Peer-Reviewed Journal Details
Mandatory Fields
Lam M;Hill WD;Trampush JW;Yu J;Knowles E;Davies G;Stahl E;Huckins L;Liewald DC;Djurovic S;Melle I;Sundet K;Christoforou A;Reinvang I;DeRosse P;Lundervold AJ;Steen VM;Espeseth T;Räikkönen K;Widen E;Palotie A;Eriksson JG;Giegling I;Konte B;Hartmann AM;Roussos P;Giakoumaki S;Burdick KE;Payton A;Ollier W;Chiba-Falek O;Attix DK;Need AC;Cirulli ET;Voineskos AN;Stefanis NC;Avramopoulos D;Hatzimanolis A;Arking DE;Smyrnis N;Bilder RM;Freimer NA;Cannon TD;London E;Poldrack RA;Sabb FW;Congdon E;Conley ED;Scult MA;Dickinson D;Straub RE;Donohoe G;Morris D;Corvin A;Gill M;Hariri AR;Weinberger DR;Pendleton N;Bitsios P;Rujescu D;Lahti J;Le Hellard S;Keller MC;Andreassen OA;Deary IJ;Glahn DC;Malhotra AK;Lencz T;
2019
August
American Journal Of Human Genetics
Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.
Published
Optional Fields
105
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 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.
1537-6605
10.1016/j.ajhg.2019.06.012
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