Impaired Intellect and Memory

Toulopoulou, Timothea; Goldberg, Terry E.; Mesa, I. Rebollo; Picchioni, Marco; Rijsdijk, Frühling; Ståhl, Daniel; Cherny, Stacey S.; Sham, Pak C.; Faraone, Stephen V.; Tsuang, Ming T.; Weinberger, Daniel R.; Seidman, Larry J.; Murray, Robin M.

doi:10.1001/archgenpsychiatry.2010.99

Cited by 104 publications

(48 citation statements)

References 37 publications

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“…The present finding of a link between intellectual function and variation in the NMDA-RC therefore supports a genetic link between schizophrenia and intelligence, in keeping with behaviour genetic 42 research, and also with recent polygenic risk studies of a sub-set of the present cohorts that indicated an overlap of polygenic risk factors for schizophrenia and for cognitive ageing. 84 The genetic link between schizophrenia and cognitive abilities appears to be region rather than variant specific.…”

Section: Discussionsupporting

confidence: 90%

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Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins

et al. 2014

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Differences in general cognitive ability (intelligence) account for approximately half of the variation in any large battery of cognitive tests and are predictive of important life events including health. Genome-wide analyses of common single-nucleotide polymorphisms indicate that they jointly tag between a quarter and a half of the variance in intelligence. However, no single polymorphism has been reliably associated with variation in intelligence. It remains possible that these many small effects might be aggregated in networks of functionally linked genes. Here, we tested a network of 1461 genes in the postsynaptic density and associated complexes for an enriched association with intelligence. These were ascertained in 3511 individuals (the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium) phenotyped for general cognitive ability, fluid cognitive ability, crystallised cognitive ability, memory and speed of processing. By analysing the results of a genome wide association study (GWAS) using Gene Set Enrichment Analysis, a significant enrichment was found for fluid cognitive ability for the proteins found in the complexes of N-methyl-D-aspartate receptor complex; P=0.002. Replication was sought in two additional cohorts (N=670 and 2062). A meta-analytic P-value of 0.003 was found when these were combined with the CAGES consortium. The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence.

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Section: Discussionsupporting

confidence: 90%

“…40 De novo mutations in the ARC protein have been implicated in schizophrenia, 20 a disease in part predicted by a low premorbid cognitive ability, 41 which may be due to a shared genetic component between the two traits. 42 …”

Section: Introductionmentioning

confidence: 99%

Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins

et al. 2014

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“…28, 29, 30 However, as we learn more about the polygenic architecture of intelligence and mental disorders, single-nucleotide length polymorphism (SNP)-based bivariate analyses may provide more robust estimates of the shared genetic contribution of common genetic variants. 31, 32, 33 Indeed, a recent study reported that (a) polygenic SNP scores derived to predict increased cognitive ability were associated with a reduced risk of schizophrenia, and conversely that (b) polygenic SNP scores derived to predict increased risk of schizophrenia were associated with lower scores on cognitive ability.…”

Section: Discussionmentioning

confidence: 99%

The association between family history of mental disorders and general cognitive ability

et al. 2014

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There is an emerging literature linking cognitive ability with a wide range of psychiatric disorders. These findings have led to the hypothesis that diminished ‘cognitive reserve' is a causal risk factor for psychiatric disorders. However, it is also feasible that a family history of mental disorders may confound this relationship, by contributing to both a slight impairment in cognitive ability, and an increased risk of psychiatric disorder. On the basis of a large, population-based sample of young adult male conscripts (n=160 608), we examined whether the presence of a family history of a range of mental disorders was associated with cognitive ability, as tested by the Børge Priens Prøve. In those with no individual-level history of mental disorder, a family-level history of a mental disorder was associated with a slight reduction in cognitive ability. In general, this pattern was found regardless of the nature of the psychiatric disorder in the family. Our study suggests that shared familial factors may underpin both cognitive ability and the risk of a wide range of psychiatric disorders. Convergent evidence from epidemiology and genetics suggests that shared genetic factors underpin an unexpectedly diverse range of psychiatric disorders. On the basis of the findings of the current study, we speculate that these same shared genetic factors also contribute to general cognitive ability.

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“…Family studies show that the offspring of parents with schizophrenia have worse cognitive function than the offspring of unaffected parents [31], and that cognitive impairment is associated with familial risk of schizophrenia [32]. Applying genetic modeling to a combined family and twin sample, Toulopoulou and colleagues [33] showed that a large proportion of the phenotypic correlations between schizophrenia and cognition are due to shared genetic effects.…”

Section: Family Studiesmentioning

confidence: 99%

Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice

2014

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Psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder, attention-deficit/hyperactivity disorder and autism spectrum disorder are common and result in significant morbidity and mortality. Although currently classified into distinct disorder categories, they show clinical overlap and familial co-aggregation, and share genetic risk factors. Recent advances in psychiatric genomics have provided insight into the potential mechanisms underlying the overlap between these disorders, implicating genes involved in neurodevelopment, synaptic plasticity, learning and memory. Furthermore, evidence from copy number variant, exome sequencing and genome-wide association studies supports a gradient of neurodevelopmental psychopathology indexed by mutational load or mutational severity, and cognitive impairment. These findings have important implications for psychiatric research, highlighting the need for new approaches to stratifying patients for research. They also point the way for work aiming to advance our understanding of the pathways from genotype to clinical phenotype, which will be required in order to inform new classification systems and to develop novel therapeutic strategies.

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Impaired Intellect and Memory

Cited by 104 publications

References 37 publications

Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins

Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins

The association between family history of mental disorders and general cognitive ability

Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice

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