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

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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 x 10(-9), MIR2113; rs17522122, P = 2.55 x 10(-8), AKAP6; rs10119, P = 5.67 x 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P = 1x10(-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, similar to 1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N = 5487; P = 1.5 x 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.
Original languageUndefined/Unknown
Pages (from-to)183-192
Number of pages10
JournalMolecular Psychiatry
Volume20
Issue number2
DOIs
Publication statusPublished - 2015

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