Partitioning gene-mediated disease heritability without eQTLs.

Area of Science:

• Genetics
• Complex Trait Analysis
• Bioinformatics

Background:

• Linking noncoding genetic variants from GWAS to specific genes is challenging.
• Existing methods like eQTLs and fixed-distance windows have limitations in capturing true SNP-gene relationships.
• Understanding gene regulation is crucial for interpreting complex disease heritability.

Purpose of the Study:

• To develop and validate the Abstract Mediation Model (AMM) for estimating heritability mediated by genes.
• To quantify the fraction of heritability explained by the closest and more distant genes.
• To assess heritability enrichment in predefined gene sets.

Main Methods:

• The Abstract Mediation Model (AMM) was proposed to jointly estimate heritability mediation and enrichment.
• AMM matches the decay of SNP enrichment with distance to genes within a specified set.
• The model was applied to 47 complex traits and diseases using genetic association data.

Main Results:

• The closest gene to each SNP mediates an average of 27% of heritability across 47 complex traits.
• A significant portion of heritability is mediated by genes located outside the ten closest genes.
• Mendelian disease genes show strong enrichment for common-variant heritability, e.g., 21 dyslipidemia genes explaining 25% of LDL heritability.

Conclusions:

• The AMM provides a powerful framework for dissecting complex trait heritability.
• Gene proximity is a strong predictor of heritability mediation, but distal effects are also substantial.
• Identifying key genes through this approach can advance understanding of disease mechanisms and potential therapeutic targets.