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Genotype × environment interactions in gene regulation and complex traits

Abstract

Genotype × environment interactions (GxE) have long been recognized as a key mechanism underlying human phenotypic variation. Technological developments over the past 15 years have dramatically expanded our appreciation of the role of GxE in both gene regulation and complex traits. The richness and complexity of these datasets also required parallel efforts to develop robust and sensitive statistical and computational approaches. Although our understanding of the genetic architecture of molecular and complex traits has been maturing, a large proportion of complex trait heritability remains unexplained. Furthermore, there are increasing efforts to characterize the effect of environmental exposure on human health. We therefore review GxE in human gene regulation and complex traits, advocating for a comprehensive approach that jointly considers genetic and environmental factors in human health and disease.

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Fig. 1: Molecular mechanisms of GxE.
Fig. 2: Summary of popular methods to detect molecular GxE.
Fig. 3: Effect of latent environments (unmeasured environmental variables) on gene expression.

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Acknowledgements

We thank R. Pique-Regi, members of the Luca–Pique-Regi group and students of the MGG 7030 class for helpful comments on the draft of the manuscript. This work was supported by NIH/NIEHS R01ES033634 (F.L.), NIH/NHLBI R01HL162574 (F.L.), NIH/NIGMS R01GM109215 (F.L.) and NIH/NIGMS F30GM151855 (S.N.).

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All authors researched the subject, reviewed the literature and wrote the paper. F.L. developed the original concept and supervised the project. C.B., S.N. and A.R. equally contributed to the manuscript.

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Correspondence to Francesca Luca.

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Boye, C., Nirmalan, S., Ranjbaran, A. et al. Genotype × environment interactions in gene regulation and complex traits. Nat Genet 56, 1057–1068 (2024). https://doi.org/10.1038/s41588-024-01776-w

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