In a recent study published in the journal Nature Human Behaviour, researchers from the United States of America conducted a genome-wide association study (GWAS) on personality traits to identify significant genetic loci and explore the potential genetic correlations between personality traits and psychiatric disorders. They identified 208 genome-wide significant loci for neuroticism, including 79 new loci not found in previous studies and 62 novel loci overall. They identified novel loci for other personality traits, revealing complex genetic influences on personality and its relationship to psychiatric conditions like depression and anxiety.
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. Study: A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology
Background
Evidence suggests that the “big five” personality traits, including extraversion (how energetic, sociable, and friendly one is), neuroticism (tendency towards negative feelings), agreeableness (ability to be empathetic and helpful), conscientiousness, and openness, influence behavior and susceptibility to psychiatric disorders. Genetic studies have shown that neuroticism is strongly linked to depression and anxiety, and a significant fraction of the genetic risk for depression is associated with this trait. Schizophrenia is also linked to neuroticism, with shared genetic loci identified between the two. Over the past 15 years, GWAS has helped identify specific genetic variants associated with these traits, particularly neuroticism, where hundreds of loci have been discovered. Recent studies with larger sample sizes have revealed additional genetic loci related to extraversion, furthering our understanding of the genetic architecture underlying these personality dimensions.
In the present study, researchers conducted GWAS and meta-analyses on these five personality traits to explore genetic heritability, biological pathways, and potential causal relationships with depression and anxiety. The study placed significant emphasis on identifying novel genetic loci, exploring their role in the broader genetic architecture, and understanding the interplay between these traits and other complex human behaviors.
About the study
The study utilized data from the Million Veteran Program (MVP) to conduct GWAS on the “big five” personality traits, analyzing a sample of ~224,000 individuals. Data were imputed using the 1,000 Genomes and African Genome Resources panels, and analyses were stratified by European (EUR) and African (AFR) ancestry. Meta-analyses combined MVP data with other datasets, increasing sample sizes up to ~682,000 for neuroticism. The study also conducted a trans-ancestry meta-analysis, which identified 216 genome-wide significant loci for neuroticism, including 16 novel loci, further underscoring the complexity of the genetic influences on this trait. Single nucleotide polymorphism (SNP) heritability was estimated using linkage disequilibrium score regression (LDSC). Further, transcriptome-wide (TWAS) and proteome-wide (PWAS) association studies were used to identify genes linked to personality traits, followed by pathway, drug perturbation, and fine-mapping analyses. Mendelian randomization (MR) was employed to explore causal relationships between personality traits, depression, and anxiety. This analysis showed a bidirectional causal relationship, with stronger effects from neuroticism to anxiety, highlighting the significant interplay between these traits and psychiatric conditions. Finally, polygenic risk scores were validated using an independent cohort from Yale–Penn.
Results and discussion
In the EUR sample, 34 significant loci were identified across the five personality traits, with the highest numbers for extraversion and neuroticism (11 each). Notable loci included MAD1L1 and CRHR1 for neuroticism and CRHR1 and MAPT for extraversion. Conscientiousness had two loci near FOXP2 and ZNF704, openness had seven loci, including BRMS1 and RIN1, and agreeableness had three loci near SOX7 and PINX1. Two significant loci for agreeableness were found in the AFR sample, but no genome-wide significant (GWS) variants were found for the other traits.
The meta-analysis for neuroticism identified 208 GWS loci, with 79 new loci not found in previous studies and 62 novel loci overall. Significant loci included NSF, KANSL1, and CRHR1, mainly on chromosomes 1 and 11. Extraversion analysis revealed 14 significant loci, with the most notable being chromosome 12 near WSCD2. Chromosome 11 showed associations with neuroticism, extraversion, and agreeableness, with overlapping findings near ARNTL1. Complete locus details are provided in supplementary tables and figures.
A trans-ancestry meta-analysis combining EUR and AFR data identified 216 GWS loci for neuroticism, including 16 novel ones, and discovered additional loci for agreeableness and conscientiousness. TWAS found significant gene associations with traits like neuroticism and extraversion across various brain and blood tissues, highlighting genes such as CRHR1 and KANSL1-AS1. PWAS linked 47 proteins to neuroticism, with many showing colocalization signals. Neuroticism also showed the highest heritability among the traits studied and revealed a substantial genetic overlap with anxiety. Local genetic correlation analysis found varying correlations among traits, with the highest overlap between neuroticism and extraversion.
Variant fine-mapping identified 166 unique genetic variants related to these traits, with neuroticism having most of these. The study also found significant associations between personality traits and psychiatric disorders, especially between neuroticism and depression/anxiety. Drug perturbation analysis suggested potential treatments for neuroticism based on associated genes, with some overlap with depression drugs. MR analysis showed bidirectional causal effects between neuroticism and depression/anxiety, with stronger effects from neuroticism to anxiety. Finally, polygenic risk score prediction showed modest accuracy in predicting personality traits.
Conclusion
In conclusion, the study improves our understanding of the genetic basis of personality traits and their links to mental health. It identified new genetic associations for personality traits while exploring their complex interactions with conditions including depression and anxiety. Future studies could compare deeply phenotyped samples with MVP data and build on this research to increase the precision for agreeableness, conscientiousness, openness, and extraversion.
Journal reference:
- A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology. Gupta, P. et al., Nature Human Behaviour (2024), DOI: 10.1038/s41562-024-01951-3, https://www.nature.com/articles/s41562-024-01951-3