Contrasting linkage disequilibrium as a multilocus family-based association test

Area of Science:

• Genetics
• Biostatistics
• Genomic Association Studies

Background:

• Linkage disequilibrium (LD) is crucial in genetic association studies for mapping genetic loci.
• Comparing LD patterns between cases and controls is a known method for detecting genetic association.
• Extending LD pattern analysis to case-parent data offers a novel approach for association mapping.

Purpose of the Study:

• To extend the analysis of linkage disequilibrium (LD) patterns to case-parent data.
• To develop a method for testing gene-gene interactions by contrasting LD patterns between transmitted and nontransmitted genotypes.
• To provide a statistically robust and computationally efficient multilocus association mapping strategy.

Main Methods:

• Comparison of linkage disequilibrium (LD) patterns between transmitted and nontransmitted genotypes in case-parent trios.
• Development of a permutation procedure to assess the statistical significance of observed LD contrasts.
• Utilizing pairwise LD measurements to minimize the impact of missing data and avoid haplotype reconstruction biases.

Main Results:

• The proposed method for analyzing LD patterns in case-parent data is a valid strategy for multilocus association mapping.
• The methods effectively detect gene-gene interactions and multilocus associations, complementing existing techniques.
• Application to Crohn's disease data identified multilocus associations potentially missed by other methods.

Conclusions:

• Examining linkage disequilibrium (LD) patterns in case-parent data provides a powerful tool for association mapping.
• The proposed methods are straightforward to implement, free from haplotype estimation bias, and robust to missing data.
• This approach enhances the ability to detect complex genetic associations, including gene-gene interactions.