Immediate Communication

Molecular Psychiatry (2015) 20, 183–192; doi:10.1038/mp.2014.188; published online 3 February 2015

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949)
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G Davies1,2, N Armstrong3, J C Bis4, J Bressler5, V Chouraki6,7, S Giddaluru8,9, E Hofer10,11, C A Ibrahim-Verbaas12,13, M Kirin14, J Lahti15,16, S J van der Lee13, S Le Hellard8,9, T Liu17,18, R E Marioni1,19,20, C Oldmeadow21, I Postmus22,23, A V Smith24,25, J A Smith26, A Thalamuthu27, R Thomson28, V Vitart29, J Wang30,31, L Yu32, L Zgaga33,34, W Zhao26, R Boxall19, S E Harris1,19, W D Hill2, D C Liewald1, M Luciano1,2, H Adams35,36, D Ames37,38, N Amin13,36, P Amouyel6, A A Assareh27, R Au7,30, J T Becker39,40,41, A Beiser7,30, C Berr42,43, L Bertram18,44, E Boerwinkle5,45,46, B M Buckley47, H Campbell14, J Corley2, P L De Jager48,49,50, C Dufouil51,52, J G Eriksson16,53,54,55, T Espeseth56,57, J D Faul58, I Ford59, Generation Scotland60, R F Gottesman61, M E Griswold62, V Gudnason24,25, T B Harris63, G Heiss64, A Hofman35,36, E G Holliday21, J Huffman29, S L R Kardia26, N Kochan27,65, D S Knopman66, J B Kwok67,68, J-C Lambert6, T Lee27,65, G Li4, S-C Li17,69, M Loitfelder10, O L Lopez39, A J Lundervold70,71,72, A Lundqvist73, K A Mather27, S S Mirza35,36, L Nyberg73,74,75, B A Oostra13, A Palotie76,77,78, G Papenberg17,79, A Pattie2, K Petrovic10, O Polasek80, B M Psaty4,81,82,83, P Redmond2, S Reppermund27, J I Rotter84,85, H Schmidt10,86, M Schuur12,13, P W Schofield87, R J Scott21, V M Steen8,9, D J Stott88, J C van Swieten12, K D Taylor84,89, J Trollor27,90, S Trompet22,91, A G Uitterlinden35,36,92, G Weinstein7,30, E Widen77, B G Windham93, J W Jukema91,94,95, A F Wright29, M J Wright96, Q Yang30,31, H Amieva52, J R Attia21, D A Bennett32, H Brodaty27,97, A J M de Craen22,23, C Hayward29, M A Ikram12,35,36,98, U Lindenberger17, L-G Nilsson99, D J Porteous1,19,60, K Räikkönen15, I Reinvang57, I Rudan14, P S Sachdev27,65, R Schmidt10, P R Schofield100,101, V Srikanth28,102, J M Starr1,103, S T Turner104, D R Weir58, J F Wilson14, C van Duijn13,36, L Launer63, A L Fitzpatrick81,105, S Seshadri7,30, T H Mosley Jr93 and I J Deary1,2

  1. 1Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
  2. 2Department of Psychology, University of Edinburgh, Edinburgh, UK
  3. 3School of Mathematics and Statistics, University of Sydney, Sydney, NSW, Australia
  4. 4Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
  5. 5Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA
  6. 6Inserm-UMR744, Institut Pasteur de Lille, Unité d'Epidémiologie et de Santé Publique, Lille, France
  7. 7Department of Neurology, Boston University School of Medicine, Boston, MA, USA
  8. 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
  9. 9Dr Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
  10. 10Department of Neurology, Medical University of Graz, Graz, Austria
  11. 11Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria
  12. 12Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands
  13. 13Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
  14. 14Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK
  15. 15Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland
  16. 16Folkhälsan Research Centre, Helsinki, Finland
  17. 17Max Planck Institute for Human Development, Berlin, Germany
  18. 18Max Planck Institute for Molecular Genetics, Berlin, Germany
  19. 19Medical Genetics Section, University of Edinburgh Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK
  20. 20Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
  21. 21Hunter Medical Research Institute and Faculty of Health, University of Newcastle, Newcastle, NSW, Australia
  22. 22Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
  23. 23Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands
  24. 24Icelandic Heart Association, Kopavogur, Iceland
  25. 25University of Iceland, Reykjavik, Iceland
  26. 26Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA
  27. 27Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia
  28. 28Menzies Research Institute, Hobart, Tasmania
  29. 29MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
  30. 30Framingham Heart Study, Framingham, MA, USA
  31. 31Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
  32. 32Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
  33. 33Department of Public Health and Primary Care, Trinity College Dublin, Dublin, Ireland
  34. 34Andrija Stampar School of Public Health, Medical School, University of Zagreb, Zagreb, Croatia
  35. 35Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
  36. 36Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands
  37. 37National Ageing Research Institute, Royal Melbourne Hospital, Melbourne, VIC, Australia
  38. 38Academic Unit for Psychiatry of Old Age, St George’s Hospital, University of Melbourne, Kew, Australia
  39. 39Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
  40. 40Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
  41. 41Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA
  42. 42Inserm, U106, Montpellier, France
  43. 43Université Montpellier I, Montpellier, France
  44. 44Faculty of Medicine, School of Public Health, Imperial College, London, UK
  45. 45Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, TX, USA
  46. 46Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
  47. 47Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland
  48. 48Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA
  49. 49Harvard Medical School, Boston, MA, USA
  50. 50Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
  51. 51Inserm U708, Neuroepidemiology, Paris, France
  52. 52Inserm U897, Université Bordeaux Segalen, Bordeaux, France
  53. 53National Institute for Health and Welfare, Helsinki, Finland
  54. 54Department of General Practice and Primary health Care, University of Helsinki, Helsinki, Finland
  55. 55Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland
  56. 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
  57. 57Department of Psychology, University of Oslo, Oslo, Norway
  58. 58Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA
  59. 59Robertson Center for Biostatistics, Glasgow, UK
  60. 60Generation Scotland, University of Edinburgh Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK
  61. 61Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  62. 62Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS, USA
  63. 63Intramural Research Program National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA
  64. 64Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, USA
  65. 65Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, NSW, Australia
  66. 66Department of Neurology, Mayo Clinic, Rochester, MN, USA
  67. 67Neuroscience Research Australia, Randwick, NSW, Australia
  68. 68School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
  69. 69Technische Universität Dresden, Dresden, Germany
  70. 70Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway
  71. 71Kavli Research Centre for Aging and Dementia, Haraldsplass Deaconess Hospital, Bergen, Norway
  72. 72K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway
  73. 73Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden
  74. 74Department of Radiation Sciences, Umeå University, Umeå, Sweden
  75. 75Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
  76. 76Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK
  77. 77Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
  78. 78Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland
  79. 79Karolinska Institutet, Aging Research Center, Stockholm University, Stockholm, Sweden
  80. 80Faculty of Medicine, Department of Public Health, University of Split, Split, Croatia
  81. 81Deparment of Epidemiology, University of Washington, Seattle, WA, USA
  82. 82Deparment of Health Services, University of Washington, Seattle, WA, USA
  83. 83Group Health Research Unit, Group Health Cooperative, Seattle, WA, USA
  84. 84Institute for Translational Genomics and Population Sciences Los Angeles BioMedical Research Institute, Harbor-UCLA Medical Center, Los Angeles, CA, USA
  85. 85Division of Genetic Outcomes, Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles, CA, USA
  86. 86Centre for Molecular Medicine, Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
  87. 87School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
  88. 88Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
  89. 89Department of Pediatrics, Harbor-UCLA Medical Center, Los Angeles, CA, USA
  90. 90Department of Developmental Disability Neuropsychiatry, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia
  91. 91Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
  92. 92Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
  93. 93Division of Geriatrics, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA
  94. 94Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands
  95. 95Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
  96. 96Neuroimaging Genetics Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  97. 97Dementia Collaborative Research Centre, University of New South Wales, Sydney, NSW, Australia
  98. 98Department of Radiology, Erasmus University Medical Center, Rotterdam, The Netherlands
  99. 99ARC, Karolinska Institutet, Stockholm and UFBI, Umeå University, Umeå, Sweden
  100. 100Neuroscience Research Australia, Sydney, NSW, Australia
  101. 101Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
  102. 102Stroke and Ageing Research, Medicine, Southern Clinical School, Monash University, Melbourne, VIC, Australia
  103. 103Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK
  104. 104Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
  105. 105Department of Global Health, University of Washington, Seattle, WA, USA

Correspondence: Dr IJ Deary, Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, Scotland, UK. E-mail: i.deary@ed.ac.uk

Received 17 October 2014; Revised 11 November 2014; Accepted 24 November 2014
Advance online publication 3 February 2015

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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=53949) 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.