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; 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; R. 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

doi:10.1038/mp.2014.188

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. ThomsonV. 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, R. 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

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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.

Original language	English (US)
Pages (from-to)	183-192
Number of pages	10
Journal	Molecular Psychiatry
Volume	20
Issue number	2
DOIs	https://doi.org/10.1038/mp.2014.188
State	Published - Feb 1 2015

ASJC Scopus subject areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Molecular Biology

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10.1038/mp.2014.188

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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., ... Deary, I. J. (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, 20(2), 183-192. https://doi.org/10.1038/mp.2014.188

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

@article{b2f9aa5752f64df48ad05333dbed83a0,

title = "Genetic contributions to variation in general cognitive function: A meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)",

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, {R. 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.}",

note = "Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited.",

year = "2015",

month = feb,

day = "1",

doi = "10.1038/mp.2014.188",

language = "English (US)",

volume = "20",

pages = "183--192",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "2",

}

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, R. 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

M3 - Article

C2 - 25644384

AN - SCOPUS:84938550053

SN - 1359-4184

VL - 20

SP - 183

EP - 192

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 2

ER -

Genetic contributions to variation in general cognitive function: A meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

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