Examining the independent and joint effects of genomic and exposomic liabilities for schizophrenia across the psychosis spectrum

L.K. Pries; G.A. Dal Ferro; J. van Os; P. Delespaul; G. Kenis; B.D. Lin; J.J. Luykx; A.L. Richards; B. Akdede; T. Binbay; V. Altinyazar; B. Yalincetin; G. Gumus-Akay; B. Cihan; H. Soygur; H. Ulas; E.S. Cankurtaran; S.U. Kaymak; M.M. Mihaljevic; S.A. Petrovic; T. Mirjanic; M. Bernardo; G. Mezquida; S. Amoretti; J. Bobes; P.A. Saiz; M.P. Garcia-Portilla; J. Sanjuan; E.J. Aguilar; J.L. Santos; E. Jimenez-Lopez; M. Arrojo; A. Carracedo; G. Lopez; J. Gonzalez-Penas; M. Parellada; N.P. Maric; C. Atbasoglu; A. Ucok; K. Alptekin; M.C. Saka; C. Arango; M. O'Donovan; S. Tosato; B.P.F. Rutten; S. Guloksuz; Genetic Risk and Outcome of Psychosis (GROUP) Investigators

doi:10.1017/S2045796020000943

Examining the independent and joint effects of genomic and exposomic liabilities for schizophrenia across the psychosis spectrum

L.K. Pries, G.A. Dal Ferro, J. van Os, P. Delespaul, G. Kenis, B.D. Lin, J.J. Luykx, A.L. Richards, B. Akdede, T. Binbay, V. Altinyazar, B. Yalincetin, G. Gumus-Akay, B. Cihan, H. Soygur, H. Ulas, E.S. Cankurtaran, S.U. Kaymak, M.M. Mihaljevic, S.A. PetrovicT. Mirjanic, M. Bernardo, G. Mezquida, S. Amoretti, J. Bobes, P.A. Saiz, M.P. Garcia-Portilla, J. Sanjuan, E.J. Aguilar, J.L. Santos, E. Jimenez-Lopez, M. Arrojo, A. Carracedo, G. Lopez, J. Gonzalez-Penas, M. Parellada, N.P. Maric, C. Atbasoglu, A. Ucok, K. Alptekin, M.C. Saka, C. Arango, M. O'Donovan, S. Tosato, B.P.F. Rutten, S. Guloksuz^*, Genetic Risk and Outcome of Psychosis (GROUP) Investigators

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Aims

Psychosis spectrum disorder has a complex pathoetiology characterised by interacting environmental and genetic vulnerabilities. The present study aims to investigate the role of gene-environment interaction using aggregate scores of genetic (polygenic risk score for schizophrenia (PRS-SCZ)) and environment liability for schizophrenia (exposome score for schizophrenia (ES-SCZ)) across the psychosis continuum.

Methods

The sample consisted of 1699 patients, 1753 unaffected siblings, and 1542 healthy comparison participants. The Structured Interview for Schizotypy-Revised (SIS-R) was administered to analyse scores of total, positive, and negative schizotypy in siblings and healthy comparison participants. The PRS-SCZ was trained using the Psychiatric Genomics Consortiums results and the ES-SCZ was calculated guided by the approach validated in a previous report in the current data set. Regression models were applied to test the independent and joint effects of PRS-SCZ and ES-SCZ (adjusted for age, sex, and ancestry using 10 principal components).

Results

Both genetic and environmental vulnerability were associated with case-control status. Furthermore, there was evidence for additive interaction between binary modes of PRS-SCZ and ES-SCZ (above 75% of the control distribution) increasing the odds for schizophrenia spectrum diagnosis (relative excess risk due to interaction = 6.79, [95% confidential interval (CI) 3.32, 10.26], p < 0.001). Sensitivity analyses using continuous PRS-SCZ and ES-SCZ confirmed gene-environment interaction (relative excess risk due to interaction = 1.80 [95% CI 1.01, 3.32], p = 0.004). In siblings and healthy comparison participants, PRS-SCZ and ES-SCZ were associated with all SIS-R dimensions and evidence was found for an interaction between PRS-SCZ and ES-SCZ on the total (B = 0.006 [95% CI 0.003, 0.009], p < 0.001), positive (B = 0.006 [95% CI, 0.002, 0.009], p = 0.002), and negative (B = 0.006, [95% CI 0.004, 0.009], p < 0.001) schizotypy dimensions.

Conclusions

The interplay between exposome load and schizophrenia genetic liability contributing to psychosis across the spectrum of expression provide further empirical support to the notion of aetiological continuity underlying an extended psychosis phenotype.

Original language	English
Article number	182
Number of pages	10
Journal	Epidemiology and Psychiatric Sciences
Volume	29
DOIs	https://doi.org/10.1017/S2045796020000943
Publication status	Published - 17 Nov 2020

Keywords

association
birth
childhood trauma
environment
gene-environment
genetics
metaanalysis
population
psychosis
reliability
risk
schizotypy
structured interview
validation
POPULATION
METAANALYSIS
RELIABILITY
GENE-ENVIRONMENT
BIRTH
VALIDATION
RISK
CHILDHOOD TRAUMA
Environment
ASSOCIATION
STRUCTURED INTERVIEW

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Cite this

Pries, L. K., Dal Ferro, G. A., van Os, J., Delespaul, P., Kenis, G., Lin, B. D., Luykx, J. J., Richards, A. L., Akdede, B., Binbay, T., Altinyazar, V., Yalincetin, B., Gumus-Akay, G., Cihan, B., Soygur, H., Ulas, H., Cankurtaran, E. S., Kaymak, S. U., Mihaljevic, M. M., ... Genetic Risk and Outcome of Psychosis (GROUP) Investigators (2020). Examining the independent and joint effects of genomic and exposomic liabilities for schizophrenia across the psychosis spectrum. Epidemiology and Psychiatric Sciences, 29, Article 182. https://doi.org/10.1017/S2045796020000943

@article{3bf6f5a8c5274b69a1e4c9eabd327ed3,

title = "Examining the independent and joint effects of genomic and exposomic liabilities for schizophrenia across the psychosis spectrum",

abstract = "AimsPsychosis spectrum disorder has a complex pathoetiology characterised by interacting environmental and genetic vulnerabilities. The present study aims to investigate the role of gene-environment interaction using aggregate scores of genetic (polygenic risk score for schizophrenia (PRS-SCZ)) and environment liability for schizophrenia (exposome score for schizophrenia (ES-SCZ)) across the psychosis continuum.MethodsThe sample consisted of 1699 patients, 1753 unaffected siblings, and 1542 healthy comparison participants. The Structured Interview for Schizotypy-Revised (SIS-R) was administered to analyse scores of total, positive, and negative schizotypy in siblings and healthy comparison participants. The PRS-SCZ was trained using the Psychiatric Genomics Consortiums results and the ES-SCZ was calculated guided by the approach validated in a previous report in the current data set. Regression models were applied to test the independent and joint effects of PRS-SCZ and ES-SCZ (adjusted for age, sex, and ancestry using 10 principal components).ResultsBoth genetic and environmental vulnerability were associated with case-control status. Furthermore, there was evidence for additive interaction between binary modes of PRS-SCZ and ES-SCZ (above 75% of the control distribution) increasing the odds for schizophrenia spectrum diagnosis (relative excess risk due to interaction = 6.79, [95% confidential interval (CI) 3.32, 10.26], p < 0.001). Sensitivity analyses using continuous PRS-SCZ and ES-SCZ confirmed gene-environment interaction (relative excess risk due to interaction = 1.80 [95% CI 1.01, 3.32], p = 0.004). In siblings and healthy comparison participants, PRS-SCZ and ES-SCZ were associated with all SIS-R dimensions and evidence was found for an interaction between PRS-SCZ and ES-SCZ on the total (B = 0.006 [95% CI 0.003, 0.009], p < 0.001), positive (B = 0.006 [95% CI, 0.002, 0.009], p = 0.002), and negative (B = 0.006, [95% CI 0.004, 0.009], p < 0.001) schizotypy dimensions.ConclusionsThe interplay between exposome load and schizophrenia genetic liability contributing to psychosis across the spectrum of expression provide further empirical support to the notion of aetiological continuity underlying an extended psychosis phenotype.",

keywords = "association, birth, childhood trauma, environment, gene-environment, genetics, metaanalysis, population, psychosis, reliability, risk, schizotypy, structured interview, validation, POPULATION, METAANALYSIS, RELIABILITY, GENE-ENVIRONMENT, BIRTH, VALIDATION, RISK, CHILDHOOD TRAUMA, Environment, ASSOCIATION, STRUCTURED INTERVIEW",

author = "L.K. Pries and {Dal Ferro}, G.A. and {van Os}, J. and P. Delespaul and G. Kenis and B.D. Lin and J.J. Luykx and A.L. Richards and B. Akdede and T. Binbay and V. Altinyazar and B. Yalincetin and G. Gumus-Akay and B. Cihan and H. Soygur and H. Ulas and E.S. Cankurtaran and S.U. Kaymak and M.M. Mihaljevic and S.A. Petrovic and T. Mirjanic and M. Bernardo and G. Mezquida and S. Amoretti and J. Bobes and P.A. Saiz and M.P. Garcia-Portilla and J. Sanjuan and E.J. Aguilar and J.L. Santos and E. Jimenez-Lopez and M. Arrojo and A. Carracedo and G. Lopez and J. Gonzalez-Penas and M. Parellada and N.P. Maric and C. Atbasoglu and A. Ucok and K. Alptekin and M.C. Saka and C. Arango and M. O'Donovan and S. Tosato and B.P.F. Rutten and S. Guloksuz and {Genetic Risk and Outcome of Psychosis (GROUP) Investigators}",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s).",

year = "2020",

month = nov,

day = "17",

doi = "10.1017/S2045796020000943",

language = "English",

volume = "29",

journal = "Epidemiology and Psychiatric Sciences",

issn = "2045-7960",

publisher = "Cambridge University Press",

}

Pries, LK, Dal Ferro, GA, van Os, J, Delespaul, P , Kenis, G, Lin, BD, Luykx, JJ, Richards, AL, Akdede, B, Binbay, T, Altinyazar, V, Yalincetin, B, Gumus-Akay, G, Cihan, B, Soygur, H, Ulas, H, Cankurtaran, ES, Kaymak, SU, Mihaljevic, MM, Petrovic, SA, Mirjanic, T, Bernardo, M, Mezquida, G, Amoretti, S, Bobes, J, Saiz, PA, Garcia-Portilla, MP, Sanjuan, J, Aguilar, EJ, Santos, JL, Jimenez-Lopez, E, Arrojo, M, Carracedo, A, Lopez, G, Gonzalez-Penas, J, Parellada, M, Maric, NP, Atbasoglu, C, Ucok, A, Alptekin, K, Saka, MC, Arango, C, O'Donovan, M, Tosato, S, Rutten, BPF , Guloksuz, S & Genetic Risk and Outcome of Psychosis (GROUP) Investigators 2020, 'Examining the independent and joint effects of genomic and exposomic liabilities for schizophrenia across the psychosis spectrum', Epidemiology and Psychiatric Sciences, vol. 29, 182. https://doi.org/10.1017/S2045796020000943

TY - JOUR

T1 - Examining the independent and joint effects of genomic and exposomic liabilities for schizophrenia across the psychosis spectrum

AU - Pries, L.K.

AU - Dal Ferro, G.A.

AU - van Os, J.

AU - Delespaul, P.

AU - Kenis, G.

AU - Lin, B.D.

AU - Luykx, J.J.

AU - Richards, A.L.

AU - Akdede, B.

AU - Binbay, T.

AU - Altinyazar, V.

AU - Yalincetin, B.

AU - Gumus-Akay, G.

AU - Cihan, B.

AU - Soygur, H.

AU - Ulas, H.

AU - Cankurtaran, E.S.

AU - Kaymak, S.U.

AU - Mihaljevic, M.M.

AU - Petrovic, S.A.

AU - Mirjanic, T.

AU - Bernardo, M.

AU - Mezquida, G.

AU - Amoretti, S.

AU - Bobes, J.

AU - Saiz, P.A.

AU - Garcia-Portilla, M.P.

AU - Sanjuan, J.

AU - Aguilar, E.J.

AU - Santos, J.L.

AU - Jimenez-Lopez, E.

AU - Arrojo, M.

AU - Carracedo, A.

AU - Lopez, G.

AU - Gonzalez-Penas, J.

AU - Parellada, M.

AU - Maric, N.P.

AU - Atbasoglu, C.

AU - Ucok, A.

AU - Alptekin, K.

AU - Saka, M.C.

AU - Arango, C.

AU - O'Donovan, M.

AU - Tosato, S.

AU - Rutten, B.P.F.

AU - Guloksuz, S.

AU - Genetic Risk and Outcome of Psychosis (GROUP) Investigators

PY - 2020/11/17

Y1 - 2020/11/17

N2 - AimsPsychosis spectrum disorder has a complex pathoetiology characterised by interacting environmental and genetic vulnerabilities. The present study aims to investigate the role of gene-environment interaction using aggregate scores of genetic (polygenic risk score for schizophrenia (PRS-SCZ)) and environment liability for schizophrenia (exposome score for schizophrenia (ES-SCZ)) across the psychosis continuum.MethodsThe sample consisted of 1699 patients, 1753 unaffected siblings, and 1542 healthy comparison participants. The Structured Interview for Schizotypy-Revised (SIS-R) was administered to analyse scores of total, positive, and negative schizotypy in siblings and healthy comparison participants. The PRS-SCZ was trained using the Psychiatric Genomics Consortiums results and the ES-SCZ was calculated guided by the approach validated in a previous report in the current data set. Regression models were applied to test the independent and joint effects of PRS-SCZ and ES-SCZ (adjusted for age, sex, and ancestry using 10 principal components).ResultsBoth genetic and environmental vulnerability were associated with case-control status. Furthermore, there was evidence for additive interaction between binary modes of PRS-SCZ and ES-SCZ (above 75% of the control distribution) increasing the odds for schizophrenia spectrum diagnosis (relative excess risk due to interaction = 6.79, [95% confidential interval (CI) 3.32, 10.26], p < 0.001). Sensitivity analyses using continuous PRS-SCZ and ES-SCZ confirmed gene-environment interaction (relative excess risk due to interaction = 1.80 [95% CI 1.01, 3.32], p = 0.004). In siblings and healthy comparison participants, PRS-SCZ and ES-SCZ were associated with all SIS-R dimensions and evidence was found for an interaction between PRS-SCZ and ES-SCZ on the total (B = 0.006 [95% CI 0.003, 0.009], p < 0.001), positive (B = 0.006 [95% CI, 0.002, 0.009], p = 0.002), and negative (B = 0.006, [95% CI 0.004, 0.009], p < 0.001) schizotypy dimensions.ConclusionsThe interplay between exposome load and schizophrenia genetic liability contributing to psychosis across the spectrum of expression provide further empirical support to the notion of aetiological continuity underlying an extended psychosis phenotype.

AB - AimsPsychosis spectrum disorder has a complex pathoetiology characterised by interacting environmental and genetic vulnerabilities. The present study aims to investigate the role of gene-environment interaction using aggregate scores of genetic (polygenic risk score for schizophrenia (PRS-SCZ)) and environment liability for schizophrenia (exposome score for schizophrenia (ES-SCZ)) across the psychosis continuum.MethodsThe sample consisted of 1699 patients, 1753 unaffected siblings, and 1542 healthy comparison participants. The Structured Interview for Schizotypy-Revised (SIS-R) was administered to analyse scores of total, positive, and negative schizotypy in siblings and healthy comparison participants. The PRS-SCZ was trained using the Psychiatric Genomics Consortiums results and the ES-SCZ was calculated guided by the approach validated in a previous report in the current data set. Regression models were applied to test the independent and joint effects of PRS-SCZ and ES-SCZ (adjusted for age, sex, and ancestry using 10 principal components).ResultsBoth genetic and environmental vulnerability were associated with case-control status. Furthermore, there was evidence for additive interaction between binary modes of PRS-SCZ and ES-SCZ (above 75% of the control distribution) increasing the odds for schizophrenia spectrum diagnosis (relative excess risk due to interaction = 6.79, [95% confidential interval (CI) 3.32, 10.26], p < 0.001). Sensitivity analyses using continuous PRS-SCZ and ES-SCZ confirmed gene-environment interaction (relative excess risk due to interaction = 1.80 [95% CI 1.01, 3.32], p = 0.004). In siblings and healthy comparison participants, PRS-SCZ and ES-SCZ were associated with all SIS-R dimensions and evidence was found for an interaction between PRS-SCZ and ES-SCZ on the total (B = 0.006 [95% CI 0.003, 0.009], p < 0.001), positive (B = 0.006 [95% CI, 0.002, 0.009], p = 0.002), and negative (B = 0.006, [95% CI 0.004, 0.009], p < 0.001) schizotypy dimensions.ConclusionsThe interplay between exposome load and schizophrenia genetic liability contributing to psychosis across the spectrum of expression provide further empirical support to the notion of aetiological continuity underlying an extended psychosis phenotype.

KW - association

KW - birth

KW - childhood trauma

KW - environment

KW - gene-environment

KW - genetics

KW - metaanalysis

KW - population

KW - psychosis

KW - reliability

KW - risk

KW - schizotypy

KW - structured interview

KW - validation

KW - POPULATION

KW - METAANALYSIS

KW - RELIABILITY

KW - GENE-ENVIRONMENT

KW - BIRTH

KW - VALIDATION

KW - RISK

KW - CHILDHOOD TRAUMA

KW - Environment

KW - ASSOCIATION

KW - STRUCTURED INTERVIEW

U2 - 10.1017/S2045796020000943

DO - 10.1017/S2045796020000943

M3 - Article

C2 - 33200977

SN - 2045-7960

VL - 29

JO - Epidemiology and Psychiatric Sciences

JF - Epidemiology and Psychiatric Sciences

M1 - 182

ER -