Disease-associated loci share properties with response eQTLs under common environmental exposures

Area of Science:

• Genomics
• Molecular Biology
• Systems Biology

Background:

• Genetic loci associated with disease often exhibit context-dependent regulatory effects.
• These effects are underrepresented in transcriptomes from healthy, steady-state adult tissues.

Purpose of the Study:

• To investigate gene regulation across diverse environmental conditions and cellular contexts.
• To identify genetic loci that influence regulatory changes in response to environmental exposures.

Main Methods:

• Treatment of diverse human cell types with nicotine, caffeine, and ethanol in vitro.
• Generation of single-cell RNA-sequencing data from 1.4 million cells across 51 individuals.
• Identification of response expression quantitative loci (eQTLs) and dynamic regulatory effects.

Main Results:

• Hundreds of response eQTLs were identified, associated with inter-individual differences in regulatory changes.
• Dynamic regulatory effects were observed across differentiation trajectories in response to exposure.
• Response eQTLs are enriched in distal enhancers and regulate genes with complex regulatory landscapes and diverse functions, similar to disease risk loci.

Conclusions:

• Genetic regulatory effects are complex and context-dependent.
• Understanding gene-by-environment interactions in diverse biological contexts is crucial for interpreting disease-associated loci.
• Response eQTLs provide a new layer of genetic variation influencing disease risk.