Systematic differences in discovery of genetic effects on gene expression and complex traits

Area of Science:

• Genomics
• Human Genetics
• Bioinformatics

Background:

• Genome-wide association studies (GWAS) identify genetic variants associated with complex traits, often implicating noncoding regions with regulatory roles.
• Expression quantitative trait loci (eQTLs) are a key type of regulatory variant, but currently identified eQTLs explain a limited portion of GWAS signals.

Purpose of the Study:

• To investigate the systematic differences between genetic variants identified by GWAS and cis-eQTL studies.
• To understand the impact of natural selection on the discovery of functionally relevant eQTLs in complex trait genetics.

Main Methods:

• Comparative analysis of genomic locations for GWAS hits and cis-eQTLs.
• Functional annotation and selective constraint analysis of genes near GWAS hits versus eQTLs.
• Development of a computational model to explain observed differences and selection effects.

Main Results:

• GWAS hits and cis-eQTLs show distinct genomic clustering: eQTLs are near transcription start sites, while GWAS hits are not.
• Genes near GWAS hits exhibit enrichment in functional annotations, strong selective constraint, and complex, tissue-specific regulatory landscapes.
• Genes near eQTLs are depleted of functional annotations, show relaxed constraint, and possess simpler regulatory profiles.

Conclusions:

• GWAS and eQTL studies are biased towards different types of genetic variants, necessitating the use of complementary functional genomics approaches.
• Natural selection acting on complex traits can hinder the discovery of functionally relevant eQTLs, impacting our understanding of trait heritability.