In a recent study published in the journal Nature Human Behaviorresearchers from the United States of America conducted a genome-wide association study (GWAS) on personality traits to identify significant genetic loci and explore potential genetic associations 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 new loci overall. They identified new loci for other personality traits, revealing complex genetic influences on personality and its relationship to psychiatric conditions such as depression and anxiety.
The y-axis is the genetic correlation. Error bars (in black) indicate the 95% CI of the estimated genetic association. Anxiety refers to substances taken for anxiety. medication is prescribed for at least 2 weeks. Heavy DIY activities describe types of physical activity over the past 4 weeks. for example, weeding, lawn mowing, carpentry and digging. Manic behavior describes manic/hyperbehavior for 2 days. Study: A genome-wide survey of the underlying genetic architecture of personality traits and the overlap with psychopathology
Background
Evidence shows that the “big five” personality traits, including extraversion (how energetic, sociable, and friendly someone is), neuroticism (tendency toward negative emotions), agreeableness (ability to be likable and helpful), conscientiousness, and transparency, affect behavior and susceptibility to psychiatric disorders. Genetic studies have shown that neuroticism is closely related 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 common genetic loci found between the two. Over the past 15 years, GWAS have 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 associated with extraversion, enhancing 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 new genetic loci, investigating their role in the broader genetic architecture, and understanding the interplay between these traits and other complex human behaviors.
About the study
The study used 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 analyzes 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 meta-analysis of transgenic ancestry, which identified 216 genome-wide significant loci for neuroticism, including 16 new loci, further highlighting the complexity of genetic influences on this trait. Single nucleotide polymorphism (SNP) heritability was estimated using linkage disequilibrium score (LDSC) regression. Further, transcriptome-wide (TWAS) and proteome-wide (PWAS) association studies were used to identify genes associated with personality traits, followed by pathway, drug perturbation, and fine-mapping analyses. Mendelian randomization (MR) was used to investigate 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 interaction between these traits and psychiatric conditions. Finally, the 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 conscientiousness had three loci near SOX7 and PINX1. Two significant loci for compromise were found in the AFR sample, but no significant genome-wide (GWS) variation was found for the other traits.
The neuroticism meta-analysis identified 208 GWS loci, with 79 new loci not found in previous studies and 62 new loci overall. Significant loci included NSF, KANSL1 and CRHR1, mainly on chromosomes 1 and 11. Outcrossing analysis revealed 14 significant loci, most notably on chromosome 12 near WSCD2. Chromosome 11 showed associations with neuroticism, extroversion, and agreeableness, with overlapping findings near ARNTL1. Full geographic location details are provided in supplementary tables and figures.
A meta-analysis of later ancestry combining EUR and AFR data identified 216 GWS loci for neuroticism, including 16 new ones, and discovered additional loci for agreeableness and conscientiousness. TWAS found significant gene associations with traits such as neuroticism and extraversion in various brain and blood tissues, highlighting genes such as CRHR1 and KANSL1-AS1. PWAS linked 47 proteins to neuroticism, with many showing localization signals. Neuroticism also showed the highest heritability among the traits studied and revealed a significant genetic overlap with anxiety. Local genetic association analysis found varied associations between traits, with the highest overlap between neuroticism and extraversion.
Fine-mapping the variant identified 166 unique genetic variants associated with these traits, with neuroticism having the most of them. The study also found significant associations between personality traits and psychiatric disorders, particularly between neuroticism and depression/anxiety. Drug disruption analysis suggested potential treatments for neuroticism based on related genes, with some overlap with depression drugs. MRI analysis indicated bidirectional causal effects between neuroticism and depression/anxiety, with stronger effects from neuroticism to anxiety. Finally, polygenic risk score prediction showed moderate accuracy in predicting personality traits.
Conclusion
In conclusion, the study improves our understanding of the genetic basis of personality traits and their relationship to mental health. He identified new genetic correlates of personality traits while investigating their complex interactions with conditions such as depression and anxiety. Future studies could compare samples with deep phenotypic data to MVP data and build on this research to increase accuracy in terms of agreement, conscientiousness, openness, and extraversion.
