified by this resting-state fMRI study have been previously implicated in risk processing when people make risky decisions. This study provides a new perspective on the brain-behavioral relationships in risky decision making and contributes to our understanding of sex differences in risk propensity.
    Frontiers in Behavioral Neuroscience 01/2014; 8:2. DOI:10.3389/fnbeh.2014.00002 · 3.27 Impact Factor
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    • "Significant regions for rare CNVs reported in other neurocognitive disorders are not found significant by genome-wide associations using SNPs. Need et al. [78] suggest that looking for the effect of rare variants enriched in schizophrenia patients within a healthy population may reveal an association. Of the regions we examined, SHANK3 remained significant following permutation analysis, suggesting that this gene may be involved in normal variation in fluid intelligence. "
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    ABSTRACT: Differences in genomic structure between individuals are ubiquitous features of human genetic variation. Specific copy number variants (CNVs) have been associated with susceptibility to numerous complex psychiatric disorders, including attention-deficit-hyperactivity disorder, autism-spectrum disorders and schizophrenia. These disorders often display co-morbidity with low intelligence. Rare chromosomal deletions and duplications are associated with these disorders, so it has been suggested that these deletions or duplications may be associated with differences in intelligence. Here we investigate associations between large (≥500kb), rare (<1% population frequency) CNVs and both fluid and crystallized intelligence in community-dwelling older people. We observe no significant associations between intelligence and total CNV load. Examining individual CNV regions previously implicated in neuropsychological disorders, we find suggestive evidence that CNV regions around SHANK3 are associated with fluid intelligence as derived from a battery of cognitive tests. This is the first study to examine the effects of rare CNVs as called by multiple algorithms on cognition in a large non-clinical sample, and finds no effects of such variants on general cognitive ability.
    PLoS ONE 12/2012; 7(12):e37385. DOI:10.1371/journal.pone.0037385 · 3.23 Impact Factor
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Anna Need