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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=53949).

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