title: Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT).
abstract: It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.
authors.affiliation: 1] Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA [2] Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA [3] Hofstra North Shore-LIJ School of Medicine, Departments of Psychiatry and Molecular Medicine, Hempstead, NY, USA.
authors.forename: T
authors.initials: T
authors.lastname: Lencz
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: E
authors.initials: E
authors.lastname: Knowles
authors.affiliation: 1] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK [2] Department of Psychology, University of Edinburgh, Edinburgh, UK [3] Medical Genetics Section, University of Edinburgh Molecular Medicine Centre and MRC Institute of Genetics and Molecular Medicine, Edinburgh, UK.
authors.forename: G
authors.initials: G
authors.lastname: Davies
authors.affiliation: Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Guha
authors.affiliation: 1] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK [2] Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors.forename: D C
authors.initials: DC
authors.lastname: Liewald
authors.affiliation: 1] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK [2] Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
authors.forename: J M
authors.initials: JM
authors.lastname: Starr
authors.affiliation: 1] NorMent, KG Jebsen Centre, Oslo, Norway [2] Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Djurovic
authors.affiliation: 1] NorMent, KG Jebsen Centre, Oslo, Norway [2] Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway [3] Psychosis Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: I
authors.initials: I
authors.lastname: Melle
authors.affiliation: 1] NorMent, KG Jebsen Centre, Oslo, Norway [2] Psychosis Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: K
authors.initials: K
authors.lastname: Sundet
authors.affiliation: 1] K.G. Jebsen Centre for Psychosis Research, Dr. Einar Martens Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway [2] Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Christoforou
authors.affiliation: Department of Psychology, University of Oslo, Oslo, Norway.
authors.forename: I
authors.initials: I
authors.lastname: Reinvang
authors.affiliation: 1] Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA [2] Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: 1] Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA [2] Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Pamela
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authors.lastname: DeRosse
authors.affiliation: 1] K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway [2] Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway [3] Kavli Research Centre for Aging and Dementia, Haraldsplass Deaconess Hospital, Bergen, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Lundervold
authors.affiliation: 1] K.G. Jebsen Centre for Psychosis Research, Dr. Einar Martens Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway [2] Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: V M
authors.initials: VM
authors.lastname: Steen
authors.affiliation: 1] Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA [2] Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: John
authors.affiliation: 1] Department of Psychology, University of Oslo, Oslo, Norway [2] K.G. Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
authors.forename: T
authors.initials: T
authors.lastname: Espeseth
authors.affiliation: 1] Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland [2] Institute of Genetics, Folkhälsan Research Centre, Helsinki, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Räikkönen
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Widen
authors.affiliation: 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland [2] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK [3] Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Palotie
authors.affiliation: 1] National Institute for Health and Welfare, Helsinki, Finland [2] Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland [3] Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland [4] Folkhälsan Research Centre, Helsinki, Finland [5] Vasa Central Hospital, Vasa, Finland.
authors.forename: J G
authors.initials: JG
authors.lastname: Eriksson
authors.affiliation: Department of Psychiatry, University of Halle, Halle, Germany.
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authors.initials: I
authors.lastname: Giegling
authors.affiliation: Department of Psychiatry, University of Halle, Halle, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Konte
authors.affiliation: Department of Psychiatry, School of Medicine, Fujita Health University, Toyoake, Japan.
authors.forename: M
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authors.lastname: Ikeda
authors.affiliation: Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY, USA.
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authors.lastname: Roussos
authors.affiliation: Department of Psychology, School of Social Sciences, University of Crete, Heraklion, Greece.
authors.forename: S
authors.initials: S
authors.lastname: Giakoumaki
authors.affiliation: Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Burdick
authors.affiliation: Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK.
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authors.lastname: Payton
authors.affiliation: Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK.
authors.forename: W
authors.initials: W
authors.lastname: Ollier
authors.affiliation: School of Community-Based Medicine, Neurodegeneration Research Group, University of Manchester, Manchester, UK.
authors.forename: M
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authors.lastname: Horan
authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
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authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
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authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
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authors.affiliation: Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
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authors.lastname: Gill
authors.affiliation: Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK.
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authors.initials: N
authors.lastname: Pendleton
authors.affiliation: Department of Psychiatry, School of Medicine, Fujita Health University, Toyoake, Japan.
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authors.affiliation: Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
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authors.lastname: Darvasi
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Greece.
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authors.lastname: Bitsios
authors.affiliation: Department of Psychiatry, University of Halle, Halle, Germany.
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authors.forename: J
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authors.lastname: Lahti
authors.affiliation: 1] K.G. Jebsen Centre for Psychosis Research, Dr. Einar Martens Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway [2] Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: S L
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authors.lastname: Hellard
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA.
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authors.affiliation: 1] NorMent, KG Jebsen Centre, Oslo, Norway [2] Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway [3] Psychosis Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: O A
authors.initials: OA
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authors.affiliation: 1] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK [2] Department of Psychology, University of Edinburgh, Edinburgh, UK.
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authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
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authors.affiliation: 1] Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA [2] Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA [3] Hofstra North Shore-LIJ School of Medicine, Departments of Psychiatry and Molecular Medicine, Hempstead, NY, USA.
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mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D003071:Cognition; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics*; D055815:Young Adult