TY - JOUR
T1 - Genetic contributions to variation in general cognitive function
T2 - A meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)
AU - CHARGE Consortium
AU - Davies, G.
AU - Armstrong, N.
AU - Bis, J. C.
AU - Bressler, J.
AU - Chouraki, V.
AU - Giddaluru, S.
AU - Hofer, E.
AU - Ibrahim-Verbaas, C. A.
AU - Kirin, M.
AU - Lahti, J.
AU - Van Der Lee, S. J.
AU - Le Hellard, S.
AU - Liu, T.
AU - Marioni, R. E.
AU - Oldmeadow, C.
AU - Postmus, I.
AU - Smith, A. V.
AU - Smith, J. A.
AU - Thalamuthu, A.
AU - Thomson, R.
AU - Vitart, V.
AU - Wang, J.
AU - Yu, L.
AU - Zgaga, L.
AU - Zhao, W.
AU - Boxall, R.
AU - Harris, S. E.
AU - Hill, W. D.
AU - Liewald, D. C.
AU - Luciano, M.
AU - Adams, H.
AU - Ames, D.
AU - Amin, N.
AU - Amouyel, P.
AU - Assareh, A. A.
AU - Au, R.
AU - Becker, J. T.
AU - Beiser, A.
AU - Berr, C.
AU - Bertram, L.
AU - Boerwinkle, E.
AU - Buckley, B. M.
AU - Campbell, H.
AU - Corley, J.
AU - De Jager, P. L.
AU - Dufouil, C.
AU - Eriksson, J. G.
AU - Espeseth, T.
AU - Schuur, M.
AU - Van Swieten, J. C.
PY - 2015/2/1
Y1 - 2015/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84938550053&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/mp.2014.188
DO - https://doi.org/10.1038/mp.2014.188
M3 - Article
C2 - 25644384
SN - 1359-4184
VL - 20
SP - 183
EP - 192
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 2
ER -