Multi-tissue probabilistic fine-mapping of transcriptome-wide association study identifies cis-regulated genes for miserableness

Abstract

Miserableness is a behavioural trait that is characterized by strong negative feelings in an individual. Although environmental factors tend to invoke miserableness, it is common to feel miserable for no reason, suggesting an innate, potential genetic component. Currently, little is known about the functional relevance of common variants associated with miserableness. To further characterize the trait, we conducted a transcriptome-wide association study (TWAS) on 373,733 individuals and identified 104 signals across brain tissue panels with 37 unique genes. Subsequent probabilistic fine-mapping prioritized 95 genes into 90%-credible sets. Amongst these prioritized hits, C7orf50 had the highest posterior inclusion probability of 0.869 in the brain cortex. Furthermore, we demonstrate that many GWAS hits for miserableness are driven by expression. To conclude, we successfully identified several genes implicated in miserableness and highlighted the power of TWAS to prioritize genes associated with a trait.\n\nShort summaryThe first transcriptome-wide association study of miserableness identifies many genes including c7orf50 implicated in the trait.