TY - JOUR T1 - Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949). JF - Mol Psychiatry Y1 - 2015 A1 - Davies, G A1 - Armstrong, N A1 - Bis, J C A1 - Bressler, J A1 - Chouraki, V A1 - Giddaluru, S A1 - Hofer, E A1 - Ibrahim-Verbaas, C A A1 - Kirin, M A1 - Lahti, J A1 - van der Lee, S J A1 - Le Hellard, S A1 - Liu, T A1 - Marioni, R E A1 - Oldmeadow, C A1 - Postmus, I A1 - Smith, A V A1 - Smith, J A A1 - Thalamuthu, A A1 - Thomson, R A1 - Vitart, V A1 - Wang, J A1 - Yu, L A1 - Zgaga, L A1 - Zhao, W A1 - Boxall, R A1 - Harris, S E A1 - Hill, W D A1 - Liewald, D C A1 - Luciano, M A1 - Adams, H A1 - Ames, D A1 - Amin, N A1 - Amouyel, P A1 - Assareh, A A A1 - Au, R A1 - Becker, J T A1 - Beiser, A A1 - Berr, C A1 - Bertram, L A1 - Boerwinkle, E A1 - Buckley, B M A1 - Campbell, H A1 - Corley, J A1 - De Jager, P L A1 - Dufouil, C A1 - Eriksson, J G A1 - Espeseth, T A1 - Faul, J D A1 - Ford, I A1 - Gottesman, R F A1 - Griswold, M E A1 - Gudnason, V A1 - Harris, T B A1 - Heiss, G A1 - Hofman, A A1 - Holliday, E G A1 - Huffman, J A1 - Kardia, S L R A1 - Kochan, N A1 - Knopman, D S A1 - Kwok, J B A1 - Lambert, J-C A1 - Lee, T A1 - Li, G A1 - Li, S-C A1 - Loitfelder, M A1 - Lopez, O L A1 - Lundervold, A J A1 - Lundqvist, A A1 - Mather, K A A1 - Mirza, S S A1 - Nyberg, L A1 - Oostra, B A A1 - Palotie, A A1 - Papenberg, G A1 - Pattie, A A1 - Petrovic, K A1 - Polasek, O A1 - Psaty, B M A1 - Redmond, P A1 - Reppermund, S A1 - Rotter, J I A1 - Schmidt, H A1 - Schuur, M A1 - Schofield, P W A1 - Scott, R J A1 - Steen, V M A1 - Stott, D J A1 - van Swieten, J C A1 - Taylor, K D A1 - Trollor, J A1 - Trompet, S A1 - Uitterlinden, A G A1 - Weinstein, G A1 - Widen, E A1 - Windham, B G A1 - Jukema, J W A1 - Wright, A F A1 - Wright, M J A1 - Yang, Q A1 - Amieva, H A1 - Attia, J R A1 - Bennett, D A A1 - Brodaty, H A1 - de Craen, A J M A1 - Hayward, C A1 - Ikram, M A A1 - Lindenberger, U A1 - Nilsson, L-G A1 - Porteous, D J A1 - Räikkönen, K A1 - Reinvang, I A1 - Rudan, I A1 - Sachdev, P S A1 - Schmidt, R A1 - Schofield, P R A1 - Srikanth, V A1 - Starr, J M A1 - Turner, S T A1 - Weir, D R A1 - Wilson, J F A1 - van Duijn, C A1 - Launer, L A1 - Fitzpatrick, A L A1 - Seshadri, S A1 - Mosley, T H A1 - Deary, I J KW - Aged KW - Aged, 80 and over KW - Atherosclerosis KW - Cognition KW - Cognition Disorders KW - Cohort Studies KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - HMGN1 Protein KW - Humans KW - Male KW - Middle Aged KW - Neuropsychological Tests KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Scotland AB -

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.

VL - 20 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25644384?dopt=Abstract ER -