Title | Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949). |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Davies, 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 |
Journal | Mol Psychiatry |
Volume | 20 |
Issue | 2 |
Pagination | 183-92 |
Date Published | 2015 Feb |
ISSN Number | 1476-5578 |
Keywords | Aged, 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 | Times Cited: 0 0 |
DOI | 10.1038/mp.2014.188 |
User Guide Notes | |
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 Journal | Mol Psychiatry |
Citation Key | 8297 |
PubMed ID | 25644384 |
PubMed Central ID | PMC4356746 |
Grant List | R01 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 |