Identification of trans-eQTLs using mediation analysis with multiple mediators.

Area of Science:

• Genetics
• Genomics
• Systems Biology

Background:

• Expression quantitative trait loci (eQTLs) offer insights into gene regulation.
• The mechanisms of trans-eQTLs, unlike cis-eQTLs, are less understood.
• Trans-eQTLs may regulate distant genes indirectly by influencing nearby genes, often through multiple mediators.

Purpose of the Study:

• To develop a computational method for identifying trans-eQTLs mediated by multiple cis-genes.
• To address limitations of single-mediator models in capturing complex gene correlations.

Main Methods:

• Proposed two hypothesis tests: one for total mediation effect (TME) and one for component-wise mediation effects (CME).
• Utilized simulation studies to evaluate test performance and power.
• Applied the method to HapMap3 data, analyzing multiple cis-gene mediators.

Main Results:

• Both TME and CME tests controlled type I error rates effectively, even with model misspecification.
• Multiple mediator analysis demonstrated increased power for detecting mediated trans-eQTLs, particularly in larger sample sizes.
• Identified 11 novel mediated trans-eQTLs in HapMap3 African populations, not found by single-mediator analysis, which were also more likely to be trait-associated SNPs.

Conclusions:

• Trans-eQTLs frequently associate with multiple cis-genes.
• Employing multiple mediators in analysis significantly enhances the power to identify mediated trans-eQTLs, especially with large datasets.