Plasma Proteomic Signatures of Social Isolation and Loneliness Associated with Morbidity and Mortality

The biology underlying the connection between social relationships and health is largely unknown. Here, leveraging data from 42,062 participants across 2,920 plasma proteins in the UK Biobank, we characterized the proteomic signatures of social isolation and loneliness through proteome-wide association study and protein co-expression network analysis. Proteins linked to these constructs were implicated in inflammation, antiviral responses and complement systems. More than half of these proteins were prospectively linked to cardiovascular disease, type 2 diabetes, stroke and mortality during a 14 year follow-up. Moreover, Mendelian randomization (MR) analysis suggested causal relationships from loneliness to five proteins, with two proteins (ADM and ASGR1) further supported by colocalization. These MR-identified proteins (GFRA1, ADM, FABP4, TNFRSF10A and ASGR1) exhibited broad associations with other blood biomarkers, as well as volumes in brain regions involved in interoception and emotional and social processes. Finally, the MR-identified proteins partly mediated the relationship between loneliness and cardiovascular diseases, stroke and mortality. The exploration of the peripheral physiology through which social relationships influence morbidity and mortality is timely and has potential implications for public health.