Case-only exome sequencing and complex disease susceptibility gene discovery: study design considerations

Area of Science:

• Genomics
• Human Genetics
• Complex Diseases

Background:

• Whole exome sequencing (WES) is a powerful tool for identifying rare functional variants contributing to human complex diseases.
• Large datasets of germline WES data exist for disease cohorts (e.g., cancer) but are less common for healthy controls.
• Existing WES data represent a valuable resource for discovering novel disease susceptibility loci.

Purpose of the Study:

• To review strategies and technical considerations for utilizing WES data in case-only study designs for complex diseases.
• To propose a framework for maximizing the utility of WES data in identifying rare variant associations.

Main Methods:

• Focus on case-only study designs leveraging whole exome sequencing data.
• Variant filtering based on frequency and predicted functionality.
• Gene prioritization techniques.
• Integration of diverse data types.
• Validation through targeted sequencing.

Main Results:

• Case-only WES designs, when appropriately implemented, can effectively identify rare variants.
• This approach facilitates the detection of novel susceptibility genes for complex human diseases.

Conclusions:

• Case-only study designs using whole exome sequencing data are a viable strategy for discovering new disease susceptibility genes.
• Careful application of variant filtering, gene prioritization, and validation methods is crucial for success.