A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology

doi:10.1038/s41562-024-01951-3

. 2024 Aug 12.

doi: 10.1038/s41562-024-01951-3. Online ahead of print.

A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology

Priya Gupta^{1

2}, Marco Galimberti^{1

2}, Yue Liu³, Sarah Beck^{1

2}, Aliza Wingo^{4

5}, Thomas Wingo³, Keyrun Adhikari^{1

2}, Henry R Kranzler^{6

7}; VA Million Veteran Program; Murray B Stein^{8

9}, Joel Gelernter^{1

2}, Daniel F Levey^{10

11}

Affiliations

¹ Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
² Department of Psychiatry, Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA.
³ Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
⁴ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
⁵ Atlanta Veterans Affairs Medical Center, Atlanta, GA, USA.
⁶ Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA.
⁷ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁸ Psychiatry Service, VA San Diego Healthcare System, San Diego, CA, USA.
⁹ Departments of Psychiatry, School of Medicine, and Herbert Wertheim School of Public Health, University of California San Diego, La Jolla, CA, USA.
¹⁰ Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. daniel.levey@yale.edu.
¹¹ Department of Psychiatry, Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA. daniel.levey@yale.edu.

PMID: 39134740
DOI: 10.1038/s41562-024-01951-3

A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology

Priya Gupta et al. Nat Hum Behav. 2024.

. 2024 Aug 12.

doi: 10.1038/s41562-024-01951-3. Online ahead of print.

Authors

Affiliations

¹ Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
² Department of Psychiatry, Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA.
³ Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
⁴ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
⁵ Atlanta Veterans Affairs Medical Center, Atlanta, GA, USA.
⁶ Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA.
⁷ Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁸ Psychiatry Service, VA San Diego Healthcare System, San Diego, CA, USA.
⁹ Departments of Psychiatry, School of Medicine, and Herbert Wertheim School of Public Health, University of California San Diego, La Jolla, CA, USA.
¹⁰ Division of Human Genetics, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. daniel.levey@yale.edu.
¹¹ Department of Psychiatry, Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA. daniel.levey@yale.edu.

PMID: 39134740
DOI: 10.1038/s41562-024-01951-3

Abstract

Personality is influenced by both genetic and environmental factors and is associated with other psychiatric traits such as anxiety and depression. The 'big five' personality traits, which include neuroticism, extraversion, agreeableness, conscientiousness and openness, are a widely accepted and influential framework for understanding and describing human personality. Of the big five personality traits, neuroticism has most often been the focus of genetic studies and is linked to various mental illnesses, including depression, anxiety and schizophrenia. Our knowledge of the genetic architecture of the other four personality traits is more limited. Here, utilizing the Million Veteran Program cohort, we conducted a genome-wide association study in individuals of European and African ancestry. Adding other published data, we performed genome-wide association study meta-analysis for each of the five personality traits with sample sizes ranging from 237,390 to 682,688. We identified 208, 14, 3, 2 and 7 independent genome-wide significant loci associated with neuroticism, extraversion, agreeableness, conscientiousness and openness, respectively. These findings represent 62 novel loci for neuroticism, as well as the first genome-wide significant loci discovered for agreeableness. Gene-based association testing revealed 254 genes showing significant association with at least one of the five personality traits. Transcriptome-wide and proteome-wide analysis identified altered expression of genes and proteins such as CRHR1, SLC12A5, MAPT and STX4. Pathway enrichment and drug perturbation analyses identified complex biology underlying human personality traits. We also studied the inter-relationship of personality traits with 1,437 other traits in a phenome-wide genetic correlation analysis, identifying new associations. Mendelian randomization showed positive bidirectional effects between neuroticism and depression and anxiety, while a negative bidirectional effect was observed for agreeableness and these psychiatric traits. This study improves our comprehensive understanding of the genetic architecture underlying personality traits and their relationship to other complex human traits.

PubMed Disclaimer

Update of

A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology.
Gupta P, Galimberti M, Liu Y, Beck S, Wingo A, Wingo T, Adhikari K; VA Million Veteran Program; Stein MB, Gelernter J, Levey DF. Gupta P, et al. medRxiv [Preprint]. 2024 Jan 17:2024.01.17.24301428. doi: 10.1101/2024.01.17.24301428. medRxiv. 2024. Update in: Nat Hum Behav. 2024 Aug 12. doi: 10.1038/s41562-024-01951-3. PMID: 38293137 Free PMC article. Updated. Preprint.

References

1. John, O. P. & Srivastava, S. in Handbook of Personality: Theory and Research (eds Pervin, L. A. and John, O. P.) (Guilford Press, 1999).
1. McCrae, R. R. & Costa, P. T. Personality in Adulthood: A Five-factor Theory Perspective (Guilford Press, 2003).
1. Kendler, K. S. & Myers, J. The genetic and environmental relationship between major depression and the five-factor model of personality. Psychol. Med. 40, 801–806 (2010). - PubMed - DOI
1. Hettema, J. M. et al. A population-based twin study of the relationship between neuroticism and internalizing disorders. Am. J. Psychiatry 163, 857–864 (2006). - PubMed - DOI
1. Hettema, J. M., Prescott, C. A. & Kendler, K. S. Genetic and environmental sources of covariation between generalized anxiety disorder and neuroticism. Am. J. Psychiatry 161, 1581–1587 (2004). - PubMed - DOI

Grants and funding

5IK2BX005058/Office of Research and Development (VHA Office of Research and Development)

LinkOut - more resources

Full Text Sources
- Nature Publishing Group

[1] John, O. P. & Srivastava, S. in Handbook of Personality: Theory and Research (eds Pervin, L. A. and John, O. P.) (Guilford Press, 1999).

[2] John, O. P. & Srivastava, S. in Handbook of Personality: Theory and Research (eds Pervin, L. A. and John, O. P.) (Guilford Press, 1999).

[3] McCrae, R. R. & Costa, P. T. Personality in Adulthood: A Five-factor Theory Perspective (Guilford Press, 2003).

[4] McCrae, R. R. & Costa, P. T. Personality in Adulthood: A Five-factor Theory Perspective (Guilford Press, 2003).

[5] Kendler, K. S. & Myers, J. The genetic and environmental relationship between major depression and the five-factor model of personality. Psychol. Med. 40, 801–806 (2010). - PubMed - DOI

[6] Kendler, K. S. & Myers, J. The genetic and environmental relationship between major depression and the five-factor model of personality. Psychol. Med. 40, 801–806 (2010). - PubMed - DOI

[7] Hettema, J. M. et al. A population-based twin study of the relationship between neuroticism and internalizing disorders. Am. J. Psychiatry 163, 857–864 (2006). - PubMed - DOI

[8] Hettema, J. M. et al. A population-based twin study of the relationship between neuroticism and internalizing disorders. Am. J. Psychiatry 163, 857–864 (2006). - PubMed - DOI

[9] Hettema, J. M., Prescott, C. A. & Kendler, K. S. Genetic and environmental sources of covariation between generalized anxiety disorder and neuroticism. Am. J. Psychiatry 161, 1581–1587 (2004). - PubMed - DOI

[10] Hettema, J. M., Prescott, C. A. & Kendler, K. S. Genetic and environmental sources of covariation between generalized anxiety disorder and neuroticism. Am. J. Psychiatry 161, 1581–1587 (2004). - PubMed - DOI

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

A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology

Affiliations

A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology

Authors

Affiliations

Abstract

Update of

Similar articles

References

Grants and funding

LinkOut - more resources

Full Text Sources

Abstract

Update of

Similar articles

References

Related information

Grants and funding

LinkOut - more resources

Full Text Sources