Unraveling the Shared Genetic Architecture and Polygenic Overlap Between Loneliness, Major Depressive Disorder, and Sleep-Related Traits.

Background: Loneliness (LON) is a heritable psychosocial trait that frequently co-occurs with major depressive disorder (MDD) and sleep traits. Despite known genetic contributions, the shared genetic architecture and molecular mechanisms underlying their co-occurrence remain largely unknown. This study aimed to uncover novel genetic risk loci and cross-trait gene expression effects. Methods: Large-scale genome-wide association study (GWAS) datasets were analyzed using the causal mixture model (MiXeR) to estimate polygenicity and shared genetic architecture. Genetic correlation analyses were performed using linkage disequilibrium score regression (LDSC) and local analysis of [co]variant annotation (LAVA). Conditional and conjunctional FDR methods further identified single nucleotide polymorphisms (SNPs). FUMA was used for gene mapping and annotation, and transcriptome-wide association studies (TWAS) assessed cross-trait gene expression effects. Results: Analyses revealed extensive polygenic overlap between LON, MDD, and sleep-related traits, with concordant and discordant effects. Several novel loci were identified, and cross-trait gene expression effects were observed in multiple brain-expressed genes, including WNT3, ARHGAP27, PLEKHM1, and FOXP2. These findings provide insight into the shared genetic architecture and relevance of these traits. Conclusions: This study demonstrates a significant shared polygenic architecture among LON, MDD, and sleep traits, providing new biological insights. It advances our understanding of cross-trait genetic mechanisms and identifies potential targets for future research, offering broader implications for trait co-occurrence.