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

Davies, G. and Armstrong, N. and Bis, J. C. and Bressler, J. and Chouraki, V. and Giddaluru, S. and Hofer, E. and Ibrahim-Verbaas, C. A. and Kirin, M. and Lahti, J. and van der Lee, S. J. and Le Hellard, S. and Liu, T. and Marioni, R. E. and Oldmeadow, C. and Postmus, I. and Smith, A. V. and Smith, J. A. and Thalamuthu, A. and Thomson, R. and Vitart, V. and Wang, J. and Yu, L. and Zgaga, Lina and Zhao, W. and Boxall, R. and Harris, S. E. and Hill, W. D. and Liewald, D. C. and Luciano, M. and Adams, H. and Ames, D. and Amin, N. and Amouyel, P. and Assareh, A. A. and Au, R. and Becker, J. T. and Beiser, A. and Berr, C. and Bertram, L. and Boerwinkle, E. and Buckley, B. M. and Campbell, H. and Corley, J. and De Jager, P. L. and Dufouil, C. and Eriksson, J. G. and Espeseth, T. and Faul, J. D. and Ford, I. and Gottesman, R. F. and Griswold, M. E. and Gudnason, V. and Harris, T. B. and Heiss, G. and Hofman, A. and Holliday, E. G. and Huffman, J. and Kardia, S. L. R. and Kochan, N. and Knopman, D. S. and Kwok, J. B. and Lambert, J.-C. and Lee, T. and Li, G. and Li, S.-C. and Loitfelder, M. and Lopez, O. L. and Lundervold, A. J. and Lundqvist, A. and Mather, K. A. and Mirza, S. S. and Nyberg, L. and Oostra, B. A. and Palotie, A. and Papenberg, G. and Pattie, A. and Petrovic, K. and Polašek, Ozren and Psaty, B. M. and Redmond, P. and Reppermund, S. and Rotter, J. I. and Schmidt, H. and Schuur, M. 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 Trollor, J. and Trompet, S. and Uitterlinden, A. G. and Weinstein, G. and Widen, E. and Windham, B. G. and Jukema, J. Wouter and Wright, A. F. and Wright, M. J. and Yang, Q. and Amieva, H. and Attia, J. R. and Bennett, D. A. and Brodaty, H. and de Craen, A. J. M. and Hayward, C. and Ikram, M. A. and Lindenberger, U. and Nilsson, L.-G. and Porteous, D. J. and Räikkönen, K. and Reinvang, I. and Rudan, Igor and Sachdev, P. S. and Schmidt, R. and Schofield, P. R. and Srikanth, V. and Starr, J. M. and Turner, S. T. and Weir, D. R. and Wilson, J. F. and van Duijn, C. and Launer, L. and Fitzpatrick, A. L. and Seshadri, S. and Mosley, T. H. and 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=53949). Molecular Psychiatry, 20 (2). pp. 183-192. ISSN 1476-5578

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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=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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