Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

TitleGenetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)
Publication TypeJournal Article
Year of Publication2015
AuthorsDavies, G, Armstrong, N, Joshua C. Bis, 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, AVernon
JournalMolecular Psychiatry
Volume20
Issue2
Pagination183-192
KeywordsCHARGE, Cross-National, Genetics, Health Conditions and Status, Methodology
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.

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DOI10.1038/mp.2014.188
Endnote Keywords

genetics/genetics/GENOME-WIDE ASSOCIATION/TOMM40/ABCG1/MEF2C/complex train anaysis/Atherosclerosis Risk in Communities Study/cross-national study

Endnote ID

999999

Citation Key8297
PubMed ID25644384
PubMed Central IDPMC4356746