Co-expression analysis reveals interpretable gene modules controlled by trans-acting genetic variants

Area of Science:

• Genetics
• Systems Biology
• Immunology

Background:

• Understanding genetic contributions to disease requires identifying regulatory variants.
• Trans-acting expression quantitative trait loci (trans-eQTLs) link genetic variants to gene expression changes but are difficult to detect due to small effect sizes.
• Novel therapeutic strategies depend on elucidating causal pathways in disease onset and progression.

Purpose of the Study:

• To develop and apply a robust method for detecting trans-eQTLs in diverse human blood cell types.
• To identify novel trans-eQTLs that regulate cellular processes relevant to disease.
• To investigate the temporal dynamics of cis- and trans-eQTL effects.

Main Methods:

• Analysis of gene expression and genotype data from six blood cell types (226-710 individuals).
• Inference of co-expression modules using five distinct methods.
• Application of co-expression modules as traits in trans-eQTL analysis to enhance statistical power and interpretability.
• Functional enrichment analysis to prioritize identified trans-eQTLs.

Main Results:

• Replication of three previously established trans-eQTL associations.
• Discovery of a novel trans-eQTL near SLC39A8, regulating a module of metallothionein genes in lipopolysaccharide (LPS)-stimulated monocytes.
• Identification of a transient cis-eQTL mediating the novel trans-eQTL effect, observed only during early LPS response.

Conclusions:

• Co-expression module analysis significantly improves the identification and prioritization of trans-eQTLs.
• The findings highlight the importance of cell-type-specific and temporal analyses for understanding gene regulation.
• This approach facilitates the discovery of genetic variants influencing cellular functions and disease pathways.