Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).
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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 × 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. |
| Year of Publication | 2015
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| Journal | Mol Psychiatry
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| Volume | 20
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| Issue | 2
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| Pages | 183-92
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| Date Published | 2015 Feb
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| ISSN | 1476-5578
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| URL | |
| DOI | 10.1038/mp.2014.188
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| PubMed ID | 25644384
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| PubMed Central ID | PMC4356746
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| Grant list | ETM/55 / Chief Scientist Office / United Kingdom
CZB/4/505 / Chief Scientist Office / United Kingdom
CZB/4/710 / Chief Scientist Office / United Kingdom
R01 NS017950 / NS / NINDS NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States
S18386 / Biotechnology and Biological Sciences Research Council / United Kingdom
R01 AG017917 / AG / NIA NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
MR/K026992/1 / Medical Research Council / United Kingdom
P30 DK063491 / DK / NIDDK NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
UL1 TR000135 / TR / NCATS NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
CZD/16/6/4 / Chief Scientist Office / United Kingdom
MC_PC_U127561128 / Medical Research Council / United Kingdom
G0700704 / Medical Research Council / United Kingdom
BB/F019394/1 / Biotechnology and Biological Sciences Research Council / United Kingdom
U01 AG049505 / AG / NIA NIH HHS / United States
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