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

Author

Listed:
  • Priya Gupta

    (Yale University School of Medicine
    Veterans Affairs Connecticut Healthcare Center)

  • Marco Galimberti

    (Yale University School of Medicine
    Veterans Affairs Connecticut Healthcare Center)

  • Yue Liu

    (Emory University School of Medicine)

  • Sarah Beck

    (Yale University School of Medicine
    Veterans Affairs Connecticut Healthcare Center)

  • Aliza Wingo

    (Emory University School of Medicine
    Atlanta Veterans Affairs Medical Center)

  • Thomas Wingo

    (Emory University School of Medicine)

  • Keyrun Adhikari

    (Yale University School of Medicine
    Veterans Affairs Connecticut Healthcare Center)

  • Henry R. Kranzler

    (Crescenz Veterans Affairs Medical Center
    University of Pennsylvania Perelman School of Medicine)

  • Murray B. Stein

    (VA San Diego Healthcare System
    University of California San Diego)

  • Joel Gelernter

    (Yale University School of Medicine
    Veterans Affairs Connecticut Healthcare Center)

  • Daniel F. Levey

    (Yale University School of Medicine
    Veterans Affairs Connecticut Healthcare Center)

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.

Suggested Citation

  • Priya Gupta & Marco Galimberti & Yue Liu & Sarah Beck & Aliza Wingo & Thomas Wingo & Keyrun Adhikari & Henry R. Kranzler & Murray B. Stein & Joel Gelernter & Daniel F. Levey, 2024. "A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology," Nature Human Behaviour, Nature, vol. 8(11), pages 2235-2249, November.
    • Handle: RePEc:nat:nathum:v:8:y:2024:i:11:d:10.1038_s41562-024-01951-3
    DOI: 10.1038/s41562-024-01951-3
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    1. Claudia Giambartolomei & Damjan Vukcevic & Eric E Schadt & Lude Franke & Aroon D Hingorani & Chris Wallace & Vincent Plagnol, 2014. "Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics," PLOS Genetics, Public Library of Science, vol. 10(5), pages 1-15, May.
    2. Tian Ge & Chia-Yen Chen & Yang Ni & Yen-Chen Anne Feng & Jordan W. Smoller, 2019. "Polygenic prediction via Bayesian regression and continuous shrinkage priors," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    3. Christiaan A de Leeuw & Joris M Mooij & Tom Heskes & Danielle Posthuma, 2015. "MAGMA: Generalized Gene-Set Analysis of GWAS Data," PLOS Computational Biology, Public Library of Science, vol. 11(4), pages 1-19, April.
    4. Kyoko Watanabe & Erdogan Taskesen & Arjen Bochoven & Danielle Posthuma, 2017. "Functional mapping and annotation of genetic associations with FUMA," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    5. Zhihong Zhu & Zhili Zheng & Futao Zhang & Yang Wu & Maciej Trzaskowski & Robert Maier & Matthew R. Robinson & John J. McGrath & Peter M. Visscher & Naomi R. Wray & Jian Yang, 2018. "Causal associations between risk factors and common diseases inferred from GWAS summary data," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    6. Gao Wang & Abhishek Sarkar & Peter Carbonetto & Matthew Stephens, 2020. "A simple new approach to variable selection in regression, with application to genetic fine mapping," Journal of the Royal Statistical Society Series B, Royal Statistical Society, vol. 82(5), pages 1273-1300, December.
    7. Magnus Johannesson & David I. Laibson & Sarah E. Medland & Michelle N. Meyer & Joseph K. Pickrell & Tõnu Esko & Robert F. Krueger & Jonathan P. Beauchamp & Philipp D. Koellinger & Daniel J. Benjamin &, 2016. "Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses," Post-Print hal-02017373, HAL.
    8. Thomas S. Wingo & Yue Liu & Ekaterina S. Gerasimov & Selina M. Vattathil & Meghan E. Wynne & Jiaqi Liu & Adriana Lori & Victor Faundez & David A. Bennett & Nicholas T. Seyfried & Allan I. Levey & Aliz, 2022. "Shared mechanisms across the major psychiatric and neurodegenerative diseases," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    9. Joel Becker & Casper A. P. Burik & Grant Goldman & Nancy Wang & Hariharan Jayashankar & Michael Bennett & Daniel W. Belsky & Richard Karlsson Linnér & Rafael Ahlskog & Aaron Kleinman & David A. Hinds , 2021. "Resource profile and user guide of the Polygenic Index Repository," Nature Human Behaviour, Nature, vol. 5(12), pages 1744-1758, December.
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