Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways
| Autor: | Panos Bitsios, Nikos C. Stefanis, Eliza Congdon, Dwight Dickinson, Elizabeth T. Cirulli, Jari Lahti, Neil Pendleton, Thomas Espeseth, Stephanie Le Hellard, Fred W. Sabb, Deborah K. Attix, Anil K. Malhotra, Aarno Palotie, Ina Giegling, W. David Hill, Joey W. Trampush, Edythe D. London, Elisabeth Widen, Todd Lencz, Emily Drabant Conley, Anna C. Need, Ian J. Deary, Srdjan Djurovic, Astri J. Lundervold, Emma Knowles, Gary Donohoe, David C. Liewald, Matthew C. Keller, Johan G. Eriksson, Katri Räikkönen, Laura M. Huckins, Panos Roussos, Gail Davies, Max Lam, Eli A. Stahl, Andrea Christoforou, Annette M. Hartmann, Ivar Reinvang, Ahmad R. Hariri, Matthew A. Scult, Dan E. Arking, Aiden Corvin, Jin Yu, Dimitrios Avramopoulos, Robert M. Bilder, Katherine E. Burdick, Richard E. Straub, Ornit Chiba-Falek, Dan Rujescu, Michael Gill, Daniel R. Weinberger, Vidar M. Steen, Ingrid Melle, Pamela DeRosse, Bettina Konte, Tyrone D. Cannon, David C. Glahn, Alex Hatzimanolis, Nelson A. Freimer, Ole A. Andreassen, Stella Giakoumaki, Antony Payton, Kjetil Sundet, William Ollier, Aristotle N. Voineskos, Nikolaos Smyrnis, Russell A. Poldrack, Derek W. Morris |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
pathways Genome-wide association study Medical and Health Sciences Synaptic Transmission 0302 clinical medicine Cognition cognitive ability 2.1 Biological and endogenous factors GWAS Aetiology Genetics (clinical) Genetics & Heredity 0303 health sciences Single Nucleotide Biological Sciences Serious Mental Illness genetic correlation Mental Health educational attainment Meta-analysis Educational Status Psychology Biotechnology Clinical psychology Adult Schizophrenia (object-oriented programming) Genetic correlation Polymorphism Single Nucleotide Article 03 medical and health sciences pleiotropy mental disorders Genetics medicine Humans Genetic Predisposition to Disease Bipolar disorder Polymorphism 030304 developmental biology Genetic association Prevention Human Genome Counterintuitive Neurosciences medicine.disease Educational attainment Brain Disorders schizophrenia 030104 developmental biology Neurodevelopmental Disorders Schizophrenia Autism Cognition Disorders 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | Lam, M, Hill, W D, Trampush, J W, Yu, J, Knowles, E, Davies, G, Stahl, E A, Huckins, L M, Liewald, D, Djurovic, S, Melle, I, Sundet, K, Christoforou, A, Reinvang, I, Derosse, P, Lundervold, A J, Steen, V M, Espeseth, T, Raikkonen, K, Widen, E, Palotie, A, Eriksson, J G, Giegling, I, Konte, B, Hartmann, A M, Roussos, P, Giakoumaki, S, Burdick, K E, Payton, A, Ollier, W, Chiba-Falek, O, Attix, D K, Need, A C, Cirulli, E T, Voineskos, A N, Stefanis, N C, Avramopoulos, D, Hatzimanolis, A, Arking, D E, Smyrnis, N, Bilder, R M, Freimer, N A, Cannon, T D, London, E, Poldrack, R A, Sabb, F W, Congdon, E, Conley, E D, Scult, M A, Dickinson, D, Straub, R E, Donohoe, G, Morris, D, Corvin, A, Gill, M, Hariri, A R, Weinberger, D R, Pendleton, N, Bitsios, P, Rujescu, D, Lahti, J, Le Hellard, S, Keller, M C, Andreassen, O A, Deary, I, Glahn, D C, Malhotra, A K & Lencz, T 2019, ' Pleiotropic meta-analysis of cognition, education, and schizophrenia differentiates roles of early neurodevelopmental and adult synaptic pathways ', American Journal of Human Genetics, vol. 105, no. 2, pp. 334-350 . https://doi.org/10.1016/j.ajhg.2019.06.012 American journal of human genetics, vol 105, iss 2 |
| ISSN: | 0002-9297 |
| Popis: | Liability to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and 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 GWAS 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 demonstrating 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−8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs, and many of these have been validated by larger, more recent single-phenotype GWAS. 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. Further, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia, but also to the broader biological dimensions that are implicated in both general health outcomes and psychiatric illness. |
| Databáze: | OpenAIRE |
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