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 Stahl; Laura Huckins; David C Liewald; Srdjan Djurovic; Ingrid Melle; Kjetil Sundet; Andrea Christoforou; Ivar Reinvang; Pamela DeRosse; Astri J Lundervold; Vidar M Steen; Thomas Espeseth; Katri Räikkönen; Elisabeth Widen; Aarno 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; Stephanie Le Hellard; Matthew C Keller; Ole A Andreassen; Ian J Deary; David C Glahn; Anil K Malhotra; Todd Lencz

doi:10.1016/j.ajhg.2019.06.012

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

Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.

Authors

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

Affiliations

¹ Institute of Mental Health, Singapore, 539747, Singapore; Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY 11004, USA; Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
² Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, Scotland, EH8 9JZ, United Kingdom; Department of Psychology, University of Edinburgh, Edinburgh, Scotland, EH8 9JZ, United Kingdom.
³ Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
⁴ Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY 11004, USA.
⁵ Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA.
⁶ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁷ Department of Psychology, University of Edinburgh, Edinburgh, Scotland, EH8 9JZ, United Kingdom.
⁸ Department of Medical Genetics, Oslo University Hospital, University of Bergen, Bergen 4956, Nydalen 0424, Norway; Norsk Senter for Forskning på Mentale Lidelser, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen 4956, Nydalen 0424, Norway.
⁹ Norsk Senter for Forskning på Mentale Lidelser, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen 4956, Nydalen 0424, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo 1039, Blindern 0315, Norway.
¹⁰ Division of Mental Health and Addiction, Oslo University Hospital, Oslo 1039, Blindern 0315, Norway; Department of Psychology, University of Oslo, Oslo 1094, Blindern 0317, Norway.
¹¹ Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen 7804, N-5020 Bergen, Norway.
¹² Department of Psychology, University of Oslo, Oslo 1094, Blindern 0317, Norway.
¹³ Department of Biological and Medical Psychology, University of Bergen, 7807, N-5020, Norway.
¹⁴ Norsk Senter for Forskning på Mentale Lidelser, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen 4956, Nydalen 0424, Norway; Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen 7804, N-5020 Bergen, Norway.
¹⁵ Institute of Behavioural Sciences, University of Helsinki, Helsinki, 00014, Finland.
¹⁶ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014, Finland.
¹⁷ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014, Finland; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, United Kingdom; Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, 00014, Finland.
¹⁸ Department of General Practice, University of Helsinki and Helsinki University Hospital, Helsinki, 00014, Finland; National Institute for Health and Welfare, Helsinki FI-00271, Finland; Folkhälsan Research Center, Helsinki 00290, Finland.
¹⁹ Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle 06108, Germany.
²⁰ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mental Illness Research, Education, and Clinical Center (VISN 2), James J. Peters VA Medical Center, Bronx, NY 10468, USA.
²¹ Department of Psychology, University of Crete, Crete 74100, Greece.
²² Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mental Illness Research, Education, and Clinical Center (VISN 2), James J. Peters VA Medical Center, Bronx, NY 10468, USA; Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
²³ Division of Informatics, Imaging, and Data Sciences, School of Health Sciences, University of Manchester, Manchester M139NT, United Kingdom.
²⁴ Centre for Epidemiology, Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester M139PL, United Kingdom; School of Healthcare Sciences, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom.
²⁵ Department of Neurology, Bryan Alzheimer Disease Research Center, Duke University Medical Center, Durham, NC 27705, USA; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC 27705, USA.
²⁶ Department of Neurology, Bryan Alzheimer Disease Research Center, Duke University Medical Center, Durham, NC 27705, USA; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC 27705, USA; Psychiatry and Behavioral Sciences, Division of Medical Psychology, Duke University Medical Center, Durham, NC 27708, USA; Department of Neurology, Duke University Medical Center, Durham, NC 27708, USA.
²⁷ Division of Brain Sciences, Department of Medicine, Imperial College, London W12 0NN, UK.
²⁸ Helix Inc, San Diego, CA 92121, USA.
²⁹ Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto M6J 1H4, Canada.
³⁰ Department of Psychiatry, National and Kapodistrian University of Athens Medical School, Eginition Hospital, Athens, Greece; University Mental Health Research Institute, Athens 115 27, Greece; Neurobiology Research Institute, Theodor-Theohari Cozzika Foundation, Athens, Greece.
³¹ Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³² Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto M6J 1H4, Canada; Department of Psychiatry, National and Kapodistrian University of Athens Medical School, Eginition Hospital, Athens, Greece; University Mental Health Research Institute, Athens 115 27, Greece.
³³ Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
³⁴ Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto M6J 1H4, Canada; Department of Psychiatry, National and Kapodistrian University of Athens Medical School, Eginition Hospital, Athens, Greece.
³⁵ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³⁶ Department of Psychology, Yale University, New Haven, CT 06511, USA.
³⁷ UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA 90024, USA.
³⁸ Department of Psychology, Stanford University, Palo Alto, CA 94305, USA.
³⁹ Robert and Beverly Lewis Center for Neuroimaging, University of Oregon, Eugene, OR, 97401, USA.
⁴⁰ 23andMe, Inc., Mountain View, CA, 94041, USA.
⁴¹ Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University, Durham, NC 27708, USA.
⁴² Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, National Institute of Health, Bethesda, MD 20814, USA.
⁴³ Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD 21205, USA.
⁴⁴ Neuroimaging, Cognition, and Genomics Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland, Galway, Ireland.
⁴⁵ Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
⁴⁶ Division of Neuroscience and Experimental Psychology, School of Biological Sciences, University of Manchester, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, Manchester M13 9PL, United Kingdom.
⁴⁷ Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete GR-71003, Greece.
⁴⁸ Institute of Behavioural Sciences, University of Helsinki, Helsinki, 00014, Finland; Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki 00014, Finland.
⁴⁹ Institute for Behavioral Genetics, University of Colorado, Boulder, CO 80303, USA.
⁵⁰ Norsk Senter for Forskning på Mentale Lidelser, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen 4956, Nydalen 0424, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo 1039, Blindern 0315, Norway; Institute of Clinical Medicine, University of Oslo, Oslo 0318, Norway.
⁵¹ Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY 11004, USA; Department of Psychiatry, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA; Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
⁵² Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY 11004, USA; Department of Psychiatry, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA; Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY 11030, USA. Electronic address: tlencz@northwell.edu.

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.

Keywords: GWAS; cognitive ability; educational attainment; genetic correlation; pathways; pleiotropy; schizophrenia.

Publication types

Meta-Analysis

MeSH terms

Adult
Cognition / physiology*
Cognition Disorders / physiopathology*
Educational Status*
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Neurodevelopmental Disorders / etiology*
Neurodevelopmental Disorders / pathology
Polymorphism, Single Nucleotide*
Schizophrenia / physiopathology*
Synaptic Transmission*

Abstract

Publication types

MeSH terms

Grants and funding