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1. Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Author

Gail Davies, Max Lam, Sarah E. Harris, Joey W. Trampush, Michelle Luciano, W. David Hill, Saskia P. Hagenaars, Stuart J. Ritchie, Riccardo E. Marioni, Chloe Fawns-Ritchie, David C. M. Liewald, Judith A. Okely, Ari V. Ahola-Olli, Catriona L. K. Barnes, Lars Bertram, Joshua C. Bis, Katherine E. Burdick, Andrea Christoforou, Pamela DeRosse, Srdjan Djurovic, Thomas Espeseth, Stella Giakoumaki, Sudheer Giddaluru, Daniel E. Gustavson, Caroline Hayward, Edith Hofer, M. Arfan Ikram, Robert Karlsson, Emma Knowles, Jari Lahti, Markus Leber, Shuo Li, Karen A. Mather, Ingrid Melle, Derek Morris, Christopher Oldmeadow, Teemu Palviainen, Antony Payton, Raha Pazoki, Katja Petrovic, Chandra A. Reynolds, Muralidharan Sargurupremraj, Markus Scholz, Jennifer A. Smith, Albert V. Smith, Natalie Terzikhan, Anbupalam Thalamuthu, Stella Trompet, Sven J. van der Lee, Erin B. Ware, B. Gwen Windham, Margaret J. Wright, Jingyun Yang, Jin Yu, David Ames, Najaf Amin, Philippe Amouyel, Ole A. Andreassen, Nicola J. Armstrong, Amelia A. Assareh, John R. Attia, Deborah Attix, Dimitrios Avramopoulos, David A. Bennett, Anne C. Böhmer, Patricia A. Boyle, Henry Brodaty, Harry Campbell, Tyrone D. Cannon, Elizabeth T. Cirulli, Eliza Congdon, Emily Drabant Conley, Janie Corley, Simon R. Cox, Anders M. Dale, Abbas Dehghan, Danielle Dick, Dwight Dickinson, Johan G. Eriksson, Evangelos Evangelou, Jessica D. Faul, Ian Ford, Nelson A. Freimer, He Gao, Ina Giegling, Nathan A. Gillespie, Scott D. Gordon, Rebecca F. Gottesman, Michael E. Griswold, Vilmundur Gudnason, Tamara B. Harris, Annette M. Hartmann, Alex Hatzimanolis, Gerardo Heiss, Elizabeth G. Holliday, Peter K. Joshi, Mika Kähönen, Sharon L. R. Kardia, Ida Karlsson, Luca Kleineidam, David S. Knopman, Nicole A. Kochan, Bettina Konte, John B. Kwok, Stephanie Le Hellard, Teresa Lee, Terho Lehtimäki, Shu-Chen Li, Christina M. Lill, Tian Liu, Marisa Koini, Edythe London, Will T. Longstreth, Oscar L. Lopez, Anu Loukola, Tobias Luck, Astri J. Lundervold, Anders Lundquist, Leo-Pekka Lyytikäinen, Nicholas G. Martin, Grant W. Montgomery, Alison D. Murray, Anna C. Need, Raymond Noordam, Lars Nyberg, William Ollier, Goran Papenberg, Alison Pattie, Ozren Polasek, Russell A. Poldrack, Bruce M. Psaty, Simone Reppermund, Steffi G. Riedel-Heller, Richard J. Rose, Jerome I. Rotter, Panos Roussos, Suvi P. Rovio, Yasaman Saba, Fred W. Sabb, Perminder S. Sachdev, Claudia L. Satizabal, Matthias Schmid, Rodney J. Scott, Matthew A. Scult, Jeannette Simino, P. Eline Slagboom, Nikolaos Smyrnis, Aïcha Soumaré, Nikos C. Stefanis, David J. Stott, Richard E. Straub, Kjetil Sundet, Adele M. Taylor, Kent D. Taylor, Ioanna Tzoulaki, Christophe Tzourio, André Uitterlinden, Veronique Vitart, Aristotle N. Voineskos, Jaakko Kaprio, Michael Wagner, Holger Wagner, Leonie Weinhold, K. Hoyan Wen, Elisabeth Widen, Qiong Yang, Wei Zhao, Hieab H. H. Adams, Dan E. Arking, Robert M. Bilder, Panos Bitsios, Eric Boerwinkle, Ornit Chiba-Falek, Aiden Corvin, Philip L. De Jager, Stéphanie Debette, Gary Donohoe, Paul Elliott, Annette L. Fitzpatrick, Michael Gill, David C. Glahn, Sara Hägg, Narelle K. Hansell, Ahmad R. Hariri, M. Kamran Ikram, J. Wouter Jukema, Eero Vuoksimaa, Matthew C. Keller, William S. Kremen, Lenore Launer, Ulman Lindenberger, Aarno Palotie, Nancy L. Pedersen, Neil Pendleton, David J. Porteous, Katri Räikkönen, Olli T. Raitakari, Alfredo Ramirez, Ivar Reinvang, Igor Rudan, Dan Rujescu, Reinhold Schmidt, Helena Schmidt, Peter W. Schofield, Peter R. Schofield, John M. Starr, Vidar M. Steen, Julian N. Trollor, Steven T. Turner, Cornelia M. Van Duijn, Arno Villringer, Daniel R. Weinberger, David R. Weir, James F. Wilson, Anil Malhotra, Andrew M. McIntosh, Catharine R. Gale, Sudha Seshadri, Thomas H. Mosley, Jan Bressler, Todd Lencz, Ian J. Deary, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands (HÍ), University of Iceland (UI), Apollo - University of Cambridge Repository, Epidemiology, Neurology, and Radiology & Nuclear Medicine

Subjects
Genetics of the nervous system, Multifactorial Inheritance, Quantitative trait, genetics [Mental Disorders], Genome-wide association studies, cognitive neuroscience, OLD-AGE, Cognition, PARKINSONS-DISEASE, HUMAN INTELLIGENCE, lcsh:Science, genetics [Multifactorial Inheritance], GENOME-WIDE ASSOCIATION, REACTION-TIME, INTELLIGENCE DIFFERENCES, PROCESSING SPEED, COMMON VARIANTS, METAANALYSIS, SCHIZOPHRENIA, DISCOVERY, REVEALS, DCDC2, Aged, 80 and over, genetics [Neurodevelopmental Disorders], Mental Disorders, physiology [Cognition], Neurodegenerative Diseases, Middle Aged, Taugavísindi, Multidisciplinary Sciences, genetics [Reaction Time], genetics [Polymorphism, Single Nucleotide], Science & Technology - Other Topics, ddc:500, Medical Genetics, Adult, Adolescent, Science, genetics [Genetic Loci], Polymorphism, Single Nucleotide, Article, quantitative trait, Young Adult, genetics of the nervous system, MD Multidisciplinary, Journal Article, Reaction Time, Erfðafræði, Humans, Genetic Predisposition to Disease, Medicinsk genetik, Aged, EDUCATIONAL-ATTAINMENT, Science & Technology, Heilinn, Cognitive neuroscience, Rannsóknir, Genetic Loci, Neurodevelopmental Disorders, genetics [Neurodegenerative Diseases], genome-wide association studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, lcsh:Q, HUMAN LONGEVITY
Abstract

Publisher's version (útgefin grein), General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16–102) and find 148 genome-wide significant independent loci (P, This research was conducted in The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, funded by the Biotechnology and Biological Sciences Research Council and Medical Research Council (MR/K026992/1). This research was conducted using the UK Biobank Resource (Application Nos. 10279 and 4844). The Neurology Working Group within the Cohorts for Heart and Aging Research in Genomic Epidemiology is partly supported by grants from the National Institute on Aging (R01 AG033193, U01 AG049505 and U01 AG052409). Cohort-specific acknowledgements are in Supplementary Note 3.

Published
2018

2. Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways

Author

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

Subjects
0301 basic medicine, pathways, Genome-wide association study, Medical and Health Sciences, Synaptic Transmission, 0302 clinical medicine, Cognition, cognitive ability, 2.1 Biological and endogenous factors, GWAS, Aetiology, Genetics (clinical), Genetics & Heredity, 0303 health sciences, Single Nucleotide, Biological Sciences, Serious Mental Illness, genetic correlation, Mental Health, educational attainment, Meta-analysis, Educational Status, Psychology, Biotechnology, Clinical psychology, Adult, Schizophrenia (object-oriented programming), Genetic correlation, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, pleiotropy, mental disorders, Genetics, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, Polymorphism, 030304 developmental biology, Genetic association, Prevention, Human Genome, Counterintuitive, Neurosciences, medicine.disease, Educational attainment, Brain Disorders, schizophrenia, 030104 developmental biology, Neurodevelopmental Disorders, Schizophrenia, Autism, Cognition Disorders, 030217 neurology & neurosurgery, Genome-Wide Association Study
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−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.

Published
2019

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