The Post-GWAS Era: From Association to Function.

Area of Science:

• Genomics
• Genetics
• Molecular Biology

Background:

• Genome-wide association studies (GWASs) have identified thousands of genetic variants associated with complex traits and diseases over the past 12 years.
• However, functional studies to determine the causal variants and biological mechanisms behind these associations have lagged behind.
• Understanding the functional impact of these variants is crucial for translating genetic discoveries into clinical applications.

Purpose of the Study:

• To review key advances in functional genomics that aid in deriving biological meaning from GWAS findings.
• To highlight evidence suggesting causal variants often affect gene expression in a cell-type-specific manner.
• To discuss current statistical, bioinformatic, and empirical approaches for elucidating GWAS-identified disease risk loci.

Main Methods:

• Review of recent literature on functional genomics and GWAS follow-up studies.
• Analysis of evidence linking genetic variants to gene expression changes.
• Case studies illustrating statistical, bioinformatic, and experimental methods for variant function elucidation.

Main Results:

• Causal variants underlying disease risk frequently operate through regulatory effects on target gene expression.
• These expression effects can be modest and highly specific to particular cell types.
• Advances in functional genomics provide powerful tools for dissecting the biological basis of GWAS associations.

Conclusions:

• Functional genomics is essential for interpreting GWAS results and understanding disease mechanisms.
• Focusing on regulatory effects and cell-type specificity is key to identifying causal variants.
• Integrated approaches combining statistical, computational, and experimental methods are crucial for downstream GWAS analysis.