Polygenic contributions to performance on the Balloon Analogue Risk Task

doi:10.1038/s41380-023-02123-x

. 2023 Aug;28(8):3524-3530.

doi: 10.1038/s41380-023-02123-x. Epub 2023 Aug 15.

Polygenic contributions to performance on the Balloon Analogue Risk Task

E L Nurmi¹, C P Laughlin², H de Wit³, A A Palmer^{4

5}, J MacKillop⁶, T D Cannon⁷, R M Bilder², E Congdon², F W Sabb⁸, L C Seaman², J J McElroy², M R Libowitz⁹, J Weafer¹⁰, J Gray¹¹, A C Dean², G S Hellemann¹², E D London^{2

13}

Affiliations

¹ Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Los Angeles, CA, 90024, USA. enurmi@g.ucla.edu.
² Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Los Angeles, CA, 90024, USA.
³ Department of Psychiatry, University of Chicago, Chicago, IL, 60637, USA.
⁴ Department of Psychiatry, University of California at San Diego, La Jolla, CA, 92093, USA.
⁵ Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
⁶ Peter Boris Centre for Addictions Research, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, ON, L8S4L8, Canada.
⁷ Departments of Psychology and Psychiatry, Yale University, New Haven, CT, 06520, USA.
⁸ Prevention Science Institute, University of Utah, Salt Lake City, UT, 84112, USA.
⁹ Department of Neurobiology, University of Kentucky, Lexington, KY, 40506, USA.
¹⁰ Department of Psychology, University of Kentucky, Lexington, KY, 40506, USA.
¹¹ Department of Psychology, University of Georgia, Athens, GA, 30602, USA.
¹² Department of Public Health, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
¹³ Department of Molecular and Medical Pharmacology, University of California at Los Angeles, Los Angeles, CA, 90024, USA.

PMID: 37582857
PMCID: PMC10618088
DOI: 10.1038/s41380-023-02123-x

Polygenic contributions to performance on the Balloon Analogue Risk Task

E L Nurmi et al. Mol Psychiatry. 2023 Aug.

. 2023 Aug;28(8):3524-3530.

doi: 10.1038/s41380-023-02123-x. Epub 2023 Aug 15.

Authors

Affiliations

¹ Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Los Angeles, CA, 90024, USA. enurmi@g.ucla.edu.
² Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Los Angeles, CA, 90024, USA.
³ Department of Psychiatry, University of Chicago, Chicago, IL, 60637, USA.
⁴ Department of Psychiatry, University of California at San Diego, La Jolla, CA, 92093, USA.
⁵ Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
⁶ Peter Boris Centre for Addictions Research, McMaster University and St. Joseph's Healthcare Hamilton, Hamilton, ON, L8S4L8, Canada.
⁷ Departments of Psychology and Psychiatry, Yale University, New Haven, CT, 06520, USA.
⁸ Prevention Science Institute, University of Utah, Salt Lake City, UT, 84112, USA.
⁹ Department of Neurobiology, University of Kentucky, Lexington, KY, 40506, USA.
¹⁰ Department of Psychology, University of Kentucky, Lexington, KY, 40506, USA.
¹¹ Department of Psychology, University of Georgia, Athens, GA, 30602, USA.
¹² Department of Public Health, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
¹³ Department of Molecular and Medical Pharmacology, University of California at Los Angeles, Los Angeles, CA, 90024, USA.

PMID: 37582857
PMCID: PMC10618088
DOI: 10.1038/s41380-023-02123-x

Abstract

Risky decision-making is a common, heritable endophenotype seen across many psychiatric disorders. Its underlying genetic architecture is incompletely explored. We examined behavior in the Balloon Analogue Risk Task (BART), which tests risky decision-making, in two independent samples of European ancestry. One sample (n = 1138) comprised healthy participants and some psychiatric patients (53 schizophrenia, 42 bipolar disorder, 47 ADHD); the other (n = 911) excluded for recent treatment of various psychiatric disorders but not ADHD. Participants provided DNA and performed the BART, indexed by mean adjusted pumps. We constructed a polygenic risk score (PRS) for discovery in each dataset and tested it in the other as replication. Subsequently, a genome-wide MEGA-analysis, combining both samples, tested genetic correlation with risk-taking self-report in the UK Biobank sample and psychiatric phenotypes characterized by risk-taking (ADHD, Bipolar Disorder, Alcohol Use Disorder, prior cannabis use) in the Psychiatric Genomics Consortium. The PRS for BART performance in one dataset predicted task performance in the replication sample (r = 0.13, p = 0.000012, pFDR = 0.000052), as did the reciprocal analysis (r = 0.09, p = 0.0083, pFDR=0.04). Excluding participants with psychiatric diagnoses produced similar results. The MEGA-GWAS identified a single SNP (rs12023073; p = 3.24 × 10^-8) near IGSF21, a protein involved in inhibitory brain synapses; replication samples are needed to validate this result. A PRS for self-reported cannabis use (p = 0.00047, pFDR = 0.0053), but not self-reported risk-taking or psychiatric disorder status, predicted behavior on the BART in our MEGA-GWAS sample. The findings reveal polygenic architecture of risky decision-making as measured by the BART and highlight its overlap with cannabis use.

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Conflict of interest statement

ELN is an unpaid member of the Tourette Association of America and Myriad Genetics Advisory Boards. JM is a principal in Beam Therapeutics, Inc. and a consultant to Clairvoyant Therapeutics, Inc. HdW. is a scientific advisor to Awakn Life Sciences and Gilgamesh Pharmaceutics, and on the Board of Directors of PharmAla Biotech.

Figures

**Fig. 1. Polygenic Risk for Risky Decision Making as Measured by BART Performance is Replicated Across Independent Samples.**
A PRS analysis using GOI as training and CNP as replication sample. B PRS analysis using CNP as training and GOI as replication sample. The optimal threshold (0.338 in A and 0.108 in B), determined by strongest PRS correlation with BART phenotype, is highlighted by the box along with correlation (r), p-value, and FDR corrected p-value. Horizontal line indicates nominal significance.

**Fig. 2. A GWAS Performed in the Combined GOI and CNP Samples Identifies One Locus Associated with BART Performance at the Genome-wide Significance Level.**
A Q-Q plot of expected vs. observed p-values for the MEGA-GWAS. B Manhattan plot of genome-wide association with risky decision-making as measured by BART performance. Upper line demarcates genome-wide significance. Lower line indicates Bonferroni correction significance threshold.

**Fig. 3**
PRS Analysis of Cannabis Dependence Versus BART Performance in the Combined GOI and CNP Samples Reveals Shared Genetic Risk. The optimal threshold (0.11), determined by strongest PRS correlation with BART phenotype, is highlighted by the box along with correlation (r), p-value, and FDR corrected p-value. Horizontal line indicates nominal significance.

See this image and copyright information in PMC

References

1. Aklin WM, Lejuez CW, Zvolensky MJ, Kahler CW, Gwadz M. Evaluation of behavioral measures of risk taking propensity with inner city adolescents. Behav Res Ther. 2005;43:215–28. doi: 10.1016/j.brat.2003.12.007. - DOI - PubMed
1. Hidiroglu C, Demirci Esen O, Tunca Z, Neslihan Gurz Yalcin S, Lombardo L, Glahn DC, et al. Can risk-taking be an endophenotype for bipolar disorder? A study on patients with bipolar disorder type I and their first-degree relatives. J Int Neuropsychol Soc. 2013;19:474–82. doi: 10.1017/S1355617713000015. - DOI - PMC - PubMed
1. Lejuez CW, Read JP, Kahler CW, Richards JB, Ramsey SE, Stuart GL, et al. Evaluation of a behavioral measure of risk taking: the Balloon Analogue Risk Task (BART) J Exp Psychol Appl. 2002;8:75–84. doi: 10.1037/1076-898X.8.2.75. - DOI - PubMed
1. Lejuez CW, Aklin WM, Jones HA, Richards JB, Strong DR, Kahler CW, et al. The Balloon Analogue Risk Task (BART) differentiates smokers and nonsmokers. Exp Clin Psychopharmacol. 2003;11:26–33. doi: 10.1037/1064-1297.11.1.26. - DOI - PubMed
1. Reddy LF, Lee J, Davis MC, Altshuler L, Glahn DC, Miklowitz DJ, et al. Impulsivity and risk taking in bipolar disorder and schizophrenia. Neuropsychopharmacology. 2014;39:456–63. doi: 10.1038/npp.2013.218. - DOI - PMC - PubMed

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[1] Aklin WM, Lejuez CW, Zvolensky MJ, Kahler CW, Gwadz M. Evaluation of behavioral measures of risk taking propensity with inner city adolescents. Behav Res Ther. 2005;43:215–28. doi: 10.1016/j.brat.2003.12.007. - DOI - PubMed

[2] Aklin WM, Lejuez CW, Zvolensky MJ, Kahler CW, Gwadz M. Evaluation of behavioral measures of risk taking propensity with inner city adolescents. Behav Res Ther. 2005;43:215–28. doi: 10.1016/j.brat.2003.12.007. - DOI - PubMed

[3] Hidiroglu C, Demirci Esen O, Tunca Z, Neslihan Gurz Yalcin S, Lombardo L, Glahn DC, et al. Can risk-taking be an endophenotype for bipolar disorder? A study on patients with bipolar disorder type I and their first-degree relatives. J Int Neuropsychol Soc. 2013;19:474–82. doi: 10.1017/S1355617713000015. - DOI - PMC - PubMed

[4] Hidiroglu C, Demirci Esen O, Tunca Z, Neslihan Gurz Yalcin S, Lombardo L, Glahn DC, et al. Can risk-taking be an endophenotype for bipolar disorder? A study on patients with bipolar disorder type I and their first-degree relatives. J Int Neuropsychol Soc. 2013;19:474–82. doi: 10.1017/S1355617713000015. - DOI - PMC - PubMed

[5] Lejuez CW, Read JP, Kahler CW, Richards JB, Ramsey SE, Stuart GL, et al. Evaluation of a behavioral measure of risk taking: the Balloon Analogue Risk Task (BART) J Exp Psychol Appl. 2002;8:75–84. doi: 10.1037/1076-898X.8.2.75. - DOI - PubMed

[6] Lejuez CW, Read JP, Kahler CW, Richards JB, Ramsey SE, Stuart GL, et al. Evaluation of a behavioral measure of risk taking: the Balloon Analogue Risk Task (BART) J Exp Psychol Appl. 2002;8:75–84. doi: 10.1037/1076-898X.8.2.75. - DOI - PubMed

[7] Lejuez CW, Aklin WM, Jones HA, Richards JB, Strong DR, Kahler CW, et al. The Balloon Analogue Risk Task (BART) differentiates smokers and nonsmokers. Exp Clin Psychopharmacol. 2003;11:26–33. doi: 10.1037/1064-1297.11.1.26. - DOI - PubMed

[8] Lejuez CW, Aklin WM, Jones HA, Richards JB, Strong DR, Kahler CW, et al. The Balloon Analogue Risk Task (BART) differentiates smokers and nonsmokers. Exp Clin Psychopharmacol. 2003;11:26–33. doi: 10.1037/1064-1297.11.1.26. - DOI - PubMed

[9] Reddy LF, Lee J, Davis MC, Altshuler L, Glahn DC, Miklowitz DJ, et al. Impulsivity and risk taking in bipolar disorder and schizophrenia. Neuropsychopharmacology. 2014;39:456–63. doi: 10.1038/npp.2013.218. - DOI - PMC - PubMed

[10] Reddy LF, Lee J, Davis MC, Altshuler L, Glahn DC, Miklowitz DJ, et al. Impulsivity and risk taking in bipolar disorder and schizophrenia. Neuropsychopharmacology. 2014;39:456–63. doi: 10.1038/npp.2013.218. - DOI - PMC - PubMed

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Polygenic contributions to performance on the Balloon Analogue Risk Task

Affiliations

Polygenic contributions to performance on the Balloon Analogue Risk Task

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Abstract

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