Fine-mapping causal tissues and genes at disease-associated loci

Area of Science:

• Genetics
• Genomics
• Systems Biology

Background:

• Complex diseases involve multiple tissues, requiring integrated analysis.
• Understanding gene function in specific tissues is crucial for disease research.

Purpose of the Study:

• To develop and apply a novel method, tissue-gene fine-mapping (TGFM), for identifying causal genetic elements in complex diseases.
• To pinpoint specific gene-tissue interactions that mediate disease risk.

Main Methods:

• TGFM analyzes summary statistics and expression quantitative trait loci (eQTL) data.
• It infers posterior inclusion probabilities (PIPs) for gene-tissue pairs and non-mediated variants.
• The method accounts for co-regulation and models uncertainty in expression predictions.

Main Results:

• Applied to 45 UK Biobank traits, TGFM identified an average of 147 causal genetic elements per trait (PIP > 0.5).
• Eleven percent of these causal elements were specific gene-tissue pairs, linking genes to disease mediation in particular tissues.
• Examples include TPO-thyroid for hypothyroidism and SLC20A2-artery aorta for diastolic blood pressure.

Conclusions:

• TGFM effectively identifies biologically relevant gene-tissue causal links for complex diseases.
• Integrating single-cell eQTL data with GTEx tissues revealed additional causal gene-cell type pairs.
• This approach enhances the understanding of genetic architecture in complex diseases across diverse tissues and cell types.