High-throughput allele-specific expression across 250 environmental conditions.

Gene-by-environment (GxE) interactions determine common disease risk factors and biomedically relevant complex traits. However, quantifying how the environment modulates genetic effects on human quantitative phenotypes presents unique challenges. Environmental covariates are complex and difficult to measure and control at the organismal level, as found in GWAS and epidemiological studies. An alternative approach focuses on the cellular environment using in vitro treatments as a proxy for the organismal environment. These cellular environments simplify the organism-level environmental exposures to provide a tractable influence on subcellular phenotypes, such as gene expression. Expression quantitative trait loci (eQTL) mapping studies identified GxE interactions in response to drug treatment and pathogen exposure. However, eQTL mapping approaches are infeasible for large-scale analysis of multiple cellular environments. Recently, allele-specific expression (ASE) analysis emerged as a powerful tool to identify GxE interactions in gene expression patterns by exploiting naturally occurring environmental exposures. Here we characterized genetic effects on the transcriptional response to 50 treatments in five cell types. We discovered 1455 genes with ASE (FDR < 10%) and 215 genes with GxE interactions. We demonstrated a major role for GxE interactions in complex traits. Genes with a transcriptional response to environmental perturbations showed sevenfold higher odds of being found in GWAS. Additionally, 105 genes that indicated GxE interactions (49%) were identified by GWAS as associated with complex traits. Examples include GIPR-caffeine interaction and obesity and include LAMP3-selenium interaction and Parkinson disease. Our results demonstrate that comprehensive catalogs of GxE interactions are indispensable to thoroughly annotate genes and bridge epidemiological and genome-wide association studies.

Cumulative trauma and partner conflict predict post-traumatic stress disorder in postpartum African-American women.

AIM AND OBJECTIVE: To describe relationships between cumulative trauma, partner conflict and post-traumatic stress in African-American postpartum women. BACKGROUND: Cumulative trauma exposure estimates for women in the USA range from 51-69%. During pregnancy, most trauma research has focused on physical injury to the mother. Post-traumatic stress disorder (PTSD) is associated with trauma and more prevalent in African-American women than women of other groups. Knowledge about both the rate and impact of cumulative trauma on pregnancy may contribute to our understanding of women seeking prenatal care, and disparities in infant morbidity and mortality. DESIGN: This retrospective, correlational, cross-sectional study took place on postpartum units of two Detroit hospitals. Participants were 150 African-American women aged between 18-45 who had given birth. METHODS: Mothers completed the Cumulative Trauma Scale, Conflict Tactics Scale, Clinician Administered Post-traumatic Stress Scale, Edinburgh Postnatal Depression Scale and a Demographic Data form. Descriptive statistics, correlations and multiple regressions were used for data analysis. RESULTS: All participants reported at least one traumatic event in their lifetime. Cumulative trauma and partner conflict predicted PTSD, with the trauma of a life-threatening event for a loved one reported by 60% of the sample. Nearly, one-fourth of the women screened were at risk for PTSD. Increased cumulative trauma, increased partner conflict and lower level of education were related to higher rates of PTSD symptoms. CONCLUSION: Both cumulative trauma and partner conflict in the past year predict PTSD. Reasoning was used most often for partner conflict resolution. RELEVANCE TO CLINICAL PRACTICE: The results of this study offer additional knowledge regarding relationships between cumulative trauma, partner conflict and PTSD in African-American women. Healthcare providers need to be sensitive to patient life-threatening events, personal failures, abuse and other types of trauma. Current evidence supports the need to assess for post-traumatic stress symptoms during pregnancy.

Interpreting Coronary Artery Disease Risk Through Gene-Environment Interactions in Gene Regulation.

GWAS and eQTL studies identified thousands of genetic variants associated with complex traits and gene expression. Despite the important role of environmental exposures in complex traits, only a limited number of environmental factors were measured in these studies. Measuring molecular phenotypes in tightly controlled cellular environments provides a more tractable setting to study gene-environment interactions in the absence of other confounding variables. We performed RNA-seq and ATAC-seq in endothelial cells exposed to retinoic acid, dexamethasone, caffeine, and selenium to model genetic and environmental effects on gene regulation in the vascular endothelium-a common site of pathology in cardiovascular disease. We found that genes near regions of differentially accessible chromatin were more likely to be differentially expressed [OR = (3.41, 6.52), [Formula: see text]]. Furthermore, we confirmed that environment-specific changes in transcription factor binding are a key mechanism for cellular response to environmental stimuli. Single nucleotide polymorphisms (SNPs) in these transcription response factor footprints for dexamethasone, caffeine, and retinoic acid were enriched in GTEx eQTLs from artery tissues, indicating that these environmental conditions are latently present in GTEx samples. Additionally, SNPs in footprints for response factors in caffeine are enriched in colocalized eQTLs for coronary artery disease (CAD), suggesting a role for caffeine in CAD risk. By combining GWAS, eQTLs, and response genes, we annotated environmental components that can increase or decrease disease risk through changes in gene expression in 43 genes. Interestingly, each treatment may amplify or buffer genetic risk for CAD, depending on the particular SNP or gene considered.