Wang Yi-Xuan, Fei Chen-Jie, Shen Chun, Ou Ya-Nan, Liu Wei-Shi, Yang Liu, Wu Bang-Sheng, Deng Yue-Ting, Feng Jian-Feng, Cheng Wei, Yu Jin-Tai
Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.
Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China; Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Ministry of Education, Shanghai, China.
J Affect Disord. 2025 Apr 15;375:192-204. doi: 10.1016/j.jad.2025.01.096. Epub 2025 Jan 20.
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.
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.
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.
The measurements of loneliness and social isolation in UK Biobank are brief for these multi-layer social factors, some relevant aspects may be missed.
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.
孤独和社会隔离是严重但未得到充分重视的公共卫生问题，其遗传基础在很大程度上仍不为人知。我们旨在探讨蛋白质编码变异在孤独和社会隔离表现中的作用。
我们对孤独和社会隔离进行了首次全外显子组关联分析，使用了336115名具有英国白人血统的参与者来研究孤独，346115名参与者来研究社会隔离。进行了敏感性分析以验证遗传研究结果。我们估计了孤独和社会隔离的遗传负担遗传力，并对其进行了生物学洞察。
通过对罕见编码变异的分析，我们鉴定出六个与孤独相关的新风险基因（ANKRD12、RIPOR2、PTEN、ARL8B、NF1和PIMREG）以及两个与社会隔离相关的基因（EDARADD和GIGYF1）。全脑关联分析发现了已鉴定基因与脑结构表型之间的47种关联，其中许多对社会加工和互动至关重要。全表型组关联分析在五个类别中建立了这些基因与表型之间的显著联系，主要是血液生物标志物和认知指标。
英国生物银行中对孤独和社会隔离的测量对于这些多层面的社会因素来说较为简略，可能会遗漏一些相关方面。
我们的研究揭示了13个与孤独相关的风险基因和6个与社会隔离相关的风险基因，其中大多数是新发现。这些发现推进了我们对这两种特征遗传基础的理解。该研究为未来旨在探索这些基因的功能机制及其对针对孤独和社会隔离的公共卫生干预潜在影响的研究奠定了基础。
