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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)

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Davies, G and Armstrong, N and Bis, JC and Blesser, J and Chouraki, V and Giddaluru, S and Hofer, E and Ibrahim-Verbaas, CA and Kirin, M and Lahti, J and van der Lee, SJ and Le Hellard, S and Liu, T and Marioni, RE and Oldmeadow, C and Postmus, I and Smith, AV and Thalamuthu, A and Thomson, R and Vitart, V and Wang, J and Yu, L and Zgaga, L and Zhao, W and Boxall, R and Harris, SE and Hill, WD and Liewald, DC and Luciano, M and Adams, H and Ames, D and Amin, N and Amouyel, P and Assareh, AA and Au, R and Becker, JT and Beiser, A and Berr, C and Bertram, L and Boerwinkle, E and Buckley, BM and Campbell, H and Corley, J and De Jager, PL and Dufouil, C and Eriksson, JG and Espeseth, T and Faul, JD and Ford, I and Gottesman, RF and Griswold, ME and Gudnason, V and Harris, TB and Heiss, G and Hofman, A and Holliday, EG and Huffman, J and Kardia, SLR and Kochan, N and Knopman, DS and Kwok, JB and Lambert, J-C and Lee, T and Li, S-C and Li, G and Loitfelder, M and Lopez, OL and Lundervold, AJ and Lundqvist, A and Mather, KA and Mirza, SS and Nyberg, L and Ostra, BA and Palotie, A and Papenberg, G and Pattie, A and Petrovic, K and Polasek, O and Psaty, BM and Redmond, P and Reppermund, S and Rotter, JI and Schmidt, H and Schuur, M and Schofield, PW and Scott, RJ and Steen, VM and Stott, DJ and van Swieten, JC and Taylor, KD and Trollor, J and Trompet, S and Uitterlinden, AG and Weinstein, G and Widen, E and Windham, BG and Jukema, JW and Wright, MJ and Wright, AF and Yang, Q and Amieva, H and Attia, JR and Bennett, DA and Porteous, H and Raikkonen, K and Reinvang, I and Rudan, I and Sachdev, PS and Schmidt, R and Schofield, PR and Srikanth, V and Starr, JM and Turner, ST and Weir, DR and Wilson, JF and van Dujin, C and Launer, L and Fitzpatrick, AL and Seshadri, S and Mosley Jr, TH and Deary, IJ, Generation Scotland, 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) pp. 183-192. ISSN 1359-4184 (2015) [Refereed Article]


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Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) http://creativecommons.org/licenses/by/4.0/

DOI: doi:10.1038/mp.2014.188

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.

Item Details

Item Type:Refereed Article
Research Division:Biomedical and Clinical Sciences
Research Group:Clinical sciences
Research Field:Medical genetics (excl. cancer genetics)
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in psychology
UTAS Author:Thomson, R (Dr Russell Thomson)
UTAS Author:Srikanth, V (Dr Velandai Srikanth)
ID Code:99878
Year Published:2015
Web of Science® Times Cited:223
Deposited By:Menzies Institute for Medical Research
Deposited On:2015-04-15
Last Modified:2017-11-03
Downloads:561 View Download Statistics

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