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Background <p>Observational studies have found isolation or loneliness to be associated with depression. However, the causal relationship between isolation or loneliness and depression, as well as the mediating factors involved, remains unclear.</p> Methods <p>This study aims to establish the causal effects of social isolation and loneliness on depression and to identify key mediators using a two-sample Mendelian randomization (MR) approach. Using genetic variants from the UK Biobank (<i>N</i> = 455,364 for social isolation/loneliness; <i>N</i> = 462,933 for depression), we applied univariate and multivariate MR (UVMR and MVMR) to assess causal relationships and mediation effects.</p> Results <p>Genetically predicted social isolation and loneliness (β = 0.188, 95% CI 0.109, 0.268, <i>P</i> = 3.594e-06) were significantly associated with increased depression levels. Of the 25 potential risk factors for depression, two were identified as mediators of the relationship between isolation, loneliness, and depression: neuroticism (mediation ratio: 54.3% [95% CI: 43.1%, 65.5%]) and insomnia (15.5% [95% CI: 7.7%, 23.3%]). Multiple sensitivity analyses confirmed the robustness of the findings.</p> Conclusion <p>This study provides genetic evidence that social isolation and loneliness causally contribute to increased depression risk, with neuroticism and insomnia as key mediators, though generalizability to non-European populations requires further investigation.</p>

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Identification of genetic associations and key influences contributing to the pathway from social isolation or loneliness to depression

  • 期刊论文

  • 发表日期：

    2025年11月8日

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  • Wenxi Sun,
  • Chao Sun,
  • Haonan Zhang,
  • Ping Sun,
  • Huihui Song,
  • Xiaohui Wu,
  • Jun Chen,
  • Yiru Fang,
  • Xiaobin Zhang

摘要

Background

Observational studies have found isolation or loneliness to be associated with depression. However, the causal relationship between isolation or loneliness and depression, as well as the mediating factors involved, remains unclear.

Methods

This study aims to establish the causal effects of social isolation and loneliness on depression and to identify key mediators using a two-sample Mendelian randomization (MR) approach. Using genetic variants from the UK Biobank (N = 455,364 for social isolation/loneliness; N = 462,933 for depression), we applied univariate and multivariate MR (UVMR and MVMR) to assess causal relationships and mediation effects.

Results

Genetically predicted social isolation and loneliness (β = 0.188, 95% CI 0.109, 0.268, P = 3.594e-06) were significantly associated with increased depression levels. Of the 25 potential risk factors for depression, two were identified as mediators of the relationship between isolation, loneliness, and depression: neuroticism (mediation ratio: 54.3% [95% CI: 43.1%, 65.5%]) and insomnia (15.5% [95% CI: 7.7%, 23.3%]). Multiple sensitivity analyses confirmed the robustness of the findings.

Conclusion

This study provides genetic evidence that social isolation and loneliness causally contribute to increased depression risk, with neuroticism and insomnia as key mediators, though generalizability to non-European populations requires further investigation.