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

Cornelius A. Rietveld; Tõnu 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. Smithk; John M. Starr; Henning Tiemeier; Nicholas J. Timpsonm; Maciej Trzaskowskin; André 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, Tõnu 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. Smithk, John M. Starr, Henning Tiemeier, Nicholas J. Timpsonm, Maciej Trzaskowskin, André 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

Psychology (Twin Cities)

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Abstract

We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxyphenotype 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 (US)
Pages (from-to)	13790-13794
Number of pages	5
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	111
Issue number	38
DOIs	https://doi.org/10.1073/pnas.1404623111
State	Published - Sep 23 2014

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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 of the United States of America, 111(38), 13790-13794. https://doi.org/10.1073/pnas.1404623111

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, Smithk, BH, Starr, JM, Tiemeier, H, Timpsonm, NJ, Trzaskowskin, 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 of the United States of America, vol. 111, no. 38, pp. 13790-13794. https://doi.org/10.1073/pnas.1404623111

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abstract = "We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxyphenotype 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.",

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AU - Rietveld, Cornelius A.

AU - Esko, Tõnu

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 - Smithk, Blair H.

AU - Starr, John M.

AU - Tiemeier, Henning

AU - Timpsonm, Nicholas J.

AU - Trzaskowskin, Maciej

AU - Uitterlinden, André 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 proxyphenotype 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 proxyphenotype 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.

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U2 - 10.1073/pnas.1404623111

DO - 10.1073/pnas.1404623111

M3 - Article

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SN - 0027-8424

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 38

ER -

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

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