Cell type-specific and disease-associated eQTL in the human lung

Area of Science:

• Genomics
• Pulmonary Medicine
• Cell Biology

Background:

• Genetic variants significantly contribute to chronic lung diseases like pulmonary fibrosis (PF).
• Understanding cell-type-specific gene expression regulation is crucial for elucidating disease mechanisms.
• Genetic variations influence complex traits and disease pathobiology through gene expression control.

Approach:

• Performed single-cell RNA-sequencing on lung tissue from 67 PF patients and 49 healthy donors.
• Utilized a pseudo-bulk approach to map expression quantitative trait loci (eQTL) across 38 distinct lung cell types.
• Identified disease-interaction eQTL and linked PF risk variants to their regulatory targets within disease-relevant cell types.

Key Points:

• Expression quantitative trait loci (eQTL) exhibit both shared and cell type-specific regulatory effects in the lung.
• Disease-interaction eQTL are frequently cell-type specific and associated with cellular dysregulation in pulmonary fibrosis.
• Genetic variation's impact on gene expression is highly dependent on cellular context.

Conclusions:

• Cellular context critically determines how genetic variation affects gene expression in the lung.
• Context-specific eQTL play a significant role in regulating lung homeostasis and the pathobiology of pulmonary fibrosis.
• This study provides a framework for understanding genetic contributions to lung diseases at a single-cell level.