Common genetic variants associated with cognitive performance identified using the proxy-phenotype method

Cornelius A. Rietveld; Tonu Esko; Gail Davies; Tune H. Pers; Patrick Turley; Beben Benyamin; Christopher F. Chabris; Valur Emilsson; Andrew D. Johnson; James J. Lee; Christiaan de Leeuw; Riccardo E. Marioni; Sarah E. Medland; Michael B. Miller; Olga Rostapshova; Sven J. van der Lee; Anna A. E. Vinkhuyzen; Najaf Amin; Dalton Conley; Jaime Derringer; Cornelia M. van Duijn; Rudolf Fehrmann; Lude Franke; Edward L. Glaeser; Narelle K. Hansell; Caroline Hayward; William G. Iacono; Carla Ibrahim-Verbaas; Vincent Jaddoe; Juha Karjalainen; David Laibson; Paul Lichtenstein; David C. Liewald; Patrik K. E. Magnusson; Nicholas G. Martin; Matt McGue; George McMahon; Nancy L. Pedersen; Steven Pinker; David J. Porteous; Danielle Posthuma; Fernando Rivadeneira; Blair H. Smith; John M. Starr; Henning Tiemeier; Nicholas J. Timpson; Maciej Trzaskowski; Andre G. Uitterlinden; Frank C. Verhulst; Mary E. Ward; Margaret J. Wright; George Davey Smith; Ian J. Deary; Magnus Johannesson; Robert Plomin; Peter M. Visscher; Daniel J. Benjamin; David Cesarini; Philipp D. Koellinger

doi:10.1073/pnas.1404623111

Common genetic variants associated with cognitive performance identified using the proxy-phenotype method

Cornelius A. Rietveld, Tonu Esko, Gail Davies, Tune H. Pers, Patrick Turley, Beben Benyamin, Christopher F. Chabris, Valur Emilsson, Andrew D. Johnson, James J. Lee, Christiaan de Leeuw, Riccardo E. Marioni, Sarah E. Medland, Michael B. Miller, Olga Rostapshova, Sven J. van der Lee, Anna A. E. Vinkhuyzen, Najaf Amin, Dalton Conley, Jaime DerringerCornelia M. van Duijn, Rudolf Fehrmann, Lude Franke, Edward L. Glaeser, Narelle K. Hansell, Caroline Hayward, William G. Iacono, Carla Ibrahim-Verbaas, Vincent Jaddoe, Juha Karjalainen, David Laibson, Paul Lichtenstein, David C. Liewald, Patrik K. E. Magnusson, Nicholas G. Martin, Matt McGue, George McMahon, Nancy L. Pedersen, Steven Pinker, David J. Porteous, Danielle Posthuma, Fernando Rivadeneira, Blair H. Smith, John M. Starr, Henning Tiemeier, Nicholas J. Timpson, Maciej Trzaskowski, Andre G. Uitterlinden, Frank C. Verhulst, Mary E. Ward, Margaret J. Wright, George Davey Smith, Ian J. Deary, Magnus Johannesson, Robert Plomin, Peter M. Visscher, Daniel J. Benjamin^*, David Cesarini, Philipp D. Koellinger

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory.

Original language	English
Pages (from-to)	13790-13794
Number of pages	5
Journal	Proceedings of the National Academy of Sciences (PNAS)
Volume	111
Issue number	38
DOIs	https://doi.org/10.1073/pnas.1404623111
Publication status	Published - 23 Sept 2014

Keywords / Materials (for Non-textual outputs)

GENOME-WIDE ASSOCIATION
ACADEMIC-ACHIEVEMENT
INTELLIGENCE
LOCI
COMPONENTS
GWAS

Access to Document

10.1073/pnas.1404623111

Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.
Maclullich, A.
1/09/13 → 31/08/19
Project: Research
RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.
Deary, I., Gale, C., Holmes, M., Logie, P., Maclullich, A., Porteous, D., Seckl, J., Starr, J., Wardlaw, J. & Okely, J.
1/09/13 → 31/08/19
Project: Research
A genome wide association study of non pathological cognitive ageing
Deary, I., Porteous, D. & Tenesa, A.
BBSRC
1/09/08 → 31/08/10
Project: Research

Cite this

Rietveld, C. A., Esko, T., Davies, G., Pers, T. H., Turley, P., Benyamin, B., Chabris, C. F., Emilsson, V., Johnson, A. D., Lee, J. J., de Leeuw, C., Marioni, R. E., Medland, S. E., Miller, M. B., Rostapshova, O., van der Lee, S. J., Vinkhuyzen, A. A. E., Amin, N., Conley, D., ... Koellinger, P. D. (2014). Common genetic variants associated with cognitive performance identified using the proxy-phenotype method. Proceedings of the National Academy of Sciences (PNAS), 111(38), 13790-13794. https://doi.org/10.1073/pnas.1404623111

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title = "Common genetic variants associated with cognitive performance identified using the proxy-phenotype method",

abstract = "We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory.",

keywords = "GENOME-WIDE ASSOCIATION, ACADEMIC-ACHIEVEMENT, INTELLIGENCE, LOCI, COMPONENTS, GWAS",

author = "Rietveld, {Cornelius A.} and Tonu Esko and Gail Davies and Pers, {Tune H.} and Patrick Turley and Beben Benyamin and Chabris, {Christopher F.} and Valur Emilsson and Johnson, {Andrew D.} and Lee, {James J.} and {de Leeuw}, Christiaan and Marioni, {Riccardo E.} and Medland, {Sarah E.} and Miller, {Michael B.} and Olga Rostapshova and {van der Lee}, {Sven J.} and Vinkhuyzen, {Anna A. E.} and Najaf Amin and Dalton Conley and Jaime Derringer and {van Duijn}, {Cornelia M.} and Rudolf Fehrmann and Lude Franke and Glaeser, {Edward L.} and Hansell, {Narelle K.} and Caroline Hayward and Iacono, {William G.} and Carla Ibrahim-Verbaas and Vincent Jaddoe and Juha Karjalainen and David Laibson and Paul Lichtenstein and Liewald, {David C.} and Magnusson, {Patrik K. E.} and Martin, {Nicholas G.} and Matt McGue and George McMahon and Pedersen, {Nancy L.} and Steven Pinker and Porteous, {David J.} and Danielle Posthuma and Fernando Rivadeneira and Smith, {Blair H.} and Starr, {John M.} and Henning Tiemeier and Timpson, {Nicholas J.} and Maciej Trzaskowski and Uitterlinden, {Andre G.} and Verhulst, {Frank C.} and Ward, {Mary E.} and Wright, {Margaret J.} and Smith, {George Davey} and Deary, {Ian J.} and Magnus Johannesson and Robert Plomin and Visscher, {Peter M.} and Benjamin, {Daniel J.} and David Cesarini and Koellinger, {Philipp D.}",

year = "2014",

month = sep,

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doi = "10.1073/pnas.1404623111",

language = "English",

volume = "111",

pages = "13790--13794",

journal = "Proceedings of the National Academy of Sciences (PNAS)",

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publisher = "National Academy of Sciences",

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Rietveld, CA, Esko, T, Davies, G, Pers, TH, Turley, P, Benyamin, B, Chabris, CF, Emilsson, V, Johnson, AD, Lee, JJ, de Leeuw, C, Marioni, RE, Medland, SE, Miller, MB, Rostapshova, O, van der Lee, SJ, Vinkhuyzen, AAE, Amin, N, Conley, D, Derringer, J, van Duijn, CM, Fehrmann, R, Franke, L, Glaeser, EL, Hansell, NK, Hayward, C, Iacono, WG, Ibrahim-Verbaas, C, Jaddoe, V, Karjalainen, J, Laibson, D, Lichtenstein, P, Liewald, DC, Magnusson, PKE, Martin, NG, McGue, M, McMahon, G, Pedersen, NL, Pinker, S, Porteous, DJ, Posthuma, D, Rivadeneira, F, Smith, BH, Starr, JM, Tiemeier, H, Timpson, NJ, Trzaskowski, M, Uitterlinden, AG, Verhulst, FC, Ward, ME, Wright, MJ, Smith, GD, Deary, IJ, Johannesson, M, Plomin, R, Visscher, PM, Benjamin, DJ, Cesarini, D & Koellinger, PD 2014, 'Common genetic variants associated with cognitive performance identified using the proxy-phenotype method', Proceedings of the National Academy of Sciences (PNAS), vol. 111, no. 38, pp. 13790-13794. https://doi.org/10.1073/pnas.1404623111

TY - JOUR

T1 - Common genetic variants associated with cognitive performance identified using the proxy-phenotype method

AU - Rietveld, Cornelius A.

AU - Esko, Tonu

AU - Davies, Gail

AU - Pers, Tune H.

AU - Turley, Patrick

AU - Benyamin, Beben

AU - Chabris, Christopher F.

AU - Emilsson, Valur

AU - Johnson, Andrew D.

AU - Lee, James J.

AU - de Leeuw, Christiaan

AU - Marioni, Riccardo E.

AU - Medland, Sarah E.

AU - Miller, Michael B.

AU - Rostapshova, Olga

AU - van der Lee, Sven J.

AU - Vinkhuyzen, Anna A. E.

AU - Amin, Najaf

AU - Conley, Dalton

AU - Derringer, Jaime

AU - van Duijn, Cornelia M.

AU - Fehrmann, Rudolf

AU - Franke, Lude

AU - Glaeser, Edward L.

AU - Hansell, Narelle K.

AU - Hayward, Caroline

AU - Iacono, William G.

AU - Ibrahim-Verbaas, Carla

AU - Jaddoe, Vincent

AU - Karjalainen, Juha

AU - Laibson, David

AU - Lichtenstein, Paul

AU - Liewald, David C.

AU - Magnusson, Patrik K. E.

AU - Martin, Nicholas G.

AU - McGue, Matt

AU - McMahon, George

AU - Pedersen, Nancy L.

AU - Pinker, Steven

AU - Porteous, David J.

AU - Posthuma, Danielle

AU - Rivadeneira, Fernando

AU - Smith, Blair H.

AU - Starr, John M.

AU - Tiemeier, Henning

AU - Timpson, Nicholas J.

AU - Trzaskowski, Maciej

AU - Uitterlinden, Andre G.

AU - Verhulst, Frank C.

AU - Ward, Mary E.

AU - Wright, Margaret J.

AU - Smith, George Davey

AU - Deary, Ian J.

AU - Johannesson, Magnus

AU - Plomin, Robert

AU - Visscher, Peter M.

AU - Benjamin, Daniel J.

AU - Cesarini, David

AU - Koellinger, Philipp D.

PY - 2014/9/23

Y1 - 2014/9/23

N2 - We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory.

AB - We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated SNPs. Second, using independent samples (n = 24,189), we measure the association of these education-associated SNPs with cognitive performance. Three SNPs (rs1487441, rs7923609, and rs2721173) are significantly associated with cognitive performance after correction for multiple hypothesis testing. In an independent sample of older Americans (n = 8,652), we also show that a polygenic score derived from the education-associated SNPs is associated with memory and absence of dementia. Convergent evidence from a set of bioinformatics analyses implicates four specific genes (KNCMA1, NRXN1, POU2F3, and SCRT). All of these genes are associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory.

KW - GENOME-WIDE ASSOCIATION

KW - ACADEMIC-ACHIEVEMENT

KW - INTELLIGENCE

KW - LOCI

KW - COMPONENTS

KW - GWAS

U2 - 10.1073/pnas.1404623111

DO - 10.1073/pnas.1404623111

M3 - Article

SN - 0027-8424

VL - 111

SP - 13790

EP - 13794

JO - Proceedings of the National Academy of Sciences (PNAS)

JF - Proceedings of the National Academy of Sciences (PNAS)

IS - 38

ER -

Common genetic variants associated with cognitive performance identified using the proxy-phenotype method

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

Access to Document

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Projects

Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

A genome wide association study of non pathological cognitive ageing

Cite this