Epigenome-wide association study of loneliness in a sample of U.S. middle-aged twins.

Loneliness is a complex human trait that is highly polygenic and found to affect gene expression related to inflammatory and immunological functioning. To date, no epigenome-wide association studies of loneliness have tested whether differentially methylated sites are annotated to genes associated with inflammatory and immunological processes. Using 281 individual adult twins' DNA methylation data from the Louisville Twin Study, we performed an epigenome-wide analysis of loneliness to address this gap in the literature. In the discovery analysis, 169 twins were used to prioritize probes and test associations with DNA methylation age acceleration, and 56 independent monozygotic (MZ) twin pairs (112 individuals) were used in a within-family replication analysis. Among the 837,274 sites analyzed, no probe sites were statistically significant at the genome-wide level (p < 5.97 × 10^-8), but 25 suggestive sites (p < 5 × 10^-5) were annotated to genes related to various biological processes, including inflammatory response and protein-binding functions that extend prior findings. The nominal associations at these suggestive probe sites were highly correlated (r = .72) between the discovery sample and the MZ pair replication sample. Finally, loneliness significantly correlated with the DunedinPACE DNA methylation measure, suggesting that higher levels of loneliness were associated with accelerated epigenetic age as quantified by a measure that indexes longitudinal changes across multiple organ systems.