Efficient strategy for detecting gene × gene joint action and its application in schizophrenia.
The possible evidence for association comprises three types of information: differences between cases and controls in allele frequencies, in parameters for Hardy-Weinberg disequilibrium (HWD), and in parameters for linkage disequilibrium (LD). LD between marker and disease alleles results in a difference in at least one of the three types of parameters [Won and Elston, 2008]. However, the parameters for LD require knowledge about phase, which is usually unknown, making the LD contrast test without modification infeasible in practice. Methods for handling phase uncertainty are: (1) the most probable haplotype pair for each individual can be considered as the true phase; (2) a weighted average of haplotypes can be used; (3) we can consider the composite LD, which does not require any information about phase. We compare these methods to handle phase uncertainty in terms of validity and efficiency, and the effect on them of HWD in the population, at the same time confirming results for the three types of information. When the LD between markers is high, the LD contrast test that uses a weighted average of haplotypes or the most probable haplotypes to calculate the LD is recommended, but otherwise the LD contrast test that uses the composite LD is recommended. We conclude that, even though the difference in allele frequencies is usually the most informative test except in the case of a recessive disease, the LD contrast test can be more powerful if the markers are dense enough.