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; JC Bis; J Bressler; V Chouraki; S Giddaluru; E Hofer; Carla Verbaas; M Kirin; J Lahti; Sven van der Lee; S Le Hellard; T Liu; RE Marioni; C Oldmeadow; I Postmus; AV Smith; JA Smith; A Thalamuthu; R Thomson; V Vitart; Johnny Wang; L Yu; L Zgaga; W Zhao; R Boxall; SE Harris; WD Hill; DC Liewald; M Luciano; Hieab Adams; D Ames; Najaf Amin; P Amouyel; AA Assareh; R (Rhoda) Au; JT Becker; A Beiser; C Berr; L Bertram; E Boerwinkle; BM Buckley; H Campbell; J Corley; PL De Jager; C Dufouil; JG Eriksson; T Espeseth; JD Faul; I Ford; RF Gottesman; ME Griswold; V Gudnason; TB Harris; G Heiss; Bert Hofman; EG Holliday; J Huffman; SLR Kardia; N Kochan; DS Knopman; JB Kwok; JC Lambert; T Lee; G Li; Shan Li; M Loitfelder; OL Lopez; AJ Lundervold; A Lundqvist; KA Mather; Saira Mirza; L Nyberg; Ben Oostra; A Palotie; G Papenberg; A Pattie; K Petrovic; O Polasek; BM Psaty; P Redmond; S Reppermund; JI Rotter; Heléna Schmidt; Maaike Schuur; PW Schofield; RJ Scott; VM Steen; DJ Stott; J.C. van Swieten; KD Taylor; J Trollor; S Trompet; André Uitterlinden; G Weinstein; E Widen; BG Windham; JW Jukema; AF Wright; MJ Wright; Q Yang; H Amieva; JR Attia; DA Bennett; H Brodaty; AJM de Craen; C Hayward; Arfan Ikram; U Lindenberger; LG Nilsson; DJ Porteous; K Raikkonen; I Reinvang; I Rudan; PS Sachdev; R Schmidt; PR Schofield; V Srikanth; JM Starr; ST Turner; DR Weir; JF Wilson; Cornelia Duijn; L Launer; AL Fitzpatrick; S Seshadri; TH Mosely; IJ 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, JC Bis, J Bressler, V Chouraki, S Giddaluru, E Hofer, Carla Verbaas, M Kirin, J Lahti, Sven van der Lee, S Le Hellard, T Liu, RE Marioni, C Oldmeadow, I Postmus, AV Smith, JA Smith, A Thalamuthu, R ThomsonV Vitart, Johnny Wang, L Yu, L Zgaga, W Zhao, R Boxall, SE Harris, WD Hill, DC Liewald, M Luciano, Hieab Adams, D Ames, Najaf Amin, P Amouyel, AA Assareh, R (Rhoda) Au, JT Becker, A Beiser, C Berr, L Bertram, E Boerwinkle, BM Buckley, H Campbell, J Corley, PL De Jager, C Dufouil, JG Eriksson, T Espeseth, JD Faul, I Ford, RF Gottesman, ME Griswold, V Gudnason, TB Harris, G Heiss, Bert Hofman, EG Holliday, J Huffman, SLR Kardia, N Kochan, DS Knopman, JB Kwok, JC Lambert, T Lee, G Li, Shan Li, M Loitfelder, OL Lopez, AJ Lundervold, A Lundqvist, KA Mather, Saira Mirza, L Nyberg, Ben Oostra, A Palotie, G Papenberg, A Pattie, K Petrovic, O Polasek, BM Psaty, P Redmond, S Reppermund, JI Rotter, Heléna Schmidt, Maaike Schuur, PW Schofield, RJ Scott, VM Steen, DJ Stott, J.C. van Swieten, KD Taylor, J Trollor, S Trompet, André Uitterlinden, G Weinstein, E Widen, BG Windham, JW Jukema, AF Wright, MJ Wright, Q Yang, H Amieva, JR Attia, DA Bennett, H Brodaty, AJM de Craen, C Hayward, Arfan Ikram, U Lindenberger, LG Nilsson, DJ Porteous, K Raikkonen, I Reinvang, I Rudan, PS Sachdev, R Schmidt, PR Schofield, V Srikanth, JM Starr, ST Turner, DR Weir, JF Wilson, Cornelia Duijn, L Launer, AL Fitzpatrick, S Seshadri, TH Mosely, IJ 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 x 10(-9), MIR2113; rs17522122, P = 2.55 x 10(-8), AKAP6; rs10119, P = 5.67 x 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P = 1x10(-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, similar to 1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N = 5487; P = 1.5 x 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	Undefined/Unknown
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
Publication status	Published - 2015

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Cite this

Davies, G., Armstrong, N., Bis, JC., Bressler, J., Chouraki, V., Giddaluru, S., Hofer, E., Verbaas, C., Kirin, M., Lahti, J., van der Lee, S., Le Hellard, S., Liu, T., Marioni, RE., Oldmeadow, C., Postmus, I., Smith, AV., Smith, JA., Thalamuthu, A., ... 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, 20(2), 183-192. https://doi.org/10.1038/mp.2014.188

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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 x 10(-9), MIR2113; rs17522122, P = 2.55 x 10(-8), AKAP6; rs10119, P = 5.67 x 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P = 1x10(-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, similar to 1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N = 5487; P = 1.5 x 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 JC Bis and J Bressler and V Chouraki and S Giddaluru and E Hofer and Carla Verbaas and M Kirin and J Lahti and {van der Lee}, Sven and {Le Hellard}, S and T Liu and RE Marioni and C Oldmeadow and I Postmus and AV Smith and JA Smith and A Thalamuthu and R Thomson and V Vitart and Johnny Wang and L Yu and L Zgaga and W Zhao and R Boxall and SE Harris and WD Hill and DC Liewald and M Luciano and Hieab Adams and D Ames and Najaf Amin and P Amouyel and AA Assareh and Au, {R (Rhoda)} and JT Becker and A Beiser and C Berr and L Bertram and E Boerwinkle and BM Buckley and H Campbell and J Corley and {De Jager}, PL and C Dufouil and JG Eriksson and T Espeseth and JD Faul and I Ford and RF Gottesman and ME Griswold and V Gudnason and TB Harris and G Heiss and Bert Hofman and EG Holliday and J Huffman and SLR Kardia and N Kochan and DS Knopman and JB Kwok and JC Lambert and T Lee and G Li and Shan Li and M Loitfelder and OL Lopez and AJ Lundervold and A Lundqvist and KA Mather and Saira Mirza and L Nyberg and Ben Oostra and A Palotie and G Papenberg and A Pattie and K Petrovic and O Polasek and BM Psaty and P Redmond and S Reppermund and JI Rotter and Hel{\'e}na Schmidt and Maaike Schuur and PW Schofield and RJ Scott and VM Steen and DJ Stott and {van Swieten}, J.C. and KD Taylor and J Trollor and S Trompet and Andr{\'e} Uitterlinden and G Weinstein and E Widen and BG Windham and JW Jukema and AF Wright and MJ Wright and Q Yang and H Amieva and JR Attia and DA Bennett and H Brodaty and {de Craen}, AJM and C Hayward and Arfan Ikram and U Lindenberger and LG Nilsson and DJ Porteous and K Raikkonen and I Reinvang and I Rudan and PS Sachdev and R Schmidt and PR Schofield and V Srikanth and JM Starr and ST Turner and DR Weir and JF Wilson and Cornelia Duijn and L Launer and AL Fitzpatrick and S Seshadri and TH Mosely and IJ Deary",

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volume = "20",

pages = "183--192",

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Davies, G, Armstrong, N, Bis, JC, Bressler, J, Chouraki, V, Giddaluru, S, Hofer, E, Verbaas, C, Kirin, M, Lahti, J, van der Lee, S, 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, Gottesman, RF, Griswold, ME, Gudnason, V, Harris, TB, Heiss, G, Hofman, B, Holliday, EG, Huffman, J, Kardia, SLR, Kochan, N, Knopman, DS, Kwok, JB, Lambert, JC, Lee, T, Li, G, Li, S, Loitfelder, M, Lopez, OL, Lundervold, AJ, Lundqvist, A, Mather, KA, Mirza, S, Nyberg, L, Oostra, B, 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, A, 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, A, Lindenberger, U, Nilsson, LG, Porteous, DJ, Raikkonen, K, Reinvang, I, Rudan, I, Sachdev, PS, Schmidt, R, Schofield, PR, Srikanth, V, Starr, JM, Turner, ST, Weir, DR, Wilson, JF, Duijn, C, Launer, L, Fitzpatrick, AL, Seshadri, S, Mosely, 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

TY - JOUR

T1 - Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

AU - Davies, G

AU - Armstrong, N

AU - Bis, JC

AU - Bressler, J

AU - Chouraki, V

AU - Giddaluru, S

AU - Hofer, E

AU - Verbaas, Carla

AU - Kirin, M

AU - Lahti, J

AU - van der Lee, Sven

AU - Le Hellard, S

AU - Liu, T

AU - Marioni, RE

AU - Oldmeadow, C

AU - Postmus, I

AU - Smith, AV

AU - Smith, JA

AU - Thalamuthu, A

AU - Thomson, R

AU - Vitart, V

AU - Wang, Johnny

AU - Yu, L

AU - Zgaga, L

AU - Zhao, W

AU - Boxall, R

AU - Harris, SE

AU - Hill, WD

AU - Liewald, DC

AU - Luciano, M

AU - Adams, Hieab

AU - Ames, D

AU - Amin, Najaf

AU - Amouyel, P

AU - Assareh, AA

AU - Au, R (Rhoda)

AU - Becker, JT

AU - Beiser, A

AU - Berr, C

AU - Bertram, L

AU - Boerwinkle, E

AU - Buckley, BM

AU - Campbell, H

AU - Corley, J

AU - De Jager, PL

AU - Dufouil, C

AU - Eriksson, JG

AU - Espeseth, T

AU - Faul, JD

AU - Ford, I

AU - Gottesman, RF

AU - Griswold, ME

AU - Gudnason, V

AU - Harris, TB

AU - Heiss, G

AU - Hofman, Bert

AU - Holliday, EG

AU - Huffman, J

AU - Kardia, SLR

AU - Kochan, N

AU - Knopman, DS

AU - Kwok, JB

AU - Lambert, JC

AU - Lee, T

AU - Li, G

AU - Li, Shan

AU - Loitfelder, M

AU - Lopez, OL

AU - Lundervold, AJ

AU - Lundqvist, A

AU - Mather, KA

AU - Mirza, Saira

AU - Nyberg, L

AU - Oostra, Ben

AU - Palotie, A

AU - Papenberg, G

AU - Pattie, A

AU - Petrovic, K

AU - Polasek, O

AU - Psaty, BM

AU - Redmond, P

AU - Reppermund, S

AU - Rotter, JI

AU - Schmidt, Heléna

AU - Schuur, Maaike

AU - Schofield, PW

AU - Scott, RJ

AU - Steen, VM

AU - Stott, DJ

AU - van Swieten, J.C.

AU - Taylor, KD

AU - Trollor, J

AU - Trompet, S

AU - Uitterlinden, André

AU - Weinstein, G

AU - Widen, E

AU - Windham, BG

AU - Jukema, JW

AU - Wright, AF

AU - Wright, MJ

AU - Yang, Q

AU - Amieva, H

AU - Attia, JR

AU - Bennett, DA

AU - Brodaty, H

AU - de Craen, AJM

AU - Hayward, C

AU - Ikram, Arfan

AU - Lindenberger, U

AU - Nilsson, LG

AU - Porteous, DJ

AU - Raikkonen, K

AU - Reinvang, I

AU - Rudan, I

AU - Sachdev, PS

AU - Schmidt, R

AU - Schofield, PR

AU - Srikanth, V

AU - Starr, JM

AU - Turner, ST

AU - Weir, DR

AU - Wilson, JF

AU - Duijn, Cornelia

AU - Launer, L

AU - Fitzpatrick, AL

AU - Seshadri, S

AU - Mosely, TH

AU - Deary, IJ

PY - 2015

Y1 - 2015

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 x 10(-9), MIR2113; rs17522122, P = 2.55 x 10(-8), AKAP6; rs10119, P = 5.67 x 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P = 1x10(-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, similar to 1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N = 5487; P = 1.5 x 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 x 10(-9), MIR2113; rs17522122, P = 2.55 x 10(-8), AKAP6; rs10119, P = 5.67 x 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P = 1x10(-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, similar to 1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N = 5487; P = 1.5 x 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.

U2 - 10.1038/mp.2014.188

DO - 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 -