Cell-type-specific and disease-associated expression quantitative trait loci in the human lung

Area of Science:

• Genomics
• Pulmonary Medicine
• Cell Biology

Background:

• Genetic variants significantly increase the risk of chronic lung diseases like pulmonary fibrosis.
• Understanding how genetic variations control gene expression within specific cell types is crucial for elucidating disease mechanisms.
• Cellular context plays a vital role in how genetic variations impact complex traits and disease pathobiology.

Purpose of the Study:

• To map expression quantitative trait loci (eQTLs) in a cell-type-specific manner within lung tissue.
• To identify disease interaction eQTLs and their association with cellular dysregulation in pulmonary fibrosis.
• To link lung disease risk variants to their regulatory targets in disease-relevant cell types.

Main Methods:

• Single-cell RNA sequencing was performed on lung tissue from individuals with pulmonary fibrosis and unaffected donors.
• A pseudobulk approach was utilized to map eQTLs across 38 distinct lung cell types.
• Analysis focused on identifying both shared and cell-type-specific regulatory effects and disease interaction eQTLs.

Main Results:

• Expression quantitative trait loci (eQTLs) were mapped across 38 cell types, revealing both shared and cell-type-specific regulatory effects.
• Disease interaction eQTLs were identified, showing a higher likelihood of being cell-type-specific and linked to cellular dysregulation in pulmonary fibrosis.
• Lung disease risk variants were successfully connected to their regulatory targets within disease-relevant cell types.

Conclusions:

• Cellular context is a critical determinant of how genetic variation influences gene expression.
• Context-specific eQTLs are implicated as key regulators of lung homeostasis and the pathobiology of pulmonary fibrosis.
• This study provides a framework for understanding the cell-type-specific genetic underpinnings of lung diseases.