TY - JOUR
TI - Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways
AU - Lam, M.
AU - Hill, W.D.
AU - Trampush, J.W.
AU - Yu, J.
AU - Knowles, E.
AU - Davies, G.
AU - Stahl, E.
AU - Huckins, L.
AU - Liewald, D.C.
AU - Djurovic, S.
AU - Melle, I.
AU - Sundet, K.
AU - Christoforou, A.
AU - Reinvang, I.
AU - DeRosse, P.
AU - Lundervold, A.J.
AU - Steen, V.M.
AU - Espeseth, T.
AU - Räikkönen, K.
AU - Widen, E.
AU - Palotie, A.
AU - Eriksson, J.G.
AU - Giegling, I.
AU - Konte, B.
AU - Hartmann, A.M.
AU - Roussos, P.
AU - Giakoumaki, S.
AU - Burdick, K.E.
AU - Payton, A.
AU - Ollier, W.
AU - Chiba-Falek, O.
AU - Attix, D.K.
AU - Need, A.C.
AU - Cirulli, E.T.
AU - Voineskos, A.N.
AU - Stefanis, N.C.
AU - Avramopoulos, D.
AU - Hatzimanolis, A.
AU - Arking, D.E.
AU - Smyrnis, N.
AU - Bilder, R.M.
AU - Freimer, N.A.
AU - Cannon, T.D.
AU - London, E.
AU - Poldrack, R.A.
AU - Sabb, F.W.
AU - Congdon, E.
AU - Conley, E.D.
AU - Scult, M.A.
AU - Dickinson, D.
AU - Straub, R.E.
AU - Donohoe, G.
AU - Morris, D.
AU - Corvin, A.
AU - Gill, M.
AU - Hariri, A.R.
AU - Weinberger, D.R.
AU - Pendleton, N.
AU - Bitsios, P.
AU - Rujescu, D.
AU - Lahti, J.
AU - Le Hellard, S.
AU - Keller, M.C.
AU - Andreassen, O.A.
AU - Deary, I.J.
AU - Glahn, D.C.
AU - Malhotra, A.K.
AU - Lencz, T.
JO - American Journal of Human Genetics
PY - 2019
VL - 105
TODO - 2
SP - 334-350
PB - Cell Press
SN - 0002-9297, 1537-6605
TODO - 10.1016/j.ajhg.2019.06.012
TODO - adult;  Article;  clinical evaluation;  cognition;  disease association;  education;  educational status;  gene expression regulation;  gene frequency;  gene locus;  genetic database;  genome-wide association study;  human;  meta analysis;  nerve cell differentiation;  neurologic disease assessment;  phenotype;  pleiotropy;  priority journal;  risk factor;  schizophrenia;  sequence analysis;  single nucleotide polymorphism;  synaptic transmission;  cognition;  cognitive defect;  educational status;  genetic predisposition;  mental disease;  pathology;  pathophysiology;  physiology;  schizophrenia;  single nucleotide polymorphism, Adult;  Cognition;  Cognition Disorders;  Educational Status;  Genetic Predisposition to Disease;  Genome-Wide Association Study;  Humans;  Neurodevelopmental Disorders;  Polymorphism, Single Nucleotide;  Schizophrenia;  Synaptic Transmission
TODO - 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. © 2019
ER -