Characterizing the Relation Between Expression QTLs and Complex Traits: Exploring the Role of Tissue Specificity

Area of Science:

• Genetics
• Genomics
• Molecular Biology

Background:

• Measuring gene expression quantitative trait loci (eQTLs) is challenging in tissues with limited samples, like the brain.
• High eQTL overlap across tissues suggests potential for inferring brain eQTLs from accessible tissues, such as whole blood.

Purpose of the Study:

• To quantify the enrichment of blood and brain eQTLs in genome-wide association studies (GWAS) for complex traits.
• To investigate tissue-specific eQTL effects and their association with complex diseases like rheumatoid arthritis and schizophrenia.

Main Methods:

• Stratified Linkage Disequilibrium Score Regression (SLDSR) was applied to eQTLs from 44 GTEx tissues and other studies.
• Integration of GTEx eQTLs with histone modification regions (H3K4me1) and tissue-specific differentially expressed genes.
• Analysis of eQTL enrichment in GWAS for 11 complex traits, rheumatoid arthritis, and schizophrenia.

Main Results:

• No significant tissue-specific eQTL effects were detected across 44 tissues.
• eQTLs within H3K4me1 regions showed enriched effects on schizophrenia, but not rheumatoid arthritis, and this enrichment was not tissue-specific.
• Limited enrichment was observed for eQTLs associated with tissue-specific differentially expressed genes.

Conclusions:

• eQTLs are strongly enriched in GWAS signals for complex traits, and this enrichment is not tissue-specific.
• Using accessible tissues like whole blood as a proxy for eQTL discovery is a practical strategy.
• Restricting GWAS hit lookups to specific tissues with limited sample availability may not be advisable.