Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences
Open accessAbstract
Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated ([Formula: see text] ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.
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Other genes among the 34, including CADM2, ZIC4, GABRA2, NEGR1, and FURIN, have previously been identified in GWAS of behavioral or psychiatric traits.
“Other genes among the 34 have previously been identified in GWAS of behavioral or psychiatric traits: Cell Adhesion Molecule 2 (CADM2, previously identified in GWAS related to self-regulation, including drug use and risk tolerance17,33), Zic Family Member 4 (ZIC4, associated with brain volume34), Gamma-Aminobutyric Acid Type A Receptor Subunit Alpha 2 (GABRA2; the site of action for alcohol and”
From Multivariate analysis of 1.5 million people identifies genetic associations with traits related to self-regulation and addiction. (2021) · cites this paper as [17]
The Introduction and Results describe GWAS of risk tolerance and risky behaviors, but the passages in our copy do not identify CADM2 as an associated gene. Searches for CADM2, its full name, and the other named genes found no passage establishing the gene-specific claim; page numbers were unavailable. (LLM, conf=0.73)
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- Authors
- 23and Me Research Team, Karlsson Linnér, R., eQTLgen Consortium, International Cannabis Consortium, Social Science Genetic Association Consortium, Biroli, P., Kong, E., Meddens, S. F. W., Wedow, R., Fontana, M. A., Lebreton, M., Tino, S. P., Abdellaoui, A., Hammerschlag, A. R., Nivard, M. G., Okbay, A., Rietveld, C. A., Timshel, P. N., Trzaskowski, M., Vlaming, R. D., Zünd, C. L., Bao, Y., Buzdugan, L., Caplin, A. H., Chen, C.-Y., Eibich, P., Fontanillas, P., Gonzalez, J. R., Joshi, P. K., Karhunen, V., Kleinman, A., Levin, R. Z., Lill, C. M., Meddens, G. A., Muntané, G., Sanchez-Roige, S., Rooij, F. J. V., Taskesen, E., Wu, Y., Zhang, F., Auton, A., Boardman, J. D., Clark, D. W., Conlin, A., Dolan, C. C., Fischbacher, U., Groenen, P. J. F., Harris, K. M., Hasler, G., Hofman, A., Ikram, M. A., Jain, S., Karlsson, R., Kessler, R. C., Kooyman, M., MacKillop, J., Männikkö, M., Morcillo-Suarez, C., McQueen, M. B., Schmidt, K. M., Smart, M. C., Sutter, M., Thurik, A. R., Uitterlinden, A. G., White, J., Wit, H. D., Yang, J., Bertram, L., Boomsma, D. I., Esko, T., Fehr, E., Hinds, D. A., Johannesson, M., Kumari, M., Laibson, D., Magnusson, P. K. E., Meyer, M. N., Navarro, A., Palmer, A. A., Pers, T. H., Posthuma, D., Schunk, D., Stein, M. B., Svento, R., Tiemeier, H., Timmers, P. R. H. J., Turley, P., Ursano, R. J., Wagner, G. G., Wilson, J. F., Gratten, J., Lee, J. J., Cesarini, D., Benjamin, D. J., Koellinger, P. D., & Beauchamp, J. P.
- Affiliations
- University of Zurich (CH)
- Harvard University (US)
- Amsterdam Neuroscience (NL)
- Broad Institute (US)
- Hospital for Special Surgery (US)
- University of Amsterdam (NL)
- University of Toronto (CA)
- Vrije Universiteit Amsterdam (NL)
- Erasmus MC (NL)
- Statens Serum Institut (DK)
- The University of Queensland (AU)
- University of Essex (GB)
- German Institute for Economic Research (DE)
- 23andMe (United States) (US)
- University of Edinburgh (GB)
- University of Oulu (FI)
- University of California San Diego (US)
- University of Lübeck (DE)
- Universitat Pompeu Fabra (ES)
- University of Colorado Boulder (US)
- University of Konstanz (DE)
- Erasmus University Rotterdam (NL)
- University of North Carolina at Chapel Hill (US)
- University of Fribourg (CH)
- Karolinska Institutet (SE)
- SURFsara (Netherlands) (NL)
- Homewood Research Institute (CA)
- Ludwig-Maximilians-Universität München (DE)
- University of Cologne (DE)
- University College London (GB)
- University of Chicago (US)
- University of Oslo (NO)
- University of Tartu (EE)
- Stockholm School of Economics (SE)
- Geisinger Medical Center (US)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Johannes Gutenberg University Mainz (DE)
- Uniformed Services University of the Health Sciences (US)
- Western General Hospital (GB)
- Translational Research Institute (AU)
- University of Minnesota (US)
- New York University (US)
- University of Southern California (US)
- ORCID
- Karlsson Linnér, Richard
- Biroli, Pietro
- Kong, Edward
- Meddens, S. Fleur W.
- Wedow, Robbee
- Lebreton, Maël
- Abdellaoui, Abdel
- Hammerschlag, Anke R.
- Nivard, Michel G.
- Okbay, Aysu
- Rietveld, Cornelius A.
- Timshel, Pascal N.
- Trzaskowski, Maciej
- Vlaming, Ronald de
- Zünd, Christian L.
- Bao, Yanchun
- Caplin, Ann H.
- Chen, Chia-Yen
- Eibich, Peter
- Fontanillas, Pierre
- Joshi, Peter K.
- Karhunen, Ville
- Lill, Christina M.
- Muntané, Gerard
- Taskesen, Erdogan
- Wu, Yang
- Zhang, Futao
- Auton, Adam
- Clark, David W.
- Conlin, Andrew
- Fischbacher, Urs
- Groenen, Patrick J. F.
- Harris, Kathleen Mullan
- Hasler, Gregor
- Ikram, Mohammad A.
- Jain, Sonia
- Karlsson, Robert
- Kessler, Ronald C.
- Kooyman, Maarten
- MacKillop, James
- Männikkö, Minna
- McQueen, Matthew B.
- Schmidt, Klaus M.
- Smart, Melissa C.
- Sutter, Matthias
- Thurik, A. Roy
- Uitterlinden, André G.
- White, Jon
- Wit, Harriet de
- Yang, Jian
- Bertram, Lars
- Boomsma, Dorret I.
- Esko, Tõnu
- Fehr, Ernst
- Hinds, David A.
- Johannesson, Magnus
- Laibson, David
- Magnusson, Patrik K. E.
- Meyer, Michelle N.
- Navarro, Arcadi
- Palmer, Abraham A.
- Pers, Tune H.
- Posthuma, Danielle
- Schunk, Daniel
- Stein, Murray B.
- Svento, Rauli
- Tiemeier, Henning
- Timmers, Paul R. H. J.
- Turley, Patrick
- Ursano, Robert J.
- Wagner, Gert G.
- Wilson, James F.
- Gratten, Jacob
- Lee, James J.
- Cesarini, David
- Benjamin, Daniel J.
- Koellinger, Philipp D.
- Beauchamp, Jonathan P.
- Venue
- Nature Genetics
- Published
- 2019-01-14
- Volume
- 51
- Issue
- 2
- Pages
- 245-257
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC6713272
- OpenAlex
- W2909486692
- Cited by
- 756
- References
- 56
- Citations by year
- 2026: 45 · 2025: 97 · 2024: 122 · 2023: 100 · 2022: 106 · 2021: 127 · 2020: 127 · 2019: 31 · 2018: 1
- FWCI
- 12.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
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- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Open Access at Essex (University of Essex) (acceptedVersion)
- IRIS (submittedVersion, cc-by)
- KOPS (University of Konstanz) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
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- RePEc: Research Papers in Economics (submittedVersion)
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- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- QUT ePrints (Queensland University of Technology) (submittedVersion)
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- Figshare (submittedVersion)
- UnissResearch (Università degli Studi di Sassari) (submittedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Leicester Research Archive (University of Leicester) (submittedVersion, other-oa)
- Site cant be reached (submittedVersion, other-oa)
- Publikationen an der Universität Bielefeld (Universität Bielefeld) (submittedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion)
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- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion)
- OPUS (Augsburg University) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion)
- NOVA (University of Newcastle Australia) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- WOS
- Funders
- Sanofi
- University of Southern California
- Genome Canada (OGI-152)
- Wellcome Trust (208806/Z/17/Z, 213422/Z/18/Z)
- Ontario Genomics
- Open Philanthropy Project
- Government of Canada
- Ontario Genomics Institute
- Cancer Research UK (10119)
- National Institute for Health and Care Research (NF-SI-0507-10228, NF-SI-0514-10027, NIHR-RP-R3-12-013)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (016.Veni.198.058)
- Lundbeckfonden (R190 2014-3904)
- Vetenskapsrådet (421-2013-1061)
- Novo Nordisk Fonden (NNF16OC0021496)
- National Institutes of Health (AG042568)
- Social Sciences and Humanities Research Council of Canada (11425)
- Medical Research Council (1811434, 1805084, MR/N01104X/1, MR/K026992/1, MR/N01104X/2, MC_UU_00007/10)
- Biotechnology and Biological Sciences Research Council (BB/F022441/1, BB/F019394/1)
- Economic and Social Research Council (ES/N00812X/1, ES/M008592/1, ES/S008349/1)
- National Institute on Aging (R01AG017917, R01AG015819, P30AG010161, T32AG000186, R56AG042568, AG005842, R01AG042568, R01AG033678, P01AG005842, P30AG012810)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P2CHD066613, R03HD097630, P01HD031921)
- H2020 European Research Council (647648)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- risk tolerance, adventurousness, risk-taking, genetic loci, shared genetic influences, genetic correlation, driving risk, alcohol consumption, smoking, sexual behavior, brain gene expression, glutamatergic neurotransmission, GABAergic neurotransmission, personality genetics
- MeSH terms
- Behavior, Female, Genetics, Behavioral, Genotype, Humans, Male, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Loci
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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