title: Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).
abstract: General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.
authors: 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: Davies
authors: School of Mathematics and Statistics, University of Sydney, Sydney, NSW, Australia.
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authors: Bressler
authors: 1] Inserm-UMR744, Institut Pasteur de Lille, Unité d'Epidémiologie et de Santé Publique, Lille, France [2] Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
authors: V
authors: 0000000246981794
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authors: Chouraki
authors: 1] K.G. Jebsen Centre for Psychosis Research and the Norwegian Centre for Mental Disorders Research (NORMENT), Department of Clinical Science, University of Bergen, Bergen, Norway [2] Dr Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors: S
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authors: 1] Department of Neurology, Medical University of Graz, Graz, Austria [2] Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria.
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authors: 1] Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
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authors: 1] Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland [2] Folkhälsan Research Centre, Helsinki, Finland.
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authors: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
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authors: 1] Max Planck Institute for Human Development, Berlin, Germany [2] Max Planck Institute for Molecular Genetics, Berlin, Germany.
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authors: 1] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK [2] Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK [3] Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
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authors: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
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authors: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
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authors: Zgaga
authors: Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
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authors: Zhao
authors: Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors: R
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authors: Boxall
authors: 1] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK [2] Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors: S E
authors: SE
authors: Harris
authors: Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors: W D
authors: WD
authors: Hill
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
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authors: Liewald
authors: 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: Luciano
authors: 1] Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
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authors: 0000000336872508
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authors: Adams
authors: 1] National Ageing Research Institute, Royal Melbourne Hospital, Melbourne, VIC, Australia [2] Academic Unit for Psychiatry of Old Age, St George's Hospital, University of Melbourne, Kew, Australia.
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authors: 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
authors: N
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authors: Amin
authors: Inserm-UMR744, Institut Pasteur de Lille, Unité d'Epidémiologie et de Santé Publique, Lille, France.
authors: P
authors: 000000019088234X
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authors: Amouyel
authors: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
authors: A A
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authors: 1] Department of Neurology, Boston University School of Medicine, Boston, MA, USA [2] Framingham Heart Study, Framingham, MA, USA.
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authors: Becker
authors: 1] Department of Neurology, Boston University School of Medicine, Boston, MA, USA [2] Framingham Heart Study, Framingham, MA, USA.
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authors: 1] Inserm, U106, Montpellier, France [2] Université Montpellier I, Montpellier, France.
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authors: 1] Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA [2] Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, TX, USA [3] Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
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authors: 1] Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
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authors: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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authors: Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
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authors: S-C
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authors: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
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authors: 1] Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway [2] Kavli Research Centre for Aging and Dementia, Haraldsplass Deaconess Hospital, Bergen, Norway [3] K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
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authors: Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden.
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authors: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
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authors: 1] Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
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authors: Mirza
authors: 1] Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden [2] Department of Radiation Sciences, Umeå University, Umeå, Sweden [3] Department of Integrative Medical Biology, Umeå University, Umeå, Sweden.
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authors: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
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authors: 1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK [2] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland [3] Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland.
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authors: 1] Max Planck Institute for Human Development, Berlin, Germany [2] Karolinska Institutet, Aging Research Center, Stockholm University, Stockholm, Sweden.
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authors: Papenberg
authors: Department of Psychology, University of Edinburgh, Edinburgh, UK.
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authors: Pattie
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authors: Faculty of Medicine, Department of Public Health, University of Split, Split, Croatia.
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authors: 1] Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA [2] Deparment of Epidemiology, University of Washington, Seattle, WA, USA [3] Deparment of Health Services, University of Washington, Seattle, WA, USA [4] Group Health Research Unit, Group Health Cooperative, Seattle, WA, USA.
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authors: Department of Psychology, University of Edinburgh, Edinburgh, UK.
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authors: Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
authors: S
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authors: 1] Institute for Translational Genomics and Population Sciences Los Angeles BioMedical Research Institute, Harbor-UCLA Medical Center, Los Angeles, CA, USA [2] Division of Genetic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles, CA, USA.
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authors: Scott
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authors: V M
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authors: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
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authors: Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: J C
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authors: van Swieten
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authors: Taylor
authors: 1] Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia [2] Department of Developmental Disability Neuropsychiatry, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
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authors: Trompet
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authors: Weinstein
authors: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
authors: E
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authors: Widen
authors: Division of Geriatrics, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
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authors: Windham
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authors: Jukema
authors: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
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authors: Wright
authors: Neuroimaging Genetics Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
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authors: 1] Framingham Heart Study, Framingham, MA, USA [2] Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
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authors: Inserm U897, Université Bordeaux Segalen, Bordeaux, France.
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authors: Amieva
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authors: J R
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authors: Attia
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authors: Brodaty
authors: 1] Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands [2] Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
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authors: de Craen
authors: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors: C
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authors: Hayward
authors: 1] Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [3] Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands [4] Department of Radiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: M A
authors: MA
authors: Ikram
authors: Max Planck Institute for Human Development, Berlin, Germany.
authors: U
authors: U
authors: Lindenberger
authors: ARC, Karolinska Institutet, Stockholm and UFBI, Umeå University, Umeå, Sweden.
authors: L-G
authors: LG
authors: Nilsson
authors: 1] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK [2] Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK [3] Generation Scotland, University of Edinburgh Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors: D J
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authors: Porteous
authors: Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
authors: K
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authors: Räikkönen
authors: Department of Psychology, University of Oslo, Oslo, Norway.
authors: I
authors: I
authors: Reinvang
authors: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors: I
authors: 0000000169936884
authors: I
authors: Rudan
authors: 1] Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia [2] Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, NSW, Australia.
authors: P S
authors: PS
authors: Sachdev
authors: Department of Neurology, Medical University of Graz, Graz, Austria.
authors: R
authors: R
authors: Schmidt
authors: 1] Neuroscience Research Australia, Sydney, NSW, Australia [2] Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
authors: P R
authors: PR
authors: Schofield
authors: 1] Menzies Research Institute, Hobart, Tasmania [2] Stroke and Ageing Research, Medicine, Southern Clinical School, Monash University, Melbourne, VIC, Australia.
authors: V
authors: V
authors: Srikanth
authors: 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: J M
authors: JM
authors: Starr
authors: Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors: S T
authors: ST
authors: Turner
authors: Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
authors: D R
authors: DR
authors: Weir
authors: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
authors: J F
authors: JF
authors: Wilson
authors: 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands.
authors: C
authors: C
authors: van Duijn
authors: Intramural Research Program National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA.
authors: L
authors: L
authors: Launer
authors: 1] Deparment of Epidemiology, University of Washington, Seattle, WA, USA [2] Department of Global Health, University of Washington, Seattle, WA, USA.
authors: A L
authors: AL
authors: Fitzpatrick
authors: 1] Department of Neurology, Boston University School of Medicine, Boston, MA, USA [2] Framingham Heart Study, Framingham, MA, USA.
authors: S
authors: S
authors: Seshadri
authors: Division of Geriatrics, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
authors: T H
authors: TH
authors: Mosley
authors: 1] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK [2] Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors: I J
authors: IJ
authors: Deary
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D050197:Atherosclerosis / Q000150:complications; D003071:Cognition / Q000502:physiology*; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D024241:HMGN1 Protein / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012606:Scotland
chemical_list: D024241:HMGN1 Protein
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