Gene-based and pathway-based testing for rare-variant association in affected sib pairs

Area of Science:

• Genetics
• Bioinformatics
• Computational Biology

Background:

• Next-generation sequencing enables rare variant (RV) investigation in disease.
• Affected sib pair (ASP) studies offer enhanced power for detecting RVs compared to case-control designs.

Purpose of the Study:

• To develop and evaluate novel statistical tests for RV-set association in ASPs.
• To assess the performance of these tests in single genomic regions and across multiple regions.

Main Methods:

• Introduction of allelic parity tests that compare rare allele frequencies on shared versus non-shared haplotypes in ASPs.
• Incorporation of minor allele frequency estimates from reference populations to boost test efficiency.
• Simulation studies under various genetic penetrance models to evaluate type I error and power.

Main Results:

• Allelic parity tests demonstrate good type I error control and improved power, particularly in smaller sample sizes.
• The methods show robustness to genetic linkage, allele frequency misspecification, sequencing errors, de novo mutations, and population stratification.
• Successful application of single- and multiple-region tests in a breast cancer early-onset study.

Conclusions:

• Allelic parity tests are a powerful and robust statistical approach for identifying rare variants associated with diseases using affected sibling pair data.
• These methods advance the analysis of rare variants in genetic epidemiology and personalized medicine.