Genetic contributions to variation in general cognitive function: A meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

G. Davies; N. Armstrong; J. C. Bis; J. Bressler; V. Chouraki; S. Giddaluru; E. Hofer; C. A. Ibrahim-Verbaas; M. Kirin; J. Lahti; S. J. Van Der Lee; S. Le Hellard; T. Liu; R. E. Marioni; C. Oldmeadow; I. Postmus; A. V. Smith; J. A. Smith; A. Thalamuthu; R. Thomson; V. Vitart; J. Wang; L. Yu; L. Zgaga; W. Zhao; R. Boxall; S. E. Harris; W. D. Hill; D. C. Liewald; M. Luciano; H. Adams; D. Ames; N. Amin; P. Amouyel; A. A. Assareh; R. Au; J. T. Becker; A. Beiser; C. Berr; L. Bertram; E. Boerwinkle; B. M. Buckley; H. Campbell; J. Corley; P. L. De Jager; C. Dufouil; J. G. Eriksson; T. Espeseth; J. D. Faul; I. Ford; Generation Scotland; R. F. Gottesman; M. E. Griswold; V. Gudnason; T. B. Harris; G. Heiss; A. Hofman; E. G. Holliday; J. Huffman; S. L.R. Kardia; N. Kochan; D. S. Knopman; J. B. Kwok; J. C. Lambert; T. Lee; G. Li; S. C. Li; M. Loitfelder; O. L. Lopez; A. J. Lundervold; A. Lundqvist; K. A. Mather; S. S. Mirza; L. Nyberg; B. A. Oostra; A. Palotie; G. Papenberg; A. Pattie; K. Petrovic; O. Polasek; B. M. Psaty; P. Redmond; S. Reppermund; J. I. Rotter; H. Schmidt; M. Schuur; P. W. Schofield; R. J. Scott; V. M. Steen; D. J. Stott; J. C. Van Swieten; K. D. Taylor; J. Trollor; S. Trompet; A. G. Uitterlinden; G. Weinstein; E. Widen; B. G. Windham; J. W. Jukema; A. F. Wright; M. J. Wright; Q. Yang; H. Amieva; J. R. Attia; D. A. Bennett; H. Brodaty; A. J.M. De Craen; C. Hayward; M. A. Ikram; U. Lindenberger; L. G. Nilsson; D. J. Porteous; K. Räikkönen; I. Reinvang; I. Rudan; P. S. Sachdev; R. Schmidt; P. R. Schofield; V. Srikanth; J. M. Starr; S. T. Turner; D. R. Weir; J. F. Wilson; C. Van Duijn; L. Launer; A. L. Fitzpatrick; S. Seshadri; T. H. Mosley; I. J. Deary

doi:10.1038/mp.2014.188

Genetic contributions to variation in general cognitive function: A meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

G. Davies, N. Armstrong, J. C. Bis, J. Bressler, V. Chouraki, S. Giddaluru, E. Hofer, C. A. Ibrahim-Verbaas, M. Kirin, J. Lahti, S. J. Van Der Lee, S. Le Hellard, T. Liu, R. E. Marioni, C. Oldmeadow, I. Postmus, A. V. Smith, J. A. Smith, A. Thalamuthu, R. ThomsonV. Vitart, J. Wang, L. Yu, L. Zgaga, W. Zhao, R. Boxall, S. E. Harris, W. D. Hill, D. C. Liewald, M. Luciano, H. Adams, D. Ames, N. Amin, P. Amouyel, A. A. Assareh, R. Au, J. T. Becker, A. Beiser, C. Berr, L. Bertram, E. Boerwinkle, B. M. Buckley, H. Campbell, J. Corley, P. L. De Jager, C. Dufouil, J. G. Eriksson, T. Espeseth, J. D. Faul, I. Ford, Generation Scotland, R. F. Gottesman, M. E. Griswold, V. Gudnason, T. B. Harris, G. Heiss, A. Hofman, E. G. Holliday, J. Huffman, S. L.R. Kardia, N. Kochan, D. S. Knopman, J. B. Kwok, J. C. Lambert, T. Lee, G. Li, S. C. Li, M. Loitfelder, O. L. Lopez, A. J. Lundervold, A. Lundqvist, K. A. Mather, S. S. Mirza, L. Nyberg, B. A. Oostra, A. Palotie, G. Papenberg, A. Pattie, K. Petrovic, O. Polasek, B. M. Psaty, P. Redmond, S. Reppermund, J. I. Rotter, H. Schmidt, M. Schuur, P. W. Schofield, R. J. Scott, V. M. Steen, D. J. Stott, J. C. Van Swieten, K. D. Taylor, J. Trollor, S. Trompet, A. G. Uitterlinden, G. Weinstein, E. Widen, B. G. Windham, J. W. Jukema, A. F. Wright, M. J. Wright, Q. Yang, H. Amieva, J. R. Attia, D. A. Bennett, H. Brodaty, A. J.M. De Craen, C. Hayward, M. A. Ikram, U. Lindenberger, L. G. Nilsson, D. J. Porteous, K. Räikkönen, I. Reinvang, I. Rudan, P. S. Sachdev, R. Schmidt, P. R. Schofield, V. Srikanth, J. M. Starr, S. T. Turner, D. R. Weir, J. F. Wilson, C. Van Duijn, L. Launer, A. L. Fitzpatrick, S. Seshadri, T. H. Mosley, I. J. Deary

Research output: Contribution to journal › Article › peer-review

260 Scopus citations

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.

Original language	English (US)
Pages (from-to)	183-192
Number of pages	10
Journal	Molecular psychiatry
Volume	20
Issue number	2
DOIs	https://doi.org/10.1038/mp.2014.188
State	Published - Feb 1 2015
Externally published	Yes

ASJC Scopus subject areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Molecular Biology

Access to Document

10.1038/mp.2014.188

Cite this

Davies, G., Armstrong, N., Bis, J. C., Bressler, J., Chouraki, V., Giddaluru, S., Hofer, E., Ibrahim-Verbaas, C. A., Kirin, M., Lahti, J., Van Der Lee, S. J., Le Hellard, S., Liu, T., Marioni, R. E., Oldmeadow, C., Postmus, I., Smith, A. V., Smith, J. A., Thalamuthu, A., ... Deary, I. J. (2015). Genetic contributions to variation in general cognitive function: A meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949). Molecular psychiatry, 20(2), 183-192. https://doi.org/10.1038/mp.2014.188

Davies, G, Armstrong, N, Bis, JC, Bressler, J, Chouraki, V, Giddaluru, S, Hofer, E, Ibrahim-Verbaas, CA, Kirin, M, Lahti, J, Van Der Lee, SJ, Le Hellard, S, Liu, T, Marioni, RE, Oldmeadow, C, Postmus, I, Smith, AV, Smith, JA, Thalamuthu, A, Thomson, R, Vitart, V, Wang, J, Yu, L, Zgaga, L, Zhao, W, Boxall, R, Harris, SE, Hill, WD, Liewald, DC, Luciano, M, Adams, H, Ames, D, Amin, N, Amouyel, P, Assareh, AA, Au, R, Becker, JT, Beiser, A, Berr, C, Bertram, L, Boerwinkle, E, Buckley, BM, Campbell, H, Corley, J, De Jager, PL, Dufouil, C, Eriksson, JG, Espeseth, T, Faul, JD, Ford, I, Scotland, G, Gottesman, RF, Griswold, ME, Gudnason, V, Harris, TB, Heiss, G, Hofman, A, Holliday, EG, Huffman, J, Kardia, SLR, Kochan, N, Knopman, DS, Kwok, JB, Lambert, JC, Lee, T, Li, G, Li, SC, Loitfelder, M, Lopez, OL, Lundervold, AJ, Lundqvist, A, Mather, KA, Mirza, SS, Nyberg, L, Oostra, BA, Palotie, A, Papenberg, G, Pattie, A, Petrovic, K, Polasek, O, Psaty, BM, Redmond, P, Reppermund, S, Rotter, JI, Schmidt, H, Schuur, M, Schofield, PW, Scott, RJ, Steen, VM, Stott, DJ, Van Swieten, JC, Taylor, KD, Trollor, J, Trompet, S, Uitterlinden, AG, Weinstein, G, Widen, E, Windham, BG, Jukema, JW, Wright, AF, Wright, MJ, Yang, Q, Amieva, H, Attia, JR, Bennett, DA, Brodaty, H, De Craen, AJM, Hayward, C, Ikram, MA, Lindenberger, U, Nilsson, LG, Porteous, DJ, Räikkönen, K, Reinvang, I, Rudan, I, Sachdev, PS, Schmidt, R, Schofield, PR, Srikanth, V, Starr, JM, Turner, ST, Weir, DR, Wilson, JF, Van Duijn, C, Launer, L, Fitzpatrick, AL, Seshadri, S, Mosley, TH & Deary, IJ 2015, 'Genetic contributions to variation in general cognitive function: A meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)', Molecular psychiatry, vol. 20, no. 2, pp. 183-192. https://doi.org/10.1038/mp.2014.188

@article{ef2cb3b39b0e4375bc2163d85fc2c1a9,

title = "Genetic contributions to variation in general cognitive function: A meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)",

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.",

author = "G. Davies and N. Armstrong and Bis, {J. C.} and J. Bressler and V. Chouraki and S. Giddaluru and E. Hofer and Ibrahim-Verbaas, {C. A.} and M. Kirin and J. Lahti and {Van Der Lee}, {S. J.} and {Le Hellard}, S. and T. Liu and Marioni, {R. E.} and C. Oldmeadow and I. Postmus and Smith, {A. V.} and Smith, {J. A.} and A. Thalamuthu and R. Thomson and V. Vitart and J. Wang and L. Yu and L. Zgaga and W. Zhao and R. Boxall and Harris, {S. E.} and Hill, {W. D.} and Liewald, {D. C.} and M. Luciano and H. Adams and D. Ames and N. Amin and P. Amouyel and Assareh, {A. A.} and R. Au and Becker, {J. T.} and A. Beiser and C. Berr and L. Bertram and E. Boerwinkle and Buckley, {B. M.} and H. Campbell and J. Corley and {De Jager}, {P. L.} and C. Dufouil and Eriksson, {J. G.} and T. Espeseth and Faul, {J. D.} and I. Ford and Generation Scotland and Gottesman, {R. F.} and Griswold, {M. E.} and V. Gudnason and Harris, {T. B.} and G. Heiss and A. Hofman and Holliday, {E. G.} and J. Huffman and Kardia, {S. L.R.} and N. Kochan and Knopman, {D. S.} and Kwok, {J. B.} and Lambert, {J. C.} and T. Lee and G. Li and Li, {S. C.} and M. Loitfelder and Lopez, {O. L.} and Lundervold, {A. J.} and A. Lundqvist and Mather, {K. A.} and Mirza, {S. S.} and L. Nyberg and Oostra, {B. A.} and A. Palotie and G. Papenberg and A. Pattie and K. Petrovic and O. Polasek and Psaty, {B. M.} and P. Redmond and S. Reppermund and Rotter, {J. I.} and H. Schmidt and M. Schuur and Schofield, {P. W.} and Scott, {R. J.} and Steen, {V. M.} and Stott, {D. J.} and {Van Swieten}, {J. C.} and Taylor, {K. D.} and J. Trollor and S. Trompet and Uitterlinden, {A. G.} and G. Weinstein and E. Widen and Windham, {B. G.} and Jukema, {J. W.} and Wright, {A. F.} and Wright, {M. J.} and Q. Yang and H. Amieva and Attia, {J. R.} and Bennett, {D. A.} and H. Brodaty and {De Craen}, {A. J.M.} and C. Hayward and Ikram, {M. A.} and U. Lindenberger and Nilsson, {L. G.} and Porteous, {D. J.} and K. R{\"a}ikk{\"o}nen and I. Reinvang and I. Rudan and Sachdev, {P. S.} and R. Schmidt and Schofield, {P. R.} and V. Srikanth and Starr, {J. M.} and Turner, {S. T.} and Weir, {D. R.} and Wilson, {J. F.} and {Van Duijn}, C. and L. Launer and Fitzpatrick, {A. L.} and S. Seshadri and Mosley, {T. H.} and Deary, {I. J.}",

note = "Funding 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, Unit{\'e} d'Epid{\'e}miologie et de Sant{\'e} 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; 16Folkh{\"a}lsan 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{\textquoteright}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; 43Universit{\'e} 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{\textquoteright}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, Universit{\'e} 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 Universit{\"a}t 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; 73Ume{\aa} Center for Functional Brain Imaging (UFBI), Ume{\aa} University, Ume{\aa}, Sweden; 74Department of Radiation Sciences, Ume{\aa} University, Ume{\aa}, Sweden; 75Department of Integrative Medical Biology, Ume{\aa} University, Ume{\aa}, Sweden; 76Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK; 77Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",

year = "2015",

month = feb,

day = "1",

doi = "10.1038/mp.2014.188",

language = "English (US)",

volume = "20",

pages = "183--192",

journal = "Molecular psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "2",

}

TY - JOUR

T1 - Genetic contributions to variation in general cognitive function

T2 - A meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

AU - Davies, G.

AU - Armstrong, N.

AU - Bis, J. C.

AU - Bressler, J.

AU - Chouraki, V.

AU - Giddaluru, S.

AU - Hofer, E.

AU - Ibrahim-Verbaas, C. A.

AU - Kirin, M.

AU - Lahti, J.

AU - Van Der Lee, S. J.

AU - Le Hellard, S.

AU - Liu, T.

AU - Marioni, R. E.

AU - Oldmeadow, C.

AU - Postmus, I.

AU - Smith, A. V.

AU - Smith, J. A.

AU - Thalamuthu, A.

AU - Thomson, R.

AU - Vitart, V.

AU - Wang, J.

AU - Yu, L.

AU - Zgaga, L.

AU - Zhao, W.

AU - Boxall, R.

AU - Harris, S. E.

AU - Hill, W. D.

AU - Liewald, D. C.

AU - Luciano, M.

AU - Adams, H.

AU - Ames, D.

AU - Amin, N.

AU - Amouyel, P.

AU - Assareh, A. A.

AU - Au, R.

AU - Becker, J. T.

AU - Beiser, A.

AU - Berr, C.

AU - Bertram, L.

AU - Boerwinkle, E.

AU - Buckley, B. M.

AU - Campbell, H.

AU - Corley, J.

AU - De Jager, P. L.

AU - Dufouil, C.

AU - Eriksson, J. G.

AU - Espeseth, T.

AU - Faul, J. D.

AU - Ford, I.

AU - Scotland, Generation

AU - Gottesman, R. F.

AU - Griswold, M. E.

AU - Gudnason, V.

AU - Harris, T. B.

AU - Heiss, G.

AU - Hofman, A.

AU - Holliday, E. G.

AU - Huffman, J.

AU - Kardia, S. L.R.

AU - Kochan, N.

AU - Knopman, D. S.

AU - Kwok, J. B.

AU - Lambert, J. C.

AU - Lee, T.

AU - Li, G.

AU - Li, S. C.

AU - Loitfelder, M.

AU - Lopez, O. L.

AU - Lundervold, A. J.

AU - Lundqvist, A.

AU - Mather, K. A.

AU - Mirza, S. S.

AU - Nyberg, L.

AU - Oostra, B. A.

AU - Palotie, A.

AU - Papenberg, G.

AU - Pattie, A.

AU - Petrovic, K.

AU - Polasek, O.

AU - Psaty, B. M.

AU - Redmond, P.

AU - Reppermund, S.

AU - Rotter, J. I.

AU - Schmidt, H.

AU - Schuur, M.

AU - Schofield, P. W.

AU - Scott, R. J.

AU - Steen, V. M.

AU - Stott, D. J.

AU - Van Swieten, J. C.

AU - Taylor, K. D.

AU - Trollor, J.

AU - Trompet, S.

AU - Uitterlinden, A. G.

AU - Weinstein, G.

AU - Widen, E.

AU - Windham, B. G.

AU - Jukema, J. W.

AU - Wright, A. F.

AU - Wright, M. J.

AU - Yang, Q.

AU - Amieva, H.

AU - Attia, J. R.

AU - Bennett, D. A.

AU - Brodaty, H.

AU - De Craen, A. J.M.

AU - Hayward, C.

AU - Ikram, M. A.

AU - Lindenberger, U.

AU - Nilsson, L. G.

AU - Porteous, D. J.

AU - Räikkönen, K.

AU - Reinvang, I.

AU - Rudan, I.

AU - Sachdev, P. S.

AU - Schmidt, R.

AU - Schofield, P. R.

AU - Srikanth, V.

AU - Starr, J. M.

AU - Turner, S. T.

AU - Weir, D. R.

AU - Wilson, J. F.

AU - Van Duijn, C.

AU - Launer, L.

AU - Fitzpatrick, A. L.

AU - Seshadri, S.

AU - Mosley, T. H.

AU - Deary, I. J.

N1 - Funding 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, Publisher Copyright: © 2015 Macmillan Publishers Limited.

PY - 2015/2/1

Y1 - 2015/2/1

N2 - 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.

AB - 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.

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U2 - 10.1038/mp.2014.188

DO - 10.1038/mp.2014.188

M3 - Article

C2 - 25644384

AN - SCOPUS:84938550053

SN - 1359-4184

VL - 20

SP - 183

EP - 192

JO - Molecular psychiatry

JF - Molecular psychiatry

IS - 2

ER -

Genetic contributions to variation in general cognitive function: A meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

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