Sequence kernel association tests for the combined effect of rare and common variants

Area of Science:

• Genetics
• Bioinformatics
• Statistical genetics

Background:

• Sequencing technologies enable identification of rare and common genetic variants.
• Genome-wide association studies (GWASs) primarily assess common variants.
• Existing groupwise association tests often prioritize rare variants, potentially losing power when both rare and common variants contribute to disease risk.

Purpose of the Study:

• To introduce novel sequence kernel association tests (SKAT) for evaluating the combined effect of rare and common genetic variants.
• To develop computationally efficient tests applicable to binary and continuous traits.
• To integrate GWAS and whole-exome sequencing data.

Main Methods:

• Development of sequence kernel association tests (SKAT).
• Application to simulated data under comprehensive scenarios.
• Evaluation on sequencing studies for Crohn disease and autism spectrum disorders.

Main Results:

• The proposed SKAT methods demonstrate substantial power increases compared to traditional burden and variance-component tests.
• SKAT effectively evaluates the cumulative effect of both rare and common variants.
• The tests are computationally efficient and versatile.

Conclusions:

• SKAT offers a powerful and flexible approach for genetic association studies incorporating both rare and common variants.
• These methods enhance the ability to identify genetic contributions to disease risk.
• The SKAT software package is available for broader application.