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

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201 Scopus citations


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 languageEnglish (US)
Pages (from-to)183-192
Number of pages10
JournalMolecular Psychiatry
Issue number2
StatePublished - Feb 1 2015

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Molecular Biology


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