The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia

Alexander L Richards; Antonio F Pardiñas; Aura Frizzati; Katherine E Tansey; Amy J Lynham; Peter Holmans; Sophie E Legge; Jeanne E Savage; Ingrid Agartz; Ole A Andreassen; Gabriella A M Blokland; Aiden Corvin; Donna Cosgrove; Franziska Degenhardt; Srdjan Djurovic; Thomas Espeseth; Laura Ferraro; Charlotte Gayer-Anderson; Ina Giegling; Neeltje E van Haren; Annette M Hartmann; John J Hubert; Erik G Jönsson; Bettina Konte; Leonhard Lennertz; Loes M Olde Loohuis; Ingrid Melle; Craig Morgan; Derek W Morris; Robin M Murray; Håkan Nyman; Roel A Ophoff; GROUP Investigators; Jim van Os; EUGEI WP2 Group; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Tracey L Petryshen; Diego Quattrone; Marcella Rietschel; Dan Rujescu; Bart P F Rutten; Fabian Streit; Jana Strohmaier; Patrick F Sullivan; Kjetil Sundet; Michael Wagner; Valentina Escott-Price; Michael J Owen; Gary Donohoe; Michael C O'Donovan; James T R Walters

doi:10.1093/schbul/sbz061

The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia

Schizophr Bull. 2020 Feb 26;46(2):336-344. doi: 10.1093/schbul/sbz061.

Authors

Alexander L Richards¹, Antonio F Pardiñas¹, Aura Frizzati¹, Katherine E Tansey¹, Amy J Lynham¹, Peter Holmans¹, Sophie E Legge¹, Jeanne E Savage², Ingrid Agartz^{3

4

5}, Ole A Andreassen⁶, Gabriella A M Blokland^{7

8

9

10}, Aiden Corvin¹¹, Donna Cosgrove¹², Franziska Degenhardt^{13

14}, Srdjan Djurovic^{6

15}, Thomas Espeseth¹⁵, Laura Ferraro¹⁶, Charlotte Gayer-Anderson¹⁷, Ina Giegling¹⁸, Neeltje E van Haren^{19

20}, Annette M Hartmann¹⁸, John J Hubert¹, Erik G Jönsson^{5

6}, Bettina Konte¹⁸, Leonhard Lennertz²¹, Loes M Olde Loohuis²², Ingrid Melle^{6

23}, Craig Morgan²⁴, Derek W Morris²⁵, Robin M Murray²⁶, Håkan Nyman²⁶, Roel A Ophoff^{22

27}; GROUP Investigators; Jim van Os^{28

29

30}; EUGEI WP2 Group; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Tracey L Petryshen^{9

10

31}, Diego Quattrone³², Marcella Rietschel³³, Dan Rujescu¹⁸, Bart P F Rutten³⁴, Fabian Streit³⁵, Jana Strohmaier³³, Patrick F Sullivan³⁶, Kjetil Sundet²³, Michael Wagner^{37

38}, Valentina Escott-Price¹, Michael J Owen¹, Gary Donohoe²⁵, Michael C O'Donovan¹, James T R Walters¹

Affiliations

¹ MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
² Complex Trait Genetics Lab, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
³ Norwegian Centre for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁴ Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
⁵ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
⁶ CoE NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁷ Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
⁸ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.
⁹ Department of Psychiatry, Harvard Medical School, Boston, MA.
¹⁰ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA.
¹¹ Neuropsychiatric Genetics Research Group, Department of Psychiatry, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
¹² Cognitive Genetics and Cognitive Therapy Group, Neuroimaging and Cognitive Genomics Center, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.
¹³ Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
¹⁴ Institute of Human Genetics, University of Bonn, Bonn, Germany.
¹⁵ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
¹⁶ Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy.
¹⁷ Department of Health Service and Population Research, Institute of Psychiatry, King's College London, London, UK.
¹⁸ Department of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
¹⁹ Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
²⁰ Department of Child and Adolescent Psychiatry/Psychology, Sophia Children's Hospital, Erasmus Medical Center, Rotterdam, The Netherlands.
²¹ Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
²² Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA.
²³ Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
²⁴ National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College, London, UK.
²⁵ Centre for Neuroimaging and Cognitive Genomics, National University of Ireland Galway, Galway, Ireland.
²⁶ Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
²⁷ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA.
²⁸ Department of Psychiatry and Medical Psychology, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands.
²⁹ Department of Psychiatry, Utrecht University Medical Centre, Utrecht, The Netherlands.
³⁰ King's Health Partners Department of Psychosis Studies, King's College London, Institute of Psychiatry, London, UK.
³¹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
³² Social, Genetics and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
³³ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
³⁴ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, South Limburg Mental Health Research and Teaching Network, Maastricht University Medical Centre, Maastricht, The Netherlands.
³⁵ Central Institute of Mental Health, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany.
³⁶ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
³⁷ Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany.
³⁸ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.

Abstract

Background: Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases.

Methods: We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases.

Results: PRS for both population IQ (P = 4.39 × 10-28) and EA (P = 1.27 × 10-26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS.

Conclusions: Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.

Keywords: bioinformatics; genomics; intelligence; psychiatry.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Bipolar Disorder / genetics*
Datasets as Topic
Depressive Disorder, Major / genetics*
Educational Status*
Genome-Wide Association Study*
Humans
Intelligence / genetics*
Multifactorial Inheritance
Psychotic Disorders / genetics*
Schizophrenia / genetics*

Abstract

Publication types

MeSH terms

Grants and funding