Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)
Authors: Davies G , Armstrong N , Bis J C , Bressler J , Chouraki V , Giddaluru S , Hofer E , Ibrahim-Verbaas C A , Kirin M , Lahti J , van der Lee S J , Le Hellard S , Liu T , Marioni R E , Oldmeadow C , Postmus I , Smith A V , Smith J A , Thalamuthu A , Thomson R , Vitart V , Wang J , Yu L , Zgaga L , Zhao W , Boxall R , Harris S E , Hill W D , Liewald D C , Luciano M , Adams H , Ames D , Amin N , Amouyel P , Assareh A A , Au R , Becker J T , Beiser A , Berr C , Bertram L , Boerwinkle E , Buckley B M , Campbell H , Corley J , De Jager P L , Dufouil C , Eriksson J G , Espeseth T , Faul J D , Ford I , Scotland Generation , Gottesman R F , Griswold M E , Gudnason V , Harris T B , Heiss G , Hofman A , Holliday E G , Huffman J , Kardia S L R , Kochan N , Knopman D S , Kwok J B , Lambert J-C , Lee T , Li G , Li S-C , Loitfelder M , Lopez O L , Lundervold A J , Lundqvist A , Mather K A , Mirza S S , Nyberg L , Oostra B A , Palotie A , Papenberg G , Pattie A , Petrovic K , Polasek O , Psaty B M , Redmond P , Reppermund S , Rotter J I , Schmidt H , Schuur M , Schofield P W , Scott R J , Steen V M , Stott D J , van Swieten J C , Taylor K D , Trollor J , Trompet S , Uitterlinden A G , Weinstein G , Widen E , Windham B G , Jukema J W , Wright A F , Wright M J , Yang Q , Amieva H , Attia J R , Bennett D A , Brodaty H , de Craen A J M , Hayward C , Ikram M A , Lindenberger U , Nilsson L-G , Porteous D J , Räikkönen K , Reinvang I , Rudan I , Sachdev P S , Schmidt R , Schofield P R , Srikanth V , Starr J M , Turner S T , Weir D R , Wilson J F , van Duijn C , Launer L , Fitzpatrick A L , Seshadri S , Mosley T H , Deary I J 
Published: February 2015

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.