From GWAS to Function: Using Functional Genomics to Identify the Mechanisms Underlying Complex Diseases

Summary

This narrative review addresses a key translational bottleneck in genetic epidemiology: the majority of genome-wide association study (GWAS) loci lie in non-coding regions with unclear functional roles. The authors synthesise a decade of methodological advances in functional genomics that enable researchers to identify which genes are regulated by disease-associated variants, in which tissues and cell types, and under which physiological contexts. These integrative approaches—particularly colocalization with molecular phenotypes and tissue enrichment methods—are presented as essential tools for converting GWAS associations into actionable insights for drug target identification and clinical intervention.

UK applicability

The methodological frameworks reviewed are applicable to UK-led genetic research and precision medicine initiatives, though the review is not geographically specific and does not address UK health policy or NHS implementation directly. UK researchers using GWAS data or designing genetic studies would benefit from these functional genomics integration strategies.

Key measures

Methodological frameworks for: (1) tissue and cell-type identification via GWAS variant enrichment in genomic annotations; (2) gene identification via colocalization of GWAS signals with quantitative trait loci (QTLs); (3) integration with single-cell sequencing data; (4) design of functionally informed polygenic risk scores (PRS)

Outcomes reported

The review synthesises methodological approaches for integrating GWAS results with functional genomics datasets to identify disease-relevant tissues, cell types, and regulated genes. It examines tissue enrichment methods, colocalization approaches using QTLs, and emerging strategies including single-cell sequencing integration and functionally informed polygenic risk scores.

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