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.
Bibliographical noteFunding Information:
1Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK; 2Department of Psychology, University of Edinburgh, Edinburgh, UK; 3School of Mathematics and Statistics, University of Sydney, Sydney, NSW, Australia; 4Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; 5Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA; 6Inserm-UMR744, Institut Pasteur de Lille, Unité d'Epidémiologie et de Santé Publique, Lille, France; 7Department of Neurology, Boston University School of Medicine, Boston, MA, USA; 8K.G. Jebsen Centre for Psychosis Research and the Norwegian Centre for Mental Disorders Research (NORMENT), Department of Clinical Science, University of Bergen, Bergen, Norway; 9Dr Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway; 10Department of Neurology, Medical University of Graz, Graz, Austria; 11Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria; 12Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands; 13Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands; 14Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK; 15Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland; 16Folkhälsan Research Centre, Helsinki, Finland; 17Max Planck Institute for Human Development, Berlin, Germany; 18Max Planck Institute for Molecular Genetics, Berlin, Germany; 19Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK; 20Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia; 21Hunter Medical Research Institute and Faculty of Health, University of Newcastle, Newcastle, NSW, Australia; 22Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands; 23Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands; 24Icelandic Heart Association, Kopavogur, Iceland; 25University of Iceland, Reykjavik, Iceland; 26Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA; 27Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia; 28Menzies Research Institute, Hobart, Tasmania; 29MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK; 30Framingham Heart Study, Framingham, MA, USA; 31Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; 32Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; 33Department of Public Health and Primary Care, Trinity College Dublin, Dublin, Ireland; 34Andrija Stampar School of Public Health, Medical School, University of Zagreb, Zagreb, Croatia; 35Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands; 36Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands; 37National Ageing Research Institute, Royal Melbourne Hospital, Melbourne, VIC, Australia; 38Academic Unit for Psychiatry of Old Age, St George’s Hospital, University of Melbourne, Kew, Australia; 39Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA; 40Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; 41Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA; 42Inserm, U106, Montpellier, France; 43Université Montpellier I, Montpellier, France; 44Faculty of Medicine, School of Public Health, Imperial College, London, UK; 45Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, TX, USA; 46Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; 47Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland; 48Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA; 49Harvard Medical School, Boston, MA, USA; 50Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; 51Inserm U708, Neuroepidemiology, Paris, France; 52Inserm U897, Université Bordeaux Segalen, Bordeaux, France; 53National Institute for Health and Welfare, Helsinki, Finland; 54Department of General Practice and Primary health Care, University of Helsinki, Helsinki, Finland; 55Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland; 56K.G. Jebsen Centre for Psychosis Research, Norwegian Centre For Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 57Department of Psychology, University of Oslo, Oslo, Norway; 58Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA; 59Robertson Center for Biostatistics, Glasgow, UK; 60Generation Scotland, University of Edinburgh Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK; 61Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 62Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS, USA; 63Intramural Research Program National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA; 64Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, USA; 65Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, NSW, Australia; 66Department of Neurology, Mayo Clinic, Rochester, MN, USA; 67Neuroscience Research Australia, Randwick, NSW, Australia; 68School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia; 69Technische Universität Dresden, Dresden, Germany; 70Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway; 71Kavli Research Centre for Aging and Dementia, Haraldsplass Deaconess Hospital, Bergen, Norway; 72K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway; 73Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden; 74Department of Radiation Sciences, Umeå University, Umeå, Sweden; 75Department of Integrative Medical Biology, Umeå University, Umeå, Sweden; 76Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK; 77Institute for Molecular Medicine Finland (FIMM), University of Helsinki,
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ASJC Scopus subject areas
- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Molecular Biology