Polygenic liability to loneliness increases psychosis risk through adolescent loneliness: evidence from the EU-GEI study

Year: 2026

Type: article

Abstract: Social isolation and loneliness are associated with schizophrenia, yet their distinct genetic contributions and developmental pathways across the psychosis spectrum remain poorly understood. Using data from the EU-GEI study (2045 patients and 2456 healthy controls), we examined whether genetic liability to loneliness and social isolation increases psychosis risk through a two-step strategy: first testing whether polygenic scores (PGS) for loneliness and four isolation-related traits (derived from UK Biobank GWAS) were associated with first-episode psychosis (FEP), schizophrenia-spectrum disorders (SSD), symptom dimensions, and retrospectively reported loneliness and social isolation during childhood and adolescence; and second testing whether these developmental experiences mediated the relationship between genetic liability and psychosis. Genetic liability to loneliness (LNL-PGS) was associated with increased psychosis risk in the combined sample and specifically with FEP, independent of schizophrenia and depression genetic risk, with stronger effects in males. In contrast, a PGS indexing frequency of family and friends’ visits (VISITS-PGS), as a proxy for objective isolation, was associated with SSD diagnosis—particularly in females—and greater negative symptom severity. At the developmental level, LNL-PGS predicted prolonged loneliness during adolescence (ages 12–16) among patients, especially males, while VISITS-PGS only predicted lower sociability in childhood in healthy controls. Mediation analyses revealed that adolescent loneliness partially mediated the association between LNL-PGS and psychosis risk, accounting for 21% of the total effect and up to 27% in males. Together, these findings support partially distinct genetic and developmental mechanisms—with sex-specific contributions—linking perceived loneliness and objective social isolation to psychosis risk, and highlighting adolescent loneliness as a potential target for early preventive interventions.

Source: Schizophrenia

DOI: 10.1038/s41537-026-00787-2

Institutions: Instituto de Salud Carlos III, Hospital General Universitario Gregorio Marañón, Centro de Investigación Biomédica en Red de Salud Mental, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Hospital Clínic de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Barcelona, Vall d'Hebron Institut de Recerca, Institut d'Investigació Sanitària Acreditat Institut de Recerca - Hospital Universitari Vall d'Hebron, Universidad de Oviedo, Instituto de Investigación Sanitaria del Principado de Asturias, Servicio de Salud del Principado de Asturias, Universitat de València, Hospital Clínico Universitario de Valencia, Hospital Virgen de la Luz, University of Castilla-La Mancha, Complejo Hospitalario Universitario de Santiago, Instituto de Investigación Sanitaria de Santiago, Universidade de Santiago de Compostela, Fundación Pública Galega de Medicina Xenómica, Servicio Gallego de Salud, Universidad Complutense de Madrid, University Medical Center Utrecht, GGNet, Maastricht University Medical Centre, University of Cologne, University Hospital Cologne, University of British Columbia, University of Northern British Columbia, Yale University, King's College London, University of Belgrade, Institute of Mental Health, Ankara University, Istanbul University, Dokuz Eylül University

Language: English

Topic: Schizophrenia research and treatment

Subfield: Psychiatry and Mental health

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,890

Funder: Instituto de Salud Carlos III

Award: G3496775721

OpenAlex ID: W7171539488