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. 2020 Nov 17:29:e182.
doi: 10.1017/S2045796020000943.

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

L-K Pries  1 , G A Dal Ferro  2 , J van Os  1   3   4 , P Delespaul  1   5 , G Kenis  1 , B D Lin  6 , J J Luykx  3   6   7 , A L Richards  8 , B Akdede  9 , T Binbay  9 , V Altınyazar  10 , B Yalınçetin  11 , G Gümüş-Akay  12   13 , B Cihan  14 , H Soygür  15 , H Ulaş  9 , E Şahin Cankurtaran  16 , S Ulusoy Kaymak  17 , M M Mihaljevic  18   19 , S Andric Petrovic  18   19 , T Mirjanic  20 , M Bernardo  21   22   23 , G Mezquida  21   22   23 , S Amoretti  21   22   23 , J Bobes  23   24   25   26 , P A Saiz  23   24   25   26 , M Paz García-Portilla  23   24   25   26 , J Sanjuan  23   27 , E J Aguilar  23   27 , J L Santos  23   28 , E Jiménez-López  23   29 , M Arrojo  30 , A Carracedo  31   32 , G López  23   33 , J González-Peñas  23   33 , M Parellada  23   33 , N P Maric  18   34 , C Atbaşoğlu  35 , A Ucok  36 , K Alptekin  9   11 , M Can Saka  35 ; Genetic Risk and Outcome of Psychosis (GROUP) investigators; C Arango  23   33 , M O'Donovan  8 , S Tosato  2 , B P F Rutten  1 , S Guloksuz  1   37
Collaborators, Affiliations

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

L-K Pries et al. Epidemiol Psychiatr Sci. .

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.

Keywords: Environment; genetics; psychosis; schizotypy.

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Conflict of interest statement

Celso Arango has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Minerva, Otsuka, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion, and Takeda. Michael O'Donovan is supported by a collaborative research grant from Takeda Pharmaceuticals.

Figures

Fig. 1.
Fig. 1.
Additive effect of the polygenic risk score for schizophrenia, 75% cut-point (PRS-SCZ75), and the exposome score for schizophrenia, 75% cut-point (ES-SCZ75) on case-control status, adjusted for age, sex, and ten PCs; RERI: relative excess risk due to interaction.
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