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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Krasnewich, Donna M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wayne State University
Schools of Medicine
United States
Zip Code
Kalita, Cynthia A; Brown, Christopher D; Freiman, Andrew et al. (2018) High-throughput characterization of genetic effects on DNA-protein binding and gene transcription. Genome Res 28:1701-1708
Burl, Rayanne B; Ramseyer, Vanesa D; Rondini, Elizabeth A et al. (2018) Deconstructing Adipogenesis Induced by ?3-Adrenergic Receptor Activation with Single-Cell Expression Profiling. Cell Metab 28:300-309.e4
Luca, Francesca; Kupfer, Sonia S; Knights, Dan et al. (2018) Functional Genomics of Host-Microbiome Interactions in Humans. Trends Genet 34:30-40
Kalita, Cynthia A; Moyerbrailean, Gregory A; Brown, Christopher et al. (2018) QuASAR-MPRA: accurate allele-specific analysis for massively parallel reporter assays. Bioinformatics 34:787-794
Pai, Athma A; Luca, Francesca (2018) Environmental influences on RNA processing: Biochemical, molecular and genetic regulators of cellular response. Wiley Interdiscip Rev RNA :e1503
Qu, Wen; Gurdziel, Katherine; Pique-Regi, Roger et al. (2018) Lead Modulates trans- and cis-Expression Quantitative Trait Loci (eQTLs) in Drosophila melanogaster Heads. Front Genet 9:395
Wen, Xiaoquan; Pique-Regi, Roger; Luca, Francesca (2017) Integrating molecular QTL data into genome-wide genetic association analysis: Probabilistic assessment of enrichment and colocalization. PLoS Genet 13:e1006646
Sen, Arko; Gurdziel, Katherine; Liu, Jenney et al. (2017) Smooth, an hnRNP-L Homolog, Might Decrease Mitochondrial Metabolism by Post-Transcriptional Regulation of Isocitrate Dehydrogenase (Idh) and Other Metabolic Genes in the Sub-Acute Phase of Traumatic Brain Injury. Front Genet 8:175
Richards, Allison L; Watza, Donovan; Findley, Anthony et al. (2017) Environmental perturbations lead to extensive directional shifts in RNA processing. PLoS Genet 13:e1006995
Qu, Wen; Gurdziel, Katherine; Pique-Regi, Roger et al. (2017) Identification of Splicing Quantitative Trait Loci (sQTL) in Drosophila melanogaster with Developmental Lead (Pb2+) Exposure. Front Genet 8:145

Showing the most recent 10 out of 17 publications