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Meta-Analysis
. 2024 Nov;8(11):2235-2249.
doi: 10.1038/s41562-024-01951-3. Epub 2024 Aug 12.

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 Liu  3 , Sarah Beck  1   2 , Aliza Wingo  4   5 , Thomas Wingo  3 , 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
Meta-Analysis

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

Priya Gupta et al. Nat Hum Behav. 2024 Nov.

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.

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Conflict of interest statement

Competing interests H.R.K. is a member of advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, Clearmind Medicine and Enthion Pharmaceuticals; a consultant to Sobrera Pharmaceuticals; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; and a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the past 3 years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi and Otsuka. J.G. and H.R.K. are holders of US patent 10,900,082 titled: ‘Genotype-guided dosing of opioid agonists’, issued 26 January 2021. J.G. is paid for editorial work on the journal Complex Psychiatry. The remaining authors declare no competing interests. J.G. is named as an inventor on PCT patent application no. 15/878,640 entitled ‘Genotype-guided dosing of opioid agonists’, filed 24 January 2018, and issued on 26 January 2021, as US patent no. 10900082. M.B.S. has stock options in Oxeia Biopharmaceuticals and EpiVario. He has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor) and UpToDate (Co-Editor-in-Chief for Psychiatry). No other authors report competing interests.

Figures

Fig. 1
Fig. 1. Personality GWAS meta-analysis and genetic correlations among the five personality traits.
a, Data collection of the five personality traits. b, Genetic correlation matrix among the five personality traits (meta-data). The heritability value of the respective trait is written in parenthesis. c, A karyogram showing the regions with significant local genetic correlation (rG > 0.3) between different personality traits.
Fig. 2
Fig. 2. Meta-analysis data GWAS Manhattan plots of the five personality traits.
The GWS variants in light-green colour. Reported P values are two-sided and not corrected for multiple testing. GWS threshold (P = 5 × 10−8) is used to define significant variants and depicted by red line.
Fig. 3
Fig. 3. Transcriptome wide association study.
a, A bar chart showing the number of significant TWAS genes per transcripts found of four personality traits with significant findings in respective subtissues. Scatter plots of neuroticism (b), agreeableness (c), extraversion (d) and openness (e) with TWAS z-scores of each gene transcript plotted on the y axis and its respective chromosomal location plotted on the x axis. The significant hits are shown in red circles with mapped gene names as labels. The blue horizontal line indicates the significance threshold of the z-score corresponding to the Bonferroni-corrected, two-sided P value. Conscientiousness data is reported in Supplementary Table 22.
Fig. 4
Fig. 4. PWAS analysis.
A Manhattan plot is displayed showing the significant protein associations observed for neuroticism. The red line in the plot depicts the Bonferroni-corrected, two-sided P value threshold at 5% FDR. The boxes on the right show the significant proteins found for the respective four personality traits.
Fig. 5
Fig. 5. Bar chart with SNP-based genetic correlation of each of the five personality traits with a different psychological disorder/trait or different behaviours plotted.
The y axis is the genetic correlation. Error bars (in black) indicate the 95% CIs of the estimated genetic correlation. Anxiety indicates substances taken for anxiety; medication is prescribed for at least 2 weeks. Heavy DIY activities describes the types of physical activity in last 4 weeks; for example, weeding, lawn mowing, carpentry and digging. Manic behaviour describes manic/hyper behaviour for 2 days. Detailed results for all traits, including the sample size of each of the traits, is presented in the Supplementary Tables 16–20.
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