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

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

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Springer Nature [academic journals on nature.com], Molecular Psychiatry, 2(20), p. 183-192, 2015

DOI: 10.1038/mp.2014.188

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

Journal article published in 2015 by T. H. Mosley Jr, G. Davies, N. Armstrong, J. C. Bis, J. Bressler, C. Duijn, V. Chouraki

, S. Giddaluru, E. Hofer, C. A. Ibrahim-verbaas, M. Kirin, J. Lahti

, S. J. van der Lee, S. Le Hellard, T. Liu and other authors.

This paper is made freely available by the publisher.

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Abstract

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

Abstract