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. Smith, John M. Starr, Henning Tiemeier, Nicholas J. Timpson, Maciej Trzaskowski, 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

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    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.

    Original languageEnglish
    Pages (from-to)13790-13794
    Number of pages5
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume111
    Issue number38
    DOIs
    Publication statusPublished - 23 Sep 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., Leeuw, C. D., 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