Lack of Support for the Genes by Early Environment Interaction Hypothesis in the Pathogenesis of Schizophrenia

Evangelos Vassos; Jiaqi Kou; Sarah Tosato; Jessye Maxwell; Charlotte A Dennison; Sophie E Legge; James T R Walters; Michael J Owen; Michael C O'Donovan; Gerome Breen; Cathryn M Lewis; Patrick F Sullivan; Christina Hultman; Mirella Ruggeri; Muriel Walshe; Elvira Bramon; Sarah E Bergen; Robin M Murray

doi:10.1093/schbul/sbab052

Lack of Support for the Genes by Early Environment Interaction Hypothesis in the Pathogenesis of Schizophrenia

Evangelos Vassos, Jiaqi Kou, Sarah Tosato, Jessye Maxwell, Charlotte A Dennison, Sophie E Legge, James T R Walters, Michael J Owen, Michael C O'Donovan, Gerome Breen, Cathryn M Lewis, Patrick F Sullivan, Christina Hultman, Mirella Ruggeri, Muriel Walshe, Elvira Bramon, Sarah E Bergen, Robin M Murray

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20 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	20-26
Number of pages	7
Journal	Schizophrenia Bulletin
Volume	48
Issue number	1
Early online date	14 May 2021
DOIs	https://doi.org/10.1093/schbul/sbab052
Publication status	Published - 21 Jan 2022

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Vassos, E., Kou, J., Tosato, S., Maxwell, J., Dennison, C. A., Legge, S. E., Walters, J. T. R., Owen, M. J., O'Donovan, M. C., Breen, G., Lewis, C. M., Sullivan, P. F., Hultman, C., Ruggeri, M., Walshe, M., Bramon, E., Bergen, S. E., & Murray, R. M. (2022). Lack of Support for the Genes by Early Environment Interaction Hypothesis in the Pathogenesis of Schizophrenia. Schizophrenia Bulletin, 48(1), 20-26. https://doi.org/10.1093/schbul/sbab052

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title = "Lack of Support for the Genes by Early Environment Interaction Hypothesis in the Pathogenesis of Schizophrenia",

abstract = "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.",

author = "Evangelos Vassos and Jiaqi Kou and Sarah Tosato and Jessye Maxwell and Dennison, {Charlotte A} and Legge, {Sophie E} and Walters, {James T R} and Owen, {Michael J} and O'Donovan, {Michael C} and Gerome Breen and Lewis, {Cathryn M} and Sullivan, {Patrick F} and Christina Hultman and Mirella Ruggeri and Muriel Walshe and Elvira Bramon and Bergen, {Sarah E} and Murray, {Robin M}",

year = "2022",

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doi = "10.1093/schbul/sbab052",

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Vassos, E, Kou, J, Tosato, S, Maxwell, J, Dennison, CA, Legge, SE, Walters, JTR, Owen, MJ, O'Donovan, MC, Breen, G , Lewis, CM, Sullivan, PF, Hultman, C, Ruggeri, M, Walshe, M, Bramon, E, Bergen, SE & Murray, RM 2022, 'Lack of Support for the Genes by Early Environment Interaction Hypothesis in the Pathogenesis of Schizophrenia', Schizophrenia Bulletin, vol. 48, no. 1, pp. 20-26. https://doi.org/10.1093/schbul/sbab052

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T1 - Lack of Support for the Genes by Early Environment Interaction Hypothesis in the Pathogenesis of Schizophrenia

AU - Vassos, Evangelos

AU - Kou, Jiaqi

AU - Tosato, Sarah

AU - Maxwell, Jessye

AU - Dennison, Charlotte A

AU - Legge, Sophie E

AU - Walters, James T R

AU - Owen, Michael J

AU - O'Donovan, Michael C

AU - Breen, Gerome

AU - Lewis, Cathryn M

AU - Sullivan, Patrick F

AU - Hultman, Christina

AU - Ruggeri, Mirella

AU - Walshe, Muriel

AU - Bramon, Elvira

AU - Bergen, Sarah E

AU - Murray, Robin M

PY - 2022/1/21

Y1 - 2022/1/21

N2 - 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.

AB - 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.

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U2 - 10.1093/schbul/sbab052

DO - 10.1093/schbul/sbab052

M3 - Article

C2 - 33987677

SN - 0586-7614

VL - 48

SP - 20

EP - 26

JO - Schizophrenia Bulletin

JF - Schizophrenia Bulletin

IS - 1

ER -

Lack of Support for the Genes by Early Environment Interaction Hypothesis in the Pathogenesis of Schizophrenia

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