| Literature DB >> 31374203 |
Max Lam1, W David Hill2, Joey W Trampush3, Jin Yu4, Emma Knowles5, Gail Davies2, Eli Stahl6, Laura Huckins6, David C Liewald7, Srdjan Djurovic8, Ingrid Melle9, Kjetil Sundet10, Andrea Christoforou11, Ivar Reinvang12, Pamela DeRosse4, Astri J Lundervold13, Vidar M Steen14, Thomas Espeseth10, Katri Räikkönen15, Elisabeth Widen16, Aarno Palotie17, Johan G Eriksson18, Ina Giegling19, Bettina Konte19, Annette M Hartmann19, Panos Roussos20, Stella Giakoumaki21, Katherine E Burdick22, Antony Payton23, William Ollier24, Ornit Chiba-Falek25, Deborah K Attix26, Anna C Need27, Elizabeth T Cirulli28, Aristotle N Voineskos29, Nikos C Stefanis30, Dimitrios Avramopoulos31, Alex Hatzimanolis32, Dan E Arking33, Nikolaos Smyrnis34, Robert M Bilder35, Nelson A Freimer35, Tyrone D Cannon36, Edythe London37, Russell A Poldrack38, Fred W Sabb39, Eliza Congdon37, Emily Drabant Conley40, Matthew A Scult41, Dwight Dickinson42, Richard E Straub43, Gary Donohoe44, Derek Morris44, Aiden Corvin45, Michael Gill45, Ahmad R Hariri41, Daniel R Weinberger43, Neil Pendleton46, Panos Bitsios47, Dan Rujescu19, Jari Lahti48, Stephanie Le Hellard14, Matthew C Keller49, Ole A Andreassen50, Ian J Deary2, David C Glahn5, Anil K Malhotra51, Todd Lencz52.
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.Entities:
Keywords: GWAS; cognitive ability; educational attainment; genetic correlation; pathways; pleiotropy; schizophrenia
Mesh：
Year: 2019 PMID： 31374203 PMCID： PMC6699140 DOI： 10.1016/j.ajhg.2019.06.012
Source DB: PubMed Journal: Am J Hum Genet ISSN： 0002-9297 Impact factor: 11.025