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

TitleGenetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).
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, CJ, Postmus, I, Smith, AVernon
JournalMol Psychiatry
Volume20
Issue2
Pagination183-92
Date Published2015 Feb
ISSN Number1476-5578
KeywordsAged, Aged, 80 and over, Atherosclerosis, Cognition, Cognition Disorders, Cohort Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, HMGN1 Protein, Humans, Male, Middle Aged, Neuropsychological tests, Phenotype, Polymorphism, Single Nucleotide, Scotland
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.

Notes

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DOI10.1038/mp.2014.188
User Guide Notes

http://www.ncbi.nlm.nih.gov/pubmed/25644384?dopt=Abstract

Endnote Keywords

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

Endnote ID

999999

Alternate JournalMol. Psychiatry
Citation Key8297
PubMed ID25644384
PubMed Central IDPMC4356746
Grant ListR01 NS017950 / NS / NINDS NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States
U01 AG009740 / AG / NIA NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
UL1 TR000135 / TR / NCATS NIH HHS / United States
R01 HL070825 / HL / NHLBI NIH HHS / United States
BB/F019394/1 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom
U01 AG049505 / AG / NIA NIH HHS / United States
ETM/55 / CSO_ / Chief Scientist Office / United Kingdom
CZB/4/505 / CSO_ / Chief Scientist Office / United Kingdom
CZB/4/710 / CSO_ / Chief Scientist Office / United Kingdom
S18386 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom
R01 AG017917 / AG / NIA NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
R01 AG008122 / AG / NIA NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
CZD/16/6/4 / CSO_ / Chief Scientist Office / United Kingdom
MC_PC_U127561128 / MRC_ / Medical Research Council / United Kingdom
G0700704 / MRC_ / Medical Research Council / United Kingdom
P30 AG010129 / AG / NIA NIH HHS / United States