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.
authors.affiliation: Department of Applied Economics, Erasmus School of Economics, Erasmus University, 3000 DR, Rotterdam, The Netherlands; Departments of Epidemiology.
authors.forename: Cornelius A
authors.initials: CA
authors.lastname: Rietveld
authors.affiliation: Division of Genetics and Endocrinology, Boston Children's Hospital, Boston, MA 02115; Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142; Department of Genetics, Harvard Medical School, Boston, MA 02115; Estonian Genome Center, University of Tartu, 51010 Tartu, Estonia;
authors.forename: Tõnu
authors.initials: T
authors.lastname: Esko
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, and.
authors.forename: Gail
authors.initials: G
authors.lastname: Davies
authors.affiliation: Division of Genetics and Endocrinology, Boston Children's Hospital, Boston, MA 02115; Program in Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142;
authors.forename: Tune H
authors.initials: TH
authors.lastname: Pers
authors.affiliation: Departments of Economics and.
authors.forename: Patrick
authors.initials: P
authors.lastname: Turley
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia;
authors.forename: Beben
authors.initials: B
authors.lastname: Benyamin
authors.affiliation: Department of Psychology, Union College, Schenectady, NY 12308;
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Chabris
authors.affiliation: Icelandic Heart Association, 201 Kopavogur, Iceland; Faculty of Pharmaceutical Sciences, University of Iceland, 107 Reykjavík, Iceland;
authors.forename: Valur
authors.initials: V
authors.lastname: Emilsson
authors.affiliation: Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA 01702;
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Johnson
authors.affiliation: Psychology, Harvard University, Cambridge, MA 02138; Department of Psychology, University of Minnesota, Minneapolis, MN 55455-0344;
authors.forename: James J
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Complex Trait Genetics, VU University Amsterdam and VU Medical Center, 1081 HV, Amsterdam, The Netherlands; Machine Learning Group, Intelligent Systems, Institute for Computing and Information Sciences, Faculty of Science, Radboud University, 6500 GL, Nijmegen, The Netherlands;
authors.forename: Christiaan
authors.initials: C
authors.lastname: de Leeuw
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia; Centre for Genomic and Experimental Medicine and.
authors.forename: Riccardo E
authors.initials: RE
authors.lastname: Marioni
authors.affiliation: Quantitative Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia;
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Medland
authors.affiliation: Department of Psychology, University of Minnesota, Minneapolis, MN 55455-0344;
authors.forename: Michael B
authors.initials: MB
authors.lastname: Miller
authors.affiliation: Harvard Kennedy School, Harvard University, Cambridge, MA 02139;
authors.forename: Olga
authors.initials: O
authors.lastname: Rostapshova
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology and Biostatistics, and.
authors.forename: Sven J
authors.initials: SJ
authors.lastname: van der Lee
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia;
authors.forename: Anna A E
authors.initials: AA
authors.lastname: Vinkhuyzen
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology and Biostatistics, and.
authors.forename: Najaf
authors.initials: N
authors.lastname: Amin
authors.affiliation: Department of Sociology and.
authors.forename: Dalton
authors.initials: D
authors.lastname: Conley
authors.affiliation: Department of Psychology, University of Illinois, Urbana-Champaign, IL 61820;
authors.forename: Jaime
authors.initials: J
authors.lastname: Derringer
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology and Biostatistics, and Centre for Medical Systems Biology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands;
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, The Netherlands;
authors.forename: Rudolf
authors.initials: R
authors.lastname: Fehrmann
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, The Netherlands;
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: Departments of Economics and.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Glaeser
authors.affiliation: Neuroimaging Genetics Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia;
authors.forename: Narelle K
authors.initials: NK
authors.lastname: Hansell
authors.affiliation: Centre for Genomic and Experimental Medicine and Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom;
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.affiliation: Department of Psychology, University of Minnesota, Minneapolis, MN 55455-0344;
authors.forename: William G
authors.initials: WG
authors.lastname: Iacono
authors.affiliation: Harvard Kennedy School, Harvard University, Cambridge, MA 02139; Neurology, and.
authors.forename: Carla
authors.initials: C
authors.lastname: Ibrahim-Verbaas
authors.affiliation: Departments of Epidemiology, Generation R Study Group, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands;
authors.forename: Vincent
authors.initials: V
authors.lastname: Jaddoe
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, The Netherlands;
authors.forename: Juha
authors.initials: J
authors.lastname: Karjalainen
authors.affiliation: Departments of Economics and.
authors.forename: David
authors.initials: D
authors.lastname: Laibson
authors.affiliation: Departments of Economics and.
authors.forename: Paul
authors.initials: P
authors.lastname: Lichtenstein
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology.
authors.forename: David C
authors.initials: DC
authors.lastname: Liewald
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden;
authors.forename: Patrik K E
authors.initials: PK
authors.lastname: Magnusson
authors.affiliation: Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia;
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Department of Psychology, University of Minnesota, Minneapolis, MN 55455-0344;
authors.forename: Matt
authors.initials: M
authors.lastname: McGue
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol BS8 2PR, United Kingdom;
authors.forename: George
authors.initials: G
authors.lastname: McMahon
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden;
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Pedersen
authors.affiliation: Psychology, Harvard University, Cambridge, MA 02138;
authors.forename: Steven
authors.initials: S
authors.lastname: Pinker
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Centre for Genomic and Experimental Medicine and.
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.affiliation: Department of Complex Trait Genetics, VU University Amsterdam and VU Medical Center, 1081 HV, Amsterdam, The Netherlands; Department of Child and Adolescent Psychiatry, Erasmus Medical Center, 3000 CB, Rotterdam, The Netherlands; Department of Clinical Genetics, VU University Medical Center, 1081 BT, Amsterdam, The Netherlands;
authors.forename: Danielle
authors.initials: D
authors.lastname: Posthuma
authors.affiliation: Departments of Epidemiology, Internal Medicine.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.affiliation: Medical Research Institute, University of Dundee, Dundee DD2 4RB, United Kingdom;
authors.forename: Blair H
authors.initials: BH
authors.lastname: Smith
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom;
authors.forename: John M
authors.initials: JM
authors.lastname: Starr
authors.affiliation: Departments of Epidemiology, Department of Child and Adolescent Psychiatry, Erasmus Medical Center, 3000 CB, Rotterdam, The Netherlands;
authors.forename: Henning
authors.initials: H
authors.lastname: Tiemeier
authors.affiliation: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2PR, United Kingdom;
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.affiliation: Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom;
authors.forename: Maciej
authors.initials: M
authors.lastname: Trzaskowski
authors.affiliation: Departments of Epidemiology, Internal Medicine.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Child and Adolescent Psychiatry, Erasmus Medical Center, 3000 CB, Rotterdam, The Netherlands;
authors.forename: Frank C
authors.initials: FC
authors.lastname: Verhulst
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol BS8 2PR, United Kingdom;
authors.forename: Mary E
authors.initials: ME
authors.lastname: Ward
authors.affiliation: Neuroimaging Genetics Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia;
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Wright
authors.affiliation: Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2PR, United Kingdom;
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, and.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.affiliation: Department of Economics, Stockholm School of Economics, 113 83 Stockholm, Sweden;
authors.forename: Magnus
authors.initials: M
authors.lastname: Johannesson
authors.affiliation: Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom;
authors.forename: Robert
authors.initials: R
authors.lastname: Plomin
authors.affiliation: Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia; University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia;
authors.forename: Peter M
authors.initials: PM
authors.lastname: Visscher
authors.affiliation: Department of Economics, Cornell University, Ithaca, NY 14853; daniel.benjamin@gmail.com p.d.koellinger@uva.nl.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Benjamin
authors.affiliation: Center for Experimental Social Science, Department of Economics, New York University, New York, NY 10012; Institute for the Interdisciplinary Study of Decision Making, New York University, New York, NY 10012; and daniel.benjamin@gmail.com p.d.koellinger@uva.nl.
authors.forename: David
authors.initials: D
authors.lastname: Cesarini
authors.affiliation: Department of Applied Economics, Erasmus School of Economics, Erasmus University, 3000 DR, Rotterdam, The Netherlands; Departments of Epidemiology, Faculty of Economics and Business, University of Amsterdam, 1012 WX, Amsterdam, The Netherlands daniel.benjamin@gmail.com p.d.koellinger@uva.nl.
authors.forename: Philipp D
authors.initials: PD
authors.lastname: Koellinger
mesh_terms: D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D003071:Cognition / Q000502:physiology*; D005260:Female; D006801:Humans; D007858:Learning / Q000502:physiology*; D008297:Male; D008568:Memory / Q000502:physiology; D020412:Multifactorial Inheritance / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics; D019006:Neural Cell Adhesion Molecules; D009473:Neuronal Plasticity / Q000235:genetics*; D050810:Octamer Transcription Factors / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D009435:Synaptic Transmission / Q000235:genetics*
chemical_list: D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; C539628:NRXN1 protein, human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D050810:Octamer Transcription Factors; C484169:POU2F3 protein, human