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

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.Molecular Psychiatry advance online publication, 3 February 2015; doi:10.1038/mp.2014.188.