Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

Pubmed ID: 25644384

Pubmed Central ID: PMC4356746

Journal: Molecular psychiatry

Publication Date: Feb. 1, 2015

Affiliation: 1] Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK [2] Department of Psychology, University of Edinburgh, Edinburgh, UK.

MeSH Terms: Humans, Male, Female, Aged, Aged, 80 and over, Cohort Studies, Genetic Predisposition to Disease, Middle Aged, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Atherosclerosis, Cognition Disorders, Neuropsychological Tests, Cognition, Phenotype, HMGN1 Protein, Scotland

Grants: UL1 TR000124, P30 DK063491, U01 AG049505, R01 HL070825, R01 NS017950, RF1 AG015819, R01 AG017917, R01 HL105756, R01 AG008122, P30 AG010161, P50 AG005133, P30 AG010129, R01 AG015819, ETM/55, CZB/4/505, CZB/4/710, S18386, MR/K026992/1, UL1 TR000135, CZD/16/6/4, MC_PC_U127561128, G0700704, BB/F019394/1, U01 AG009740

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

Cite As: 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 SL, Kochan N, Knopman DS, Kwok JB, Lambert JC, Lee T, Li G, Li SC, 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 AJ, Hayward C, Ikram MA, Lindenberger U, Nilsson LG, 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 Jr, Deary IJ. Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949). Mol Psychiatry 2015 Feb;20(2):183-92. Epub 2015 Feb 3.

Studies:

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.