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Mol Psychiatry. 2014 Feb;19(2):168-74. doi: 10.1038/mp.2013.166. Epub 2013 Dec 17.

Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT).

Author information

1
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.
2
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
3
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.
4
Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA.
5
1] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK [2] Department of Psychology, University of Edinburgh, Edinburgh, UK.
6
1] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK [2] Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
7
1] NorMent, KG Jebsen Centre, Oslo, Norway [2] Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
8
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.
9
1] NorMent, KG Jebsen Centre, Oslo, Norway [2] Psychosis Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
10
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.
11
Department of Psychology, University of Oslo, Oslo, Norway.
12
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.
13
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.
14
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.
15
1] Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland [2] Institute of Genetics, Folkhälsan Research Centre, Helsinki, Finland.
16
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
17
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.
18
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.
19
Department of Psychiatry, University of Halle, Halle, Germany.
20
Department of Psychiatry, School of Medicine, Fujita Health University, Toyoake, Japan.
21
Department of Psychiatry, The Mount Sinai School of Medicine, New York, NY, USA.
22
Department of Psychology, School of Social Sciences, University of Crete, Heraklion, Greece.
23
Centre for Integrated Genomic Medical Research, University of Manchester, Manchester, UK.
24
School of Community-Based Medicine, Neurodegeneration Research Group, University of Manchester, Manchester, UK.
25
Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
26
Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK.
27
Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
28
Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Greece.
29
Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA.

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.

PMID:
24342994
PMCID:
PMC3968799
DOI:
10.1038/mp.2013.166
[Indexed for MEDLINE]
Free PMC Article
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