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Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

ABSTRACT: Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.

SUBMITTER: Lam M

PROVIDER: S-EPMC6699140 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Lam Max M Hill W David WD Trampush Joey W JW Yu Jin J Knowles Emma E Davies Gail G Stahl Eli E Huckins Laura L Liewald David C DC Djurovic Srdjan S Melle Ingrid I Sundet Kjetil K Christoforou Andrea A Reinvang Ivar I DeRosse Pamela P Lundervold Astri J AJ Steen Vidar M VM Espeseth Thomas T Räikkönen Katri K Widen Elisabeth E Palotie Aarno A Eriksson Johan G JG Giegling Ina I Konte Bettina B Hartmann Annette M AM Roussos Panos P Giakoumaki Stella S Burdick Katherine E KE Payton Antony A Ollier William W Chiba-Falek Ornit O Attix Deborah K DK Need Anna C AC Cirulli Elizabeth T ET Voineskos Aristotle N AN Stefanis Nikos C NC Avramopoulos Dimitrios D Hatzimanolis Alex A Arking Dan E DE Smyrnis Nikolaos N Bilder Robert M RM Freimer Nelson A NA Cannon Tyrone D TD London Edythe E Poldrack Russell A RA Sabb Fred W FW Congdon Eliza E Conley Emily Drabant ED Scult Matthew A MA Dickinson Dwight D Straub Richard E RE Donohoe Gary G Morris Derek D Corvin Aiden A Gill Michael M Hariri Ahmad R AR Weinberger Daniel R DR Pendleton Neil N Bitsios Panos P Rujescu Dan D Lahti Jari J Le Hellard Stephanie S Keller Matthew C MC Andreassen Ole A OA Deary Ian J IJ Glahn David C DC Malhotra Anil K AK Lencz Todd T

American journal of human genetics 20190801 2

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse bi ...[more]

PMID: 31374203

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Project description:Early-life education (years of schooling) has been investigated in regards to cognition, health outcomes and mortality. It has been shown to confer cognitive reserve that might lessen the impact of brain pathology and its impact on cognitive and motor functioning in a variety of neurodegenerative diseases and, for instance, to influence electrical activity [Begum, T., Reza, F., Ahmed, I., & Abdullah, J. M. (2014). Influence of education level on design-induced N170 and P300 components of event related potentials in the human brain. J Integr Neurosci, 13(1), 71-88. doi:10.1142/S0219635214500058]. On the other hand, demonstrations of a direct association between education and brain-structural measures have been more equivocal and scant. The current study sought to identify univariate cortical-thickness patterns underlying education and general intelligence after adjusting for age, gender and possible in-scanner movement in 353 individuals aged 40 to 80. We followed up this idea with multivariate analyses as well. For univariate analyses, our analyses yielded no robust associations between education and general intelligence beyond confounding effects of gender, age and extraneous in-scanner movement. A subsequent multivariate analyses showed a relationship between education and regional cortical thickness with a robust pattern of negative as well as positive loadings in several right-sided brain areas, speaking to a subtle but robust distributed effect of education on cortical thickness. Cortical thickness variance that is the residual of this education-related pattern was shown to be positively associated with age and extraneous in-scanner movement. Our study thus presents a complex picture of the association of education with regional cortical thickness: education was associated with a distributed brain-wide pattern of positive as well as negative loadings with unaccounted residuals being larger for older participants. Focal regional associations beyond demographic and age covariates were not identified.

Dataset Information

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Publications

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Similar Datasets

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