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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月28日

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  • Javier González-Peñas,
  • Álvaro Andreu-Bernabeu,
  • Alberto Mora,
  • Miguel Bernardo,
  • Gisela Mezquida,
  • Silvia Amoretti,
  • Julio Bobes,
  • Pilar A. Saiz,
  • Maria Paz García-Portilla,
  • Julio Sanjuan,
  • José Luis Santos,
  • Estela Jiménez-López,
  • Manuel Arrojo,
  • Angel Carracedo,
  • Gonzalo López,
  • Mara Parellada,
  • Jim van Os,
  • Philippe Delespaul,
  • Bart P. F. Rutten,
  • Lotta-Katrin Pries,
  • Sinan Guloksuz,
  • Robin M. Murray,
  • Marta Di Forti,
  • Evangelos Vassos,
  • Nadja P. Maric,
  • Cem Atbaşoğlu,
  • Meram Can Saka,
  • Alp Üçok,
  • Köksal Alptekin,
  • Celso Arango,
  • Covadonga M. Díaz-Caneja

摘要

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.