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Mol Psychiatry. 2015 Feb;20(2):183-92. doi: 10.1038/mp.2014.188. Epub 2015 Feb 3.

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

Davies G1, Armstrong N2, Bis JC3, Bressler J4, Chouraki V5, Giddaluru S6, Hofer E7, Ibrahim-Verbaas CA8, Kirin M9, Lahti J10, van der Lee SJ11, Le Hellard S6, Liu T12, Marioni RE13, Oldmeadow C14, Postmus I15, Smith AV16, Smith JA17, Thalamuthu A18, Thomson R19, Vitart V20, Wang J21, Yu L22, Zgaga L23, Zhao W17, Boxall R24, Harris SE25, Hill WD26, Liewald DC27, Luciano M1, Adams H28, Ames D29, Amin N30, Amouyel P31, Assareh AA18, Au R32, Becker JT33, Beiser A32, Berr C34, Bertram L35, Boerwinkle E36, Buckley BM37, Campbell H9, Corley J26, De Jager PL38, Dufouil C39, Eriksson JG40, Espeseth T41, Faul JD42, Ford I43; Generation Scotland44, Gottesman RF45, Griswold ME46, Gudnason V16, Harris TB47, Heiss G48, Hofman A28, Holliday EG14, Huffman J20, Kardia SL17, Kochan N49, Knopman DS50, Kwok JB51, Lambert JC31, Lee T49, Li G3, Li SC52, Loitfelder M53, Lopez OL54, Lundervold AJ55, Lundqvist A56, Mather KA18, Mirza SS28, Nyberg L57, Oostra BA11, Palotie A58, Papenberg G59, Pattie A26, Petrovic K53, Polasek O60, Psaty BM61, Redmond P26, Reppermund S18, Rotter JI62, Schmidt H63, Schuur M8, Schofield PW64, Scott RJ14, Steen VM6, Stott DJ65, van Swieten JC66, Taylor KD67, Trollor J68, Trompet S69, Uitterlinden AG70, Weinstein G32, Widen E71, Windham BG72, Jukema JW73, Wright AF20, Wright MJ74, Yang Q21, Amieva H75, Attia JR14, Bennett DA22, Brodaty H76, de Craen AJ15, Hayward C20, Ikram MA77, Lindenberger U78, Nilsson LG79, Porteous DJ80, Räikkönen K81, Reinvang I82, Rudan I9, Sachdev PS49, Schmidt R53, Schofield PR83, Srikanth V84, Starr JM85, Turner ST86, Weir DR42, Wilson JF9, van Duijn C30, Launer L47, Fitzpatrick AL87, Seshadri S32, Mosley TH Jr72, Deary IJ1.

Author information

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

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.

PMID:
25644384
PMCID:
PMC4356746
DOI:
10.1038/mp.2014.188
[Indexed for MEDLINE]
Free PMC Article

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