Contrasting linkage disequilibrium as a multilocus family-based association test.

Linkage disequilibrium (LD) of genetic loci is routinely estimated and graphically illustrated in genetic association studies. It has been suggested that the information in LD is also useful for association mapping and genetic association can be detected by comparing LD patterns between cases and controls. Here, we extend this idea to analyze case-parents data by comparing LD patterns between transmitted and nontransmitted genotypes. We provide the condition when contrasting LD is valid for testing gene-gene interactions. A permutation procedure is given to assess statistical significance. One advantage of our proposed methods is that haplotype information is not required. Thus, the implementation of our methods is straightforward and the resulted tests are free from potential bias caused by assumptions made to estimate haplotypes in silico. Since our test statistics use pairwise LD measurements, they are less affected by missing data than many other multilocus methods. With simulated data, we demonstrate that examining LD patterns of case-parents data is a useful multilocus association mapping strategy and it complements existing association mapping methods. The application of our methods to a Crohn's disease data set shows that our methods can detect multilocus association that might be missed by other association methods. Our permutation procedure can also be modified to allow multiple offspring from a family to be analyzed.