Examining the independent and joint effects of molecular genetic liability and environmental exposures in schizophrenia: results from the EUGEI study

Sinan Guloksuz*, Lotta-Katrin Pries, Philippe Delespaul, Gunter Kenis, Jurjen J. Luykx, Bochao D. Lin, Alexander L. Richards, Berna Akdede, Tolga Binbay, Vesile Altinyazar, Berna Yalincetin, Guvem Gumus-Akay, Burcin Cihan, Haldun Soygur, Halis Ulas, Eylem Sahin Cankurtaran, Semra Ulusoy Kaymak, Marina M. Mihaljevic, Sanja Andric Petrovic, Tijana MirjanicMiguel Bernardo, Bibiana Cabrera, Julio Bobes, Pilar A. Saiz, Maria Paz Garcia-Portilla, Julio Sanjuan, Eduardo J. Aguilar, Jose Luis Santos, Estela Jimenez-Lopez, Manuel Arrojo, Angel Carracedo, Gonzalo Lopez, Javier Gonzalez-Penas, Mara Parellada, Nadja P. Maric, Cem Atbasoglu, Alp Ucok, Koksal Alptekin, Meram Can Saka, Celso Arango, Michael O'Donovan, Bart P. F. Rutten, Jim van Os, Behrooz Z. Alizadeh, Therese van Amelsvoort, Nico J. van Beveren, Richard Bruggeman, Wiepke Cahn, Inez Myin-Germeys, Ruud van Winkel, Genetic Risk and Outcome of Psychosis (GROUP) Investigators

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Schizophrenia is a heritable complex phenotype associated with a background risk involving multiple common genetic variants of small effect and a multitude of environmental exposures. Early twin and family studies using proxy-genetic liability measures suggest gene-environment interaction in the etiology of schizophrenia spectrum disorders, but the molecular evidence is scarce. Here, by analyzing the main and joint associations of polygenic risk score for schizophrenia (PRS-SCZ) and environmental exposures in 1,699 patients with a diagnosis of schizophrenia spectrum disorders and 1,542 unrelated controls with no lifetime history of a diagnosis of those disorders, we provide further evidence for gene-environment interaction in schizophrenia. Evidence was found for additive interaction of molecular genetic risk state for schizophrenia (binary mode of PRS-SCZ above 75% of the control distribution) with the presence of lifetime regular cannabis use and exposure to early-life adversities (sexual abuse, emotional abuse, emotional neglect, and bullying), but not with the presence of hearing impairment, season of birth (winter birth), and exposure to physical abuse or physical neglect in childhood. The sensitivity analyses replacing the a priori PRS-SCZ at 75% with alternative cut-points (50% and 25%) confirmed the additive interaction. Our results suggest that the etiopathogenesis of schizophrenia involves genetic underpinnings that act by making individuals more sensitive to the effects of some environmental exposures.

Original languageEnglish
Pages (from-to)173-182
Number of pages10
JournalWorld Psychiatry
Issue number2
Publication statusPublished - Jun 2019


  • Schizophrenia
  • psychosis
  • genetics
  • environment
  • gene-environment interaction
  • polygenic risk
  • childhood trauma
  • cannabis
  • bullying

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