Common genetic variants associated with cognitive performance identified using the proxy-phenotype method
Open accessAbstract
Significance: We identify several common genetic variants associated with cognitive performance using a two-stage approach: we conduct a genome-wide association study of educational attainment to generate a set of candidates, and then we estimate the association of these variants with cognitive performance. In older Americans, we find that these variants are jointly associated with cognitive health. Bioinformatics analyses implicate a set of genes that is associated with a particular neurotransmitter pathway involved in synaptic plasticity, the main cellular mechanism for learning and memory. In addition to the substantive contribution, this work also serves to show a proxy-phenotype approach to discovering common genetic variants that is likely to be useful for many phenotypes of interest to social scientists (such as personality traits).
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Loci reaching GWAS and nominal significance and SNPs in LD with them at D' ≥ 0.8 show predominant associations with traits such as cognitive decline, educational attainment, mean bone density, intelligence and performance intelligence quotient, and soluble TREM-2 levels.
“Analysis of loci that reach GWAS and nominal significance and SNPs in LD with them at D’ ≥ 0.8 reveals predominant associations with traits such as cognitive decline [12, 68, 69], educational attainment [70–73], mean bone density [57, 74], intelligence and performance intelligence quotient [75, 76] and soluble TREM-2 levels [77].”
From Genetic drivers of progression in Alzheimer’s disease are distinct from disease risk (2026) · cites this paper as [70]
The indexed Abstract reports a GWAS of educational attainment that identified 69 education-associated SNPs, supporting the educational-attainment association cited here. It does not establish that the citing paper’s selected loci—or SNPs in linkage disequilibrium with them at D’ ≥ 0.8—are among those associations. The other listed traits have separate citations and are not attributed to this source. (LLM, conf=0.82)
Experimental — accuracy not yet measuredGene Ontology sets for molecular function revealed no significant sets after Bonferroni correction for multiple testing.
“analysis of Gene Ontology sets 81,82 for molecular function from MsigDB 83 revealed no significant sets after Bonferroni correction for multiple testing”
From Identification of common genetic risk variants for autism spectrum disorder (2019) · cites this paper as [81]
The supplied passages contain bibliographic information, not findings about gene-set analysis. Searches of our copy for Gene Ontology molecular-function sets, MsigDB, and Bonferroni correction found no passage addressing whether any sets were significant. (LLM, conf=0.70)
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- Authors
- 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., Derringer, J., van Duijn, C. M., Fehrmann, R., Franke, L., Glaeser, E. L., Hansell, N. K., Hayward, C., Iacono, W. G., Ibrahim-Verbaas, C., Jaddoe, V., Karjalainen, J., Laibson, D., Lichtenstein, P., Liewald, D. C., Magnusson, P. K. E., Martin, N. G., McGue, M., McMahon, G., Pedersen, N. L., Pinker, S., Porteous, D. J., Posthuma, D., Rivadeneira, F., Smith, B. H., Starr, J. M., Tiemeier, H., Timpson, N. J., Trzaskowski, M., Uitterlinden, A. G., Verhulst, F. C., Ward, M. E., Wright, M. J., Davey Smith, G., Deary, I. J., Johannesson, M., Plomin, R., Visscher, P. M., Benjamin, D. J., Cesarini, D., & Koellinger, P. D.
- Affiliations
- Erasmus University Rotterdam (NL)
- Broad Institute (US)
- Centre for Cognitive Ageing and Cognitive Epidemiology,
- Departments of iEconomics and
- The University of Queensland (AU)
- Union College (US)
- University of Iceland (IS)
- National Heart, Lung, and Blood Institute (US)
- University of Minnesota (US)
- Radboud University Nijmegen (NL)
- QIMR Berghofer Medical Research Institute (AU)
- Harvard University (US)
- Genetic Epidemiology Unit, Department of Epidemiology and Biostatistics, and
- Department of Sociology and
- University of Illinois Urbana-Champaign (US)
- University Medical Center Groningen (NL)
- Institute of Genetics and Cancer (GB)
- Neurology, and
- Erasmus MC (NL)
- Karolinska Institutet (SE)
- University of Bristol (GB)
- Department of Complex Trait Genetics, VU University Amsterdam and VU Medical Center, 1081 HV, Amsterdam, The Netherlands;
- Departments of bEpidemiology,
- University of Dundee (GB)
- Alzheimer Scotland (GB)
- King's College London (GB)
- Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2PR, United Kingdom;
- Stockholm School of Economics (SE)
- Cornell University (US)
- New York University (US)
- University of Amsterdam (NL)
- ORCID
- Rietveld, Cornelius A.
- Esko, Tõnu
- Davies, Gail
- Pers, Tune H.
- Turley, Patrick
- Benyamin, Beben
- Emilsson, Valur
- Johnson, Andrew D.
- Lee, James J.
- Leeuw, Christiaan de
- Marioni, Riccardo E.
- Medland, Sarah E.
- Vinkhuyzen, Anna A. E.
- Amin, Najaf
- Conley, Dalton
- Derringer, Jaime
- Fehrmann, Rudolf
- Franke, Lude
- Glaeser, Edward L.
- Hansell, Narelle K.
- Hayward, Caroline
- Iacono, William G.
- Jaddoe, Vincent
- Karjalainen, Juha
- Laibson, David
- Lichtenstein, Paul
- Liewald, David C.
- Magnusson, Patrik K. E.
- Martin, Nicholas G.
- McGue, Matt
- Pedersen, Nancy L.
- Pinker, Steven
- Porteous, David J.
- Rivadeneira, Fernando
- Smith, Blair H.
- Starr, John M.
- Tiemeier, Henning
- Timpson, Nicholas J.
- Trzaskowski, Maciej
- Uitterlinden, André G.
- Verhulst, Frank C.
- Wright, Margaret J.
- Deary, Ian J.
- Johannesson, Magnus
- Plomin, Robert
- Visscher, Peter M.
- Benjamin, Daniel J.
- Cesarini, David
- Koellinger, Philipp D.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-09-08
- Volume
- 111
- Issue
- 38
- Pages
- 13790-13794
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4183313
- OpenAlex
- W2128376310
- Cited by
- 258
- References
- 3
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 11 · 2023: 23 · 2022: 13 · 2021: 22 · 2020: 10 · 2019: 27 · 2018: 37 · 2017: 35 · 2016: 40 · 2015: 24 · 2014: 3
- FWCI
- 22.27
- Type
- journal article
- Language
- en
- Update notices
- correction (2015-01-08)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UvA-DARE (University of Amsterdam) (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
- VU Research Portal (publishedVersion)
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- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- UvA-DARE (University of Amsterdam) (submittedVersion)
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- Pure Amsterdam UMC (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- ERIM Top-Core Articles
- Funders
- National Science Foundation
- Wellcome Trust (102215)
- Vetenskapsrådet
- National Institutes of Health
- Medical Research Council (MR/K026992/1, MC_PC_15018)
- Biotechnology and Biological Sciences Research Council (BB/F019394/1)
- National Institute on Alcohol Abuse and Alcoholism (R37AA009367, R01AA011886)
- National Institute on Aging (T32AG000186, P01AG005842, P30AG012810)
- National Institute of Mental Health (R01MH066140, T32MH016880)
- National Institute on Drug Abuse (F31DA029377, R01DA013240, R01DA024417, R37DA005147)
- Office of Behavioral and Social Sciences Research
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R24HD047879)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Cognitive Abilities and Testing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Keywords
- cognitive performance, educational attainment, single nucleotide polymorphisms, polygenic risk score, memory, dementia, NRXN1, POU2F3, synaptic plasticity, neurotransmitter pathways, learning
- MeSH terms
- Calcium-Binding Proteins, Cognition, Female, Humans, Learning, Male, Memory, Nerve Tissue Proteins, Synaptic Transmission, Neuronal Plasticity, Cell Adhesion Molecules, Neuronal, Neural Cell Adhesion Molecules, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Octamer Transcription Factors
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