Understanding the molecular and organismal function of genetic variants in non-coding regions is crucial to dissect the genetic and evolutionary basis of variation in complex traits. Combining complementary functional genomics datasets has proven a successful strategy to pinpoint the most likely causal variant and molecular mechanism supporting a genetic association. Current existing annotations only capture regulatory conditions at the baseline level. However, as we and others have shown, the effect of a genetic variant on a molecular pathway, and ultimately on the individual's phenotype, may be modulated by the cellular environmental context (gene-environment interactions, GxE). We de?ne these genetic variants as GxE quantitative trait nucleotides (GxE-QTNs) and consider the cellular environment as a simpli?ed but better controlled proxy of the organismal environment. Binding of TFs to speci?c genomic targets is de?ned by sequence motifs and chromatin epige- netic marks, and can be altered by the presence of GxE-QTNs. To discover genes modulated by GxE-QTNs, we have recently established a high-throughput approach to perturb the cellular environment by a panel of 50 in vitro treatments, including vitamins, metal ions, common drugs and hormones. Here we propose to use this approach to dissect these GxE-QTNs and the underlying molecular mechanism by: i) performing functional ge- nomics assays capturing chromatin accessibility; ii) analyzing the effects of naturally occurring genetic variation in regulatory elements; and iii) combining RNA-seq, ATAC-seq, MPRA and GWAS data to co-localize association signals and pinpoint complex traits causal variants.
The purpose of this project is to improve our understanding of the mechanistic links between genetic variation, epigenetic factors and differences in gene regulation across environmental contexts. This work will provide a useful resource to any researcher interested in gene by environment interactions in human complex traits, whether within the range of natural variation or in the pathological spectrum.
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