Spatial ligand-receptor gene annotations carry conditional heritability association across human tissues

Area of Science:

• Genomics
• Cell Biology
• Bioinformatics

Background:

• Genetic risk mapping typically focuses on cell-intrinsic effects.
• Existing methods cannot assess genetic contributions at molecular interfaces between cells.
• Understanding intercellular communication is crucial for disease heritability.

Purpose of the Study:

• To develop a method (EdgeMap) for partitioning heritability into cell-intrinsic and intercellular components.
• To identify specific intercellular communication channels (ligand-receptor interactions) influencing traits.
• To explore the role of intercellular communication in the genetic architecture of complex diseases.

Main Methods:

• Integration of spatial transcriptomics with genome-wide association study (GWAS) summary statistics.
• Development of EdgeMap to quantify heritability at cell-cell interfaces.
• Analysis across 17 human traits and five tissue types.

Main Results:

• EdgeMap successfully partitioned heritability, with significant enrichment in relevant trait-tissue pairings.
• Identified 67 trait-specific intercellular communication channels, including synaptic signaling for bipolar disorder and vascular adhesion for cardiovascular traits.
• Discovered that many genes involved in intercellular communication are missed by standard gene prioritization methods.

Conclusions:

• Intercellular communication represents a significant and complementary dimension to the genetic architecture of complex traits.
• EdgeMap provides a novel framework for dissecting genetic contributions at the cellular interface.
• Findings highlight the importance of cell-cell signaling pathways in disease etiology.