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Proc Natl Acad Sci U S A. 2014 Sep 23;111(38):13790-4. doi: 10.1073/pnas.1404623111. Epub 2014 Sep 8.

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

Author information

1
Department of Applied Economics, Erasmus School of Economics, Erasmus University, 3000 DR, Rotterdam, The Netherlands; Departments of Epidemiology.
2
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;
3
Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, and.
4
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;
5
Departments of Economics and.
6
Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia;
7
Department of Psychology, Union College, Schenectady, NY 12308;
8
Icelandic Heart Association, 201 Kopavogur, Iceland; Faculty of Pharmaceutical Sciences, University of Iceland, 107 Reykjavík, Iceland;
9
Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA 01702;
10
Psychology, Harvard University, Cambridge, MA 02138; Department of Psychology, University of Minnesota, Minneapolis, MN 55455-0344;
11
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;
12
Centre for Cognitive Ageing and Cognitive Epidemiology, Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia; Centre for Genomic and Experimental Medicine and.
13
Quantitative Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia;
14
Department of Psychology, University of Minnesota, Minneapolis, MN 55455-0344;
15
Harvard Kennedy School, Harvard University, Cambridge, MA 02139;
16
Genetic Epidemiology Unit, Department of Epidemiology and Biostatistics, and.
17
Department of Sociology and.
18
Department of Psychology, University of Illinois, Urbana-Champaign, IL 61820;
19
Genetic Epidemiology Unit, Department of Epidemiology and Biostatistics, and Centre for Medical Systems Biology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands;
20
Department of Genetics, University Medical Center Groningen, University of Groningen, 9713 GZ, Groningen, The Netherlands;
21
Neuroimaging Genetics Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia;
22
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;
23
Harvard Kennedy School, Harvard University, Cambridge, MA 02139; Neurology, and.
24
Departments of Epidemiology, Generation R Study Group, Erasmus Medical Center, 3000 CA, Rotterdam, The Netherlands;
25
Centre for Cognitive Ageing and Cognitive Epidemiology.
26
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden;
27
Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia;
28
School of Social and Community Medicine, University of Bristol, Bristol BS8 2PR, United Kingdom;
29
Psychology, Harvard University, Cambridge, MA 02138;
30
Centre for Cognitive Ageing and Cognitive Epidemiology, Centre for Genomic and Experimental Medicine and.
31
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;
32
Departments of Epidemiology, Internal Medicine.
33
Medical Research Institute, University of Dundee, Dundee DD2 4RB, United Kingdom;
34
Centre for Cognitive Ageing and Cognitive Epidemiology, Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom;
35
Departments of Epidemiology, Department of Child and Adolescent Psychiatry, Erasmus Medical Center, 3000 CB, Rotterdam, The Netherlands;
36
Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2PR, United Kingdom;
37
Medical Research Council Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom;
38
Department of Child and Adolescent Psychiatry, Erasmus Medical Center, 3000 CB, Rotterdam, The Netherlands;
39
Department of Economics, Stockholm School of Economics, 113 83 Stockholm, Sweden;
40
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;
41
Department of Economics, Cornell University, Ithaca, NY 14853; daniel.benjamin@gmail.com p.d.koellinger@uva.nl.
42
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.
43
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.

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.

PMID:
25201988
PMCID:
PMC4183313
DOI:
10.1073/pnas.1404623111
[Indexed for MEDLINE]
Free PMC Article

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