Weighted selective collapsing strategy for detecting rare and common variants in genetic association study

Area of Science:

• Genetics and Genomics
• Statistical Genetics
• Bioinformatics

Background:

• Genome-wide association studies (GWAS) successfully identify common variants but explain limited heritable variability in complex diseases.
• Rare variants are increasingly recognized for their role in heritability, yet are often analyzed separately from common variants.
• Existing methods often fail to capture the combined influence of common and rare variants on complex traits.

Purpose of the Study:

• To develop a robust statistical strategy for analyzing associations between complex traits and genetic regions using both common and rare variants.
• To improve the detection of genetic contributions to heritable variability that are missed by traditional association studies.

Main Methods:

• A weighted selective collapsing strategy is proposed, integrating genetic information from both common and rare variants.
• A forward selection procedure selectively collapses variants within a region, using adaptive weights to prioritize potentially causal rare variants.
• Two association tests are developed: BwSC (sensitive to effect direction) and BwSCd (robust to effect direction).

Main Results:

• The BwSC test demonstrated higher power when causal variants share the same genetic effect direction.
• The BwSCd test showed comparable power to existing methods when mixed genetic effects were present.
• Both proposed tests performed effectively whether common variants were associated with the trait or not.

Conclusions:

• The weighted selective collapsing strategy offers powerful new methods for association studies utilizing sequencing data.
• These tests enhance power when both common and rare variants contribute to heritability, particularly when common variant effects are subtle.
• Simulation studies confirmed substantially higher power across all scenarios, irrespective of common single nucleotide polymorphism (SNP) association.