Genome-wide association study of delay discounting identifies 11 loci and reveals transdiagnostic associations across mental and physical health

Hayley H A Thorpe^#¹, Renata B Cupertino^#², Shreya Reddy Pakala^#², Pierre Fontanillas³, Mariela V Jennings², Jane Yang⁴, John J Meredith², Tiffany Greenwood², Sevim B Bianchi², Laura Vilar-Ribó², Maria Niarchou^{5

6}; 23andMe Research Team; Sarah L Elson³, Trey Ideker^{7

8

9

10}, Lea K Davis^{5

6

11

12

13

14

15

16}, James MacKillop^{17

18

19}, Harriet deWit²⁰, Daniel E Gustavson²¹, Travis T Mallard^{22

23}, Abraham A Palmer^{2

24}, Sandra Sanchez-Roige^{25

26

27}

Collaborators, Affiliations

Collaborators

23andMe Research Team:
Stella Aslibekyan, Adam Auton, Elizabeth Babalola, Robert K Bell, Jessica Bielenberg, Ninad S Chaudhary, Zayn Cochinwala, Sayantan Das, Emily DelloRusso, Payam Dibaeinia, Nicholas Eriksson, Chris Eijsbouts, Teresa Filshtein, Davide Foletti, Will Freyman, Zach Fuller, Julie M Granka, Chris German, Éadaoin Harney, Alejandro Hernandez, Barry Hicks, David A Hinds, M Reza Jabalameli, Ethan M Jewett, Yunxuan Jiang, Sotiris Karagounis, Lucy Kaufmann, Matt Kmiecik, Katelyn Kukar, Alan Kwong, Keng-Han Lin, Yanyu Liang, Bianca A Llamas, Aly Khan, Steven J Micheletti, Matthew H McIntyre, Meghan E Moreno, Priyanka Nandakumar, Dominique T Nguyen, Jared O'Connell, Steve Pitts, G David Poznik, Alexandra Reynoso, Shubham Saini, Morgan Schumacher, Leah Selcer, Anjali J Shastri, Jingchunzi Shi, Suyash Shringarpure, Keaton Stagaman, Teague Sterling, Qiaojuan Jane Su, Joyce Y Tung, Susana A Tat, Vinh Tran, Xin Wang, Wei Wang, Catherine H Weldon, Amy L Williams, Peter Wilton

Affiliations

¹ Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
² Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
³ 23andMe, Inc., Sunnyvale, CA, USA.
⁴ Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
⁵ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁶ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁷ Department of Medicine, University of California San Diego, La Jolla, CA, USA.
⁸ Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA.
⁹ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
¹⁰ Department of Bioengineering, University of California San Diego, La Jolla, CA, USA.
¹¹ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
¹² Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
¹³ Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁶ Associate Faculty, New York Genome Center, New York, NY, USA.
¹⁷ Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada.
¹⁸ Peter Boris Centre for Addictions Research, St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada.
¹⁹ Michael G DeGroote Centre for Medicinal Cannabis Research, McMaster University, Hamilton, ON, Canada.
²⁰ Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
²¹ Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
²² Center for Precision Psychiatry, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
²³ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
²⁴ Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
²⁵ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. sanchezroige@ucsd.edu.
²⁶ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. sanchezroige@ucsd.edu.
²⁷ Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA. sanchezroige@ucsd.edu.

^# Contributed equally.

PMID: 41286433
DOI: 10.1038/s41380-025-03356-8

Genome-wide association study of delay discounting identifies 11 loci and reveals transdiagnostic associations across mental and physical health

Hayley H A Thorpe et al. Mol Psychiatry. 2025.

. 2025 Nov 25.

doi: 10.1038/s41380-025-03356-8. Online ahead of print.

Authors

Collaborators

23andMe Research Team:
Stella Aslibekyan, Adam Auton, Elizabeth Babalola, Robert K Bell, Jessica Bielenberg, Ninad S Chaudhary, Zayn Cochinwala, Sayantan Das, Emily DelloRusso, Payam Dibaeinia, Nicholas Eriksson, Chris Eijsbouts, Teresa Filshtein, Davide Foletti, Will Freyman, Zach Fuller, Julie M Granka, Chris German, Éadaoin Harney, Alejandro Hernandez, Barry Hicks, David A Hinds, M Reza Jabalameli, Ethan M Jewett, Yunxuan Jiang, Sotiris Karagounis, Lucy Kaufmann, Matt Kmiecik, Katelyn Kukar, Alan Kwong, Keng-Han Lin, Yanyu Liang, Bianca A Llamas, Aly Khan, Steven J Micheletti, Matthew H McIntyre, Meghan E Moreno, Priyanka Nandakumar, Dominique T Nguyen, Jared O'Connell, Steve Pitts, G David Poznik, Alexandra Reynoso, Shubham Saini, Morgan Schumacher, Leah Selcer, Anjali J Shastri, Jingchunzi Shi, Suyash Shringarpure, Keaton Stagaman, Teague Sterling, Qiaojuan Jane Su, Joyce Y Tung, Susana A Tat, Vinh Tran, Xin Wang, Wei Wang, Catherine H Weldon, Amy L Williams, Peter Wilton

Affiliations

¹ Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
² Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
³ 23andMe, Inc., Sunnyvale, CA, USA.
⁴ Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
⁵ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁶ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁷ Department of Medicine, University of California San Diego, La Jolla, CA, USA.
⁸ Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA.
⁹ Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
¹⁰ Department of Bioengineering, University of California San Diego, La Jolla, CA, USA.
¹¹ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
¹² Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
¹³ Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁶ Associate Faculty, New York Genome Center, New York, NY, USA.
¹⁷ Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada.
¹⁸ Peter Boris Centre for Addictions Research, St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada.
¹⁹ Michael G DeGroote Centre for Medicinal Cannabis Research, McMaster University, Hamilton, ON, Canada.
²⁰ Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
²¹ Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
²² Center for Precision Psychiatry, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
²³ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
²⁴ Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
²⁵ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. sanchezroige@ucsd.edu.
²⁶ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. sanchezroige@ucsd.edu.
²⁷ Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA. sanchezroige@ucsd.edu.

^# Contributed equally.

PMID: 41286433
DOI: 10.1038/s41380-025-03356-8

Abstract

Delay discounting (DD), a person's preference for smaller immediate rewards over larger delayed rewards, is a heritable trait that is associated with psychiatric and physical outcomes, yet the biological mechanisms underlying these links are not known. We performed a GWAS of DD using 134,935 23andMe research participants and identified 11 genome-wide significant loci. We did not replicate our previously reported association with rs6528024 (chrXq13.3, GPM6B; P = 5.30 × 10^-02). The SNP-heritability of DD was 9.85 ± 0.57%. We observed genetic correlations between DD and 73 behavioral, physical, and neuroimaging traits, many of which persisted even after accounting for educational attainment, intelligence, and executive function. Network analysis revealed that the associations between DD and certain traits were explained by both overlapping and trait-specific biological processes. In a hospital-based cohort (N = 66,917), DD polygenic scores were associated with 212 medical conditions. These results demonstrate that DD has a pleiotropic and polygenic common variant architecture, and is genetically associated with numerous outcomes, making it a promising endophenotype for psychiatric and physical health.

PubMed Disclaimer

Conflict of interest statement

Competing interests: P.F., the 23andMe Research Team, and S.L.E. were employed by 23andMe, Inc. P.F. and S.L.E. hold stock or stock options in 23andMe, Inc. The remaining authors have nothing to disclose. Ethics statement: All methods were performed in accordance with the relevant guidelines and regulations. Participants provided informed consent and volunteered to participate in research online under a protocol approved by the external AAHRPP-accredited Institutional Review Board (IRB), Ethical & Independent (E&I) Review Services.

References

1. Kirby KN, Petry NM, Bickel WK. Heroin addicts have higher discount rates for delayed rewards than non-drug-using controls. J Exp Psychol Gen. 1999;128:78–87. - PubMed - DOI
1. Lempert KM, Steinglass JE, Pinto A, Kable JW, Simpson HB. Can delay discounting deliver on the promise of RDoC? Psychol Med. 2019;49:190–9. - PubMed - DOI
1. Peters J, Büchel C. The neural mechanisms of inter-temporal decision-making: understanding variability. Trends Cogn Sci. 2011;15:227–39. - PubMed - DOI
1. Caswell AJ, Bond R, Duka T, Morgan MJ. Further evidence of the heterogeneous nature of impulsivity. Pers Individ Dif. 2015;76:68–74. - PubMed - PMC - DOI
1. Madden GJ, Bickel WK. Impulsivity: The behavioral and neurological science of discounting. American Psychological Association; 2010. - DOI

Grants and funding

LinkOut - more resources

Full Text Sources
- Nature Publishing Group

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Genome-wide association study of delay discounting identifies 11 loci and reveals transdiagnostic associations across mental and physical health

Collaborators

Affiliations

Genome-wide association study of delay discounting identifies 11 loci and reveals transdiagnostic associations across mental and physical health

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources