Genetic contributions to variation in general cognitive function

A meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

G. Davies, N. Armstrong, J. C. Bis, J. Bressler, V. Chouraki, S. Giddaluru, E. Hofer, C. A. Ibrahim-Verbaas, M. Kirin, J. Lahti, S. J. Van Der Lee, S. Le Hellard, T. Liu, R. E. Marioni, C. Oldmeadow, I. Postmus, A. V. Smith, J. A. Smith, A. Thalamuthu, R. Thomson & 109 others V. Vitart, J. Wang, L. Yu, L. Zgaga, W. Zhao, R. Boxall, S. E. Harris, W. D. Hill, D. C. Liewald, M. Luciano, H. Adams, D. Ames, N. Amin, P. Amouyel, A. A. Assareh, R. Au, J. T. Becker, A. Beiser, C. Berr, L. Bertram, E. Boerwinkle, B. M. Buckley, H. Campbell, J. Corley, P. L. De Jager, C. Dufouil, J. G. Eriksson, T. Espeseth, J. D. Faul, I. Ford, Generation Scotland, Rebecca F Gottesman, M. E. Griswold, V. Gudnason, T. B. Harris, G. Heiss, A. Hofman, E. G. Holliday, J. Huffman, S. L R Kardia, N. Kochan, D. S. Knopman, J. B. Kwok, J. C. Lambert, T. Lee, G. Li, S. C. Li, M. Loitfelder, O. L. Lopez, A. J. Lundervold, A. Lundqvist, K. A. Mather, S. S. Mirza, L. Nyberg, B. A. Oostra, A. Palotie, G. Papenberg, A. Pattie, K. Petrovic, O. Polasek, B. M. Psaty, P. Redmond, S. Reppermund, J. I. Rotter, H. Schmidt, M. Schuur, P. W. Schofield, R. J. Scott, V. M. Steen, D. J. Stott, J. C. Van Swieten, K. D. Taylor, J. Trollor, S. Trompet, A. G. Uitterlinden, G. Weinstein, E. Widen, B. G. Windham, J. W. Jukema, A. F. Wright, M. J. Wright, Q. Yang, H. Amieva, J. R. Attia, D. A. Bennett, H. Brodaty, A. J M De Craen, C. Hayward, M. A. Ikram, U. Lindenberger, L. G. Nilsson, D. J. Porteous, K. Räikkönen, I. Reinvang, I. Rudan, P. S. Sachdev, R. Schmidt, P. R. Schofield, V. Srikanth, J. M. Starr, S. T. Turner, D. R. Weir, J. F. Wilson, C. Van Duijn, L. Launer, A. L. Fitzpatrick, S. Seshadri, T. H. Mosley, I. J. Deary

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)183-192
Number of pages10
JournalMolecular Psychiatry
Volume20
Issue number2
DOIs
StatePublished - Feb 1 2015

Fingerprint

Genome-Wide Association Study
Cognition
Meta-Analysis
Single Nucleotide Polymorphism
Genes
HMGN1 Protein
Genome
Multifactorial Inheritance
Phenotype
Chromosomes, Human, Pair 21
Retirement
Health
Scotland
Principal Component Analysis
Atherosclerosis
Analysis of Variance
Alzheimer Disease

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Genetic contributions to variation in general cognitive function : A meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949). / Davies, G.; Armstrong, N.; Bis, J. C.; Bressler, J.; Chouraki, V.; Giddaluru, S.; Hofer, E.; Ibrahim-Verbaas, C. A.; Kirin, M.; Lahti, J.; Van Der Lee, S. J.; Le Hellard, S.; Liu, T.; Marioni, R. E.; Oldmeadow, C.; Postmus, I.; Smith, A. V.; Smith, J. A.; Thalamuthu, A.; Thomson, R.; Vitart, V.; Wang, J.; Yu, L.; Zgaga, L.; Zhao, W.; Boxall, R.; Harris, S. E.; Hill, W. D.; Liewald, D. C.; Luciano, M.; Adams, H.; Ames, D.; Amin, N.; Amouyel, P.; Assareh, A. A.; Au, R.; Becker, J. T.; Beiser, A.; Berr, C.; Bertram, L.; Boerwinkle, E.; Buckley, B. M.; Campbell, H.; Corley, J.; De Jager, P. L.; Dufouil, C.; Eriksson, J. G.; Espeseth, T.; Faul, J. D.; Ford, I.; Scotland, Generation; Gottesman, Rebecca F; Griswold, M. E.; Gudnason, V.; Harris, T. B.; Heiss, G.; Hofman, A.; Holliday, E. G.; Huffman, J.; Kardia, S. L R; Kochan, N.; Knopman, D. S.; Kwok, J. B.; Lambert, J. C.; Lee, T.; Li, G.; Li, S. C.; Loitfelder, M.; Lopez, O. L.; Lundervold, A. J.; Lundqvist, A.; Mather, K. A.; Mirza, S. S.; Nyberg, L.; Oostra, B. A.; Palotie, A.; Papenberg, G.; Pattie, A.; Petrovic, K.; Polasek, O.; Psaty, B. M.; Redmond, P.; Reppermund, S.; Rotter, J. I.; Schmidt, H.; Schuur, M.; Schofield, P. W.; Scott, R. J.; Steen, V. M.; Stott, D. J.; Van Swieten, J. C.; Taylor, K. D.; Trollor, J.; Trompet, S.; Uitterlinden, A. G.; Weinstein, G.; Widen, E.; Windham, B. G.; Jukema, J. W.; Wright, A. F.; Wright, M. J.; Yang, Q.; Amieva, H.; Attia, J. R.; Bennett, D. A.; Brodaty, H.; De Craen, A. J M; Hayward, C.; Ikram, M. A.; Lindenberger, U.; Nilsson, L. G.; Porteous, D. J.; Räikkönen, K.; Reinvang, I.; Rudan, I.; Sachdev, P. S.; Schmidt, R.; Schofield, P. R.; Srikanth, V.; Starr, J. M.; Turner, S. T.; Weir, D. R.; Wilson, J. F.; Van Duijn, C.; Launer, L.; Fitzpatrick, A. L.; Seshadri, S.; Mosley, T. H.; Deary, I. J.

In: Molecular Psychiatry, Vol. 20, No. 2, 01.02.2015, p. 183-192.

Research output: Contribution to journalArticle

Davies, G, Armstrong, N, Bis, JC, 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, AV, Smith, JA, Thalamuthu, A, Thomson, R, Vitart, V, Wang, J, Yu, L, Zgaga, L, Zhao, W, Boxall, R, Harris, SE, Hill, WD, Liewald, DC, Luciano, M, Adams, H, Ames, D, Amin, N, Amouyel, P, Assareh, AA, Au, R, Becker, JT, Beiser, A, Berr, C, Bertram, L, Boerwinkle, E, Buckley, BM, Campbell, H, Corley, J, De Jager, PL, Dufouil, C, Eriksson, JG, Espeseth, T, Faul, JD, Ford, I, Scotland, G, Gottesman, RF, Griswold, ME, Gudnason, V, Harris, TB, Heiss, G, Hofman, A, Holliday, EG, Huffman, J, Kardia, SLR, Kochan, N, Knopman, DS, Kwok, JB, Lambert, JC, Lee, T, Li, G, Li, SC, Loitfelder, M, Lopez, OL, Lundervold, AJ, Lundqvist, A, Mather, KA, Mirza, SS, Nyberg, L, Oostra, BA, Palotie, A, Papenberg, G, Pattie, A, Petrovic, K, Polasek, O, Psaty, BM, Redmond, P, Reppermund, S, Rotter, JI, Schmidt, H, Schuur, M, Schofield, PW, Scott, RJ, Steen, VM, Stott, DJ, Van Swieten, JC, Taylor, KD, Trollor, J, Trompet, S, Uitterlinden, AG, Weinstein, G, Widen, E, Windham, BG, Jukema, JW, Wright, AF, Wright, MJ, Yang, Q, Amieva, H, Attia, JR, Bennett, DA, Brodaty, H, De Craen, AJM, Hayward, C, Ikram, MA, Lindenberger, U, Nilsson, LG, Porteous, DJ, Räikkönen, K, Reinvang, I, Rudan, I, Sachdev, PS, Schmidt, R, Schofield, PR, Srikanth, V, Starr, JM, Turner, ST, Weir, DR, Wilson, JF, Van Duijn, C, Launer, L, Fitzpatrick, AL, Seshadri, S, Mosley, TH & Deary, IJ 2015, 'Genetic contributions to variation in general cognitive function: A meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)', Molecular Psychiatry, vol. 20, no. 2, pp. 183-192. https://doi.org/10.1038/mp.2014.188
Davies, G. ; Armstrong, N. ; Bis, J. C. ; Bressler, J. ; Chouraki, V. ; Giddaluru, S. ; Hofer, E. ; Ibrahim-Verbaas, C. A. ; Kirin, M. ; Lahti, J. ; Van Der Lee, S. J. ; Le Hellard, S. ; Liu, T. ; Marioni, R. E. ; Oldmeadow, C. ; Postmus, I. ; Smith, A. V. ; Smith, J. A. ; Thalamuthu, A. ; Thomson, R. ; Vitart, V. ; Wang, J. ; Yu, L. ; Zgaga, L. ; Zhao, W. ; Boxall, R. ; Harris, S. E. ; Hill, W. D. ; Liewald, D. C. ; Luciano, M. ; Adams, H. ; Ames, D. ; Amin, N. ; Amouyel, P. ; Assareh, A. A. ; Au, R. ; Becker, J. T. ; Beiser, A. ; Berr, C. ; Bertram, L. ; Boerwinkle, E. ; Buckley, B. M. ; Campbell, H. ; Corley, J. ; De Jager, P. L. ; Dufouil, C. ; Eriksson, J. G. ; Espeseth, T. ; Faul, J. D. ; Ford, I. ; Scotland, Generation ; Gottesman, Rebecca F ; Griswold, M. E. ; Gudnason, V. ; Harris, T. B. ; Heiss, G. ; Hofman, A. ; Holliday, E. G. ; Huffman, J. ; Kardia, S. L R ; Kochan, N. ; Knopman, D. S. ; Kwok, J. B. ; Lambert, J. C. ; Lee, T. ; Li, G. ; Li, S. C. ; Loitfelder, M. ; Lopez, O. L. ; Lundervold, A. J. ; Lundqvist, A. ; Mather, K. A. ; Mirza, S. S. ; Nyberg, L. ; Oostra, B. A. ; Palotie, A. ; Papenberg, G. ; Pattie, A. ; Petrovic, K. ; Polasek, O. ; Psaty, B. M. ; Redmond, P. ; Reppermund, S. ; Rotter, J. I. ; Schmidt, H. ; Schuur, M. ; Schofield, P. W. ; Scott, R. J. ; Steen, V. M. ; Stott, D. J. ; Van Swieten, J. C. ; Taylor, K. D. ; Trollor, J. ; Trompet, S. ; Uitterlinden, A. G. ; Weinstein, G. ; Widen, E. ; Windham, B. G. ; Jukema, J. W. ; Wright, A. F. ; Wright, M. J. ; Yang, Q. ; Amieva, H. ; Attia, J. R. ; Bennett, D. A. ; Brodaty, H. ; De Craen, A. J M ; Hayward, C. ; Ikram, M. A. ; Lindenberger, U. ; Nilsson, L. G. ; Porteous, D. J. ; Räikkönen, K. ; Reinvang, I. ; Rudan, I. ; Sachdev, P. S. ; Schmidt, R. ; Schofield, P. R. ; Srikanth, V. ; Starr, J. M. ; Turner, S. T. ; Weir, D. R. ; Wilson, J. F. ; Van Duijn, C. ; Launer, L. ; Fitzpatrick, A. L. ; Seshadri, S. ; Mosley, T. H. ; Deary, I. J. / Genetic contributions to variation in general cognitive function : A meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949). In: Molecular Psychiatry. 2015 ; Vol. 20, No. 2. pp. 183-192.
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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.",
author = "G. Davies and N. Armstrong and Bis, {J. C.} and J. Bressler and V. Chouraki and S. Giddaluru and E. Hofer and Ibrahim-Verbaas, {C. A.} and M. Kirin and J. Lahti and {Van Der Lee}, {S. J.} and {Le Hellard}, S. and T. Liu and Marioni, {R. E.} and C. Oldmeadow and I. Postmus and Smith, {A. V.} and Smith, {J. A.} and A. Thalamuthu and R. Thomson and V. Vitart and J. Wang and L. Yu and L. Zgaga and W. Zhao and R. Boxall and Harris, {S. E.} and Hill, {W. D.} and Liewald, {D. C.} and M. Luciano and H. Adams and D. Ames and N. Amin and P. Amouyel and Assareh, {A. A.} and R. Au and Becker, {J. T.} and A. Beiser and C. Berr and L. Bertram and E. Boerwinkle and Buckley, {B. M.} and H. Campbell and J. Corley and {De Jager}, {P. L.} and C. Dufouil and Eriksson, {J. G.} and T. Espeseth and Faul, {J. D.} and I. Ford and Generation Scotland and Gottesman, {Rebecca F} and Griswold, {M. E.} and V. Gudnason and Harris, {T. B.} and G. Heiss and A. Hofman and Holliday, {E. G.} and J. Huffman and Kardia, {S. L R} and N. Kochan and Knopman, {D. S.} and Kwok, {J. B.} and Lambert, {J. C.} and T. Lee and G. Li and Li, {S. C.} and M. Loitfelder and Lopez, {O. L.} and Lundervold, {A. J.} and A. Lundqvist and Mather, {K. A.} and Mirza, {S. S.} and L. Nyberg and Oostra, {B. A.} and A. Palotie and G. Papenberg and A. Pattie and K. Petrovic and O. Polasek and Psaty, {B. M.} and P. Redmond and S. Reppermund and Rotter, {J. I.} and H. Schmidt and M. Schuur and Schofield, {P. W.} and Scott, {R. J.} and Steen, {V. M.} and Stott, {D. J.} and {Van Swieten}, {J. C.} and Taylor, {K. D.} and J. Trollor and S. Trompet and Uitterlinden, {A. G.} and G. Weinstein and E. Widen and Windham, {B. G.} and Jukema, {J. W.} and Wright, {A. F.} and Wright, {M. J.} and Q. Yang and H. Amieva and Attia, {J. R.} and Bennett, {D. A.} and H. Brodaty and {De Craen}, {A. J M} and C. Hayward and Ikram, {M. A.} and U. Lindenberger and Nilsson, {L. G.} and Porteous, {D. J.} and K. R{\"a}ikk{\"o}nen and I. Reinvang and I. Rudan and Sachdev, {P. S.} and R. Schmidt and Schofield, {P. R.} and V. Srikanth and Starr, {J. M.} and Turner, {S. T.} and Weir, {D. R.} and Wilson, {J. F.} and {Van Duijn}, C. and L. Launer and Fitzpatrick, {A. L.} and S. Seshadri and Mosley, {T. H.} and Deary, {I. J.}",
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month = "2",
day = "1",
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language = "English (US)",
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pages = "183--192",
journal = "Molecular Psychiatry",
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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 - 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 - Faul, J. D.

AU - Ford, I.

AU - Scotland, Generation

AU - Gottesman, Rebecca F

AU - Griswold, M. E.

AU - Gudnason, V.

AU - Harris, T. B.

AU - Heiss, G.

AU - Hofman, A.

AU - Holliday, E. G.

AU - Huffman, J.

AU - Kardia, S. L R

AU - Kochan, N.

AU - Knopman, D. S.

AU - Kwok, J. B.

AU - Lambert, J. C.

AU - Lee, T.

AU - Li, G.

AU - Li, S. C.

AU - Loitfelder, M.

AU - Lopez, O. L.

AU - Lundervold, A. J.

AU - Lundqvist, A.

AU - Mather, K. A.

AU - Mirza, S. S.

AU - Nyberg, L.

AU - Oostra, B. A.

AU - Palotie, A.

AU - Papenberg, G.

AU - Pattie, A.

AU - Petrovic, K.

AU - Polasek, O.

AU - Psaty, B. M.

AU - Redmond, P.

AU - Reppermund, S.

AU - Rotter, J. I.

AU - Schmidt, H.

AU - Schuur, M.

AU - Schofield, P. W.

AU - Scott, R. J.

AU - Steen, V. M.

AU - Stott, D. J.

AU - Van Swieten, J. C.

AU - Taylor, K. D.

AU - Trollor, J.

AU - Trompet, S.

AU - Uitterlinden, A. G.

AU - Weinstein, G.

AU - Widen, E.

AU - Windham, B. G.

AU - Jukema, J. W.

AU - Wright, A. F.

AU - Wright, M. J.

AU - Yang, Q.

AU - Amieva, H.

AU - Attia, J. R.

AU - Bennett, D. A.

AU - Brodaty, H.

AU - De Craen, A. J M

AU - Hayward, C.

AU - Ikram, M. A.

AU - Lindenberger, U.

AU - Nilsson, L. G.

AU - Porteous, D. J.

AU - Räikkönen, K.

AU - Reinvang, I.

AU - Rudan, I.

AU - Sachdev, P. S.

AU - Schmidt, R.

AU - Schofield, P. R.

AU - Srikanth, V.

AU - Starr, J. M.

AU - Turner, S. T.

AU - Weir, D. R.

AU - Wilson, J. F.

AU - Van Duijn, C.

AU - Launer, L.

AU - Fitzpatrick, A. L.

AU - Seshadri, S.

AU - Mosley, T. H.

AU - Deary, I. J.

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.

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U2 - 10.1038/mp.2014.188

DO - 10.1038/mp.2014.188

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SN - 1359-4184

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