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Lack of support for the genes by early environment interaction hypothesis in the pathogenesis of schizophrenia

Vassos, Evangelos, Kou, Jiaqi, Tosato, Sarah, Maxwell, Jessye, Dennison, Charlotte ORCID:, Legge, Sophie, Walters, James ORCID:, Owen, Michael ORCID:, O'Donovan, Michael ORCID:, Breen, Gerome, Lewis, Cathryn, Sullivan, Patrick, Hultman, Christina, Ruggeri, Mirella, Walshe, Muriel, Bramon, Elvira, Bergen, Sarah and Murray, Robin 2022. Lack of support for the genes by early environment interaction hypothesis in the pathogenesis of schizophrenia. Schizophrenia Bulletin 48 (1) , pp. 20-26. 10.1093/schbul/sbab052

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Ursini et al reported recently that the liability of schizophrenia explained by a polygenic risk score (PRS) derived from the variants most associated with schizophrenia was increased 5-fold in individuals who experienced complications during pregnancy or birth. Follow-up gene expression analysis showed that the genes mapping to the most associated genetic variants are highly expressed in placental tissues. If confirmed, these findings will have major implications in our understanding of the joint effect of genes and environment in the pathogenesis of schizophrenia. We examined the interplay between PRS and obstetric complications (OCs) in 5 independent samples (effective N = 2110). OCs were assessed with the full or modified Lewis-Murray scale, or with birth weight < 2.5 kg as a proxy. In a large cohort we tested whether the pathways from placenta-relevant variants in the original report were associated with case-control status. Unlike in the original study, we did not find significant effect of PRS on the presence of OCs in cases, nor a substantial difference in the association of PRS with case-control status in samples stratified by the presence of OCs. Furthermore, none of the PRS by OCs interactions were significant, nor were any of the biological pathways, examined in the Swedish cohort. Our study could not support the hypothesis of a mediating effect of placenta biology in the pathway from genes to schizophrenia. Methodology differences, in particular the different scales measuring OCs, as well as power constraints for interaction analyses in both studies, may explain this discrepancy.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (
Publisher: Oxford University Press
ISSN: 0586-7614
Date of First Compliant Deposit: 14 April 2021
Date of Acceptance: 9 April 2021
Last Modified: 17 Jan 2024 02:22

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