Dissecting schizophrenia phenotypic variation: the contribution of genetic variation, environmental exposures, and gene–environment interactions

Hanxin Zhang, Atif Khan, Steven A. Kushner, Andrey Rzhetsky*

*Corresponding author for this work

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Abstract

Schizophrenia is among the leading causes of disability worldwide. Prior studies have conclusively demonstrated that the etiology of schizophrenia contains a strong genetic component. However, the understanding of environmental contributions and gene–environment interactions have remained less well understood. Here, we estimated the genetic and environmental contributions to schizophrenia risk using a unique combination of data sources and mathematical models. We used the administrative health records of 481,657 U.S. individuals organized into 128,989 families. In addition, we employed rich geographically specific measures of air, water, and land quality across the United States. Using models of progressively increasing complexity, we examined both linear and non-linear contributions of genetic variation and environmental exposures to schizophrenia risk. Our results demonstrate that heritability estimates differ significantly when gene–environment interactions are included in the models, dropping from 79% for the simplest model, to 46% in the best-fit model which included the full set of linear and non-linear parameters. Taken together, these findings suggest that environmental factors are an important source of explanatory variance underlying schizophrenia risk. Future studies are warranted to further explore linear and non-linear environmental contributions to schizophrenia risk and investigate the causality of these associations.

Original languageEnglish
Article number51
JournalSchizophrenia
Volume8
Issue number1
DOIs
Publication statusPublished - 10 May 2022

Bibliographical note

Acknowledgements:
The authors are grateful to Margarita Rzhetsky for comments on earlier version of this manuscript. This work was funded by the DARPA Big Mechanism program under ARO contract W911NF1410333, by National Institutes of Health grants R01HL122712, 1P50MH094267, and U01HL108634-01, and by a gift from Liz and Kent Dauten to AR; and by Horizon 2020 European Commission (ERA-PerMed2018-127) to SAK.

Publisher Copyright: © 2022, The Author(s).

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