Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways
Authors: Lam Max , Hill W. David , Trampush Joey W. , Yu Jin , Knowles Emma , Davies Gail , Stahl Eli , Huckins Laura , Liewald David C. , Djurovic Srdjan , Melle Ingrid , Sundet Kjetil , Christoforou Andrea , Reinvang Ivar , DeRosse Pamela , Lundervold Astri J. , Steen Vidar M. , Espeseth Thomas , Räikkönen Katri , Widen Elisabeth , Palotie Aarno , Eriksson Johan G. , Giegling Ina , Konte Bettina , Hartmann Annette M. , Roussos Panos , Giakoumaki Stella , Burdick Katherine E. , Payton Antony , Ollier William , Chiba-Falek Ornit , Attix Deborah K. , Need Anna C. , Cirulli Elizabeth T. , Voineskos Aristotle N. , Stefanis Nikos C. , Avramopoulos Dimitrios , Hatzimanolis Alex , Arking Dan E. , Smyrnis Nikolaos , Bilder Robert M. , Freimer Nelson A. , Cannon Tyrone D. , London Edythe , Poldrack Russell A. , Sabb Fred W. , Congdon Eliza , Conley Emily Drabant , Scult Matthew A. , Dickinson Dwight , Straub Richard E. , Donohoe Gary , Morris Derek , Corvin Aiden , Gill Michael , Hariri Ahmad R. , Weinberger Daniel R. , Pendleton Neil , Bitsios Panos , Rujescu Dan , Lahti Jari , Hellard Stephanie Le , Keller Matthew C. , Andreassen Ole A. , Deary Ian J. , Glahn David C. , Malhotra Anil K. , Lencz Todd 
Published: January 2019

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<5×10−8. 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.