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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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