Genetic architecture of the personality meta-traits - stability and plasticity - and their transdiagnostic overlap with psychopathology.

BACKGROUND

The Five Factor Model (FFM) personality meta-traits, stability and plasticity, are thought to capture broad individual differences in the parameters of goal-directed, cybernetic mechanisms in the brain, which have implications for transdiagnostic psychopathology risk. It remains unknown whether these meta-traits represent genetically coherent dimensions. Here we conduct a genomic investigation into the FFM meta-traits and characterize their association with 11 psychiatric conditions.

METHODS

We combined recent genome-wide association study (GWAS) summary statistics with data from the 23andMe Research Institute (European ancestry; total N = 279,240-682,707) and applied Genomic Structural Equation Modelling to conduct a multivariate GWAS of the FFM meta-traits. We then conducted transcriptome-wide association studies (TWAS) and stratified linkage disequilibrium score regression (S-LDSC) to prioritize candidate effector genes and brain cell types for personality traits. Finally, we used LDSC regression and CAUSE Mendelian randomization to characterize the relationship between personality traits and 11 psychiatric conditions.

RESULTS

We identified 83 (14 novel) and 13 (4 novel) independent genome-wide significant loci for stability and plasticity respectively. TWAS prioritized hundreds of candidate effector genes for personality, and S-LDSC showed heritability enrichment across several neuronal cell types. Finally, genetic correlation and Mendelian randomization analyses provided genetic evidence suggesting bidirectional links between stability and psychopathology: higher genetic propensity for stability was protective against psychopathology, whereas greater genetic liability to psychopathology was associated with reduced stability.

CONCLUSIONS

The personality meta-traits capture modest shared architecture across personality, with genetic liability for lower stability potentially representing a broad transdiagnostic link between personality and psychiatric vulnerability.