Exome sequencing identifies protein-coding variants associated with loneliness and social isolation.

Background: Loneliness and social isolation are serious yet underappreciated public health problems, with their genetic underpinnings remaining largely unknown. We aimed to explore the role of protein-coding variants in the manifestation of loneliness and social isolation.

Methods: We conducted the first exome-wide association analysis on loneliness and social isolation, utilizing 336,115 participants of white-British ancestry for loneliness and 346,115 for social isolation. Sensitivity analyses were performed to validate the genetic findings. We estimated the genetic burden heritability of loneliness and social isolation and provided biological insights into them.

Results: We identified six novel risk genes (ANKRD12, RIPOR2, PTEN, ARL8B, NF1, and PIMREG) associated with loneliness and two (EDARADD and GIGYF1) with social isolation through analysis of rare coding variants. Brain-wide association analysis uncovered 47 associations between identified genes and brain structure phenotypes, many of which are critical for social processing and interaction. Phenome-wide association analysis established significant links between these genes and phenotypes across five categories, mostly blood biomarkers and cognitive measures.

Limitations: The measurements of loneliness and social isolation in UK Biobank are brief for these multi-layer social factors, some relevant aspects may be missed.

Conclusions: Our study revealed 13 risk genes associated with loneliness and 6 with social isolation, with the majority being novel discoveries. These findings advance our understanding of the genetic basis of these two traits. The study provides a foundation for future studies aimed at exploring the functional mechanisms of these genes and their potential implications for public health interventions targeting loneliness and social isolation.