Multi-Ancestry GWAS of Neuroticism Identifies Novel Loci and Enhances Fine-Mapping Resolution

Abstract

Neuroticism is a core personality trait linked to emotional instability and increased risk for anxiety, depression, and schizophrenia. Most genome-wide association studies (GWAS) have focused on European populations, limiting the discovery of ancestry-specific genetic influences. To address this gap, we conducted the most diverse multi-ancestry GWAS meta-analysis of neuroticism to date, analyzing 668,780 individuals across African (AFR), European (EUR), East Asian (EAS), and South Asian (SAS) populations using UK Biobank (UKB) and the Million Veterans Program (MVP). We identified seven novel loci through SNP-based GWAS and another three novel genes through gene-based analysis. Multi-ancestry fine-mapping improved causal variant resolution, reducing credible set size by 61%, with 156 putatively causal SNPs, 129 of which were specific to EUR. Tissue enrichment highlighted brain, nerve, and pituitary, pointing to the involvement of GABAergic neurons. Many loci overlap with genes previously associated with psychiatric and cognitive traits, reinforcing neuroticisms pleiotropic and transdiagnostic nature. Our findings highlight the urgent need to expand genetic diversity in psychiatric genomics, ensuring that precision medicine advances benefit all populations equitably.