Pleiotropic meta-analysis of cognition, education, and schizophrenia differentiates roles of early neurodevelopmental and adult synaptic pathways

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)334-350
JournalAmerican Journal of Human Genetics
Volume105
Issue number2
DOIs
Publication statusPublished - 1 Aug 2019

Keywords

  • cognitive ability
  • educational attainment
  • schizophrenia
  • GWAS
  • pathways
  • genetic correlation
  • pleiotropy

Fingerprint

Dive into the research topics of 'Pleiotropic meta-analysis of cognition, education, and schizophrenia differentiates roles of early neurodevelopmental and adult synaptic pathways'. Together they form a unique fingerprint.

Cite this