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Multivariate Detection of Gene‐Gene Interactions

Unraveling the nature of genetic interactions is crucial to obtaining a more complete picture of complex diseases. It is thought that gene‐gene interactions play an important role in the etiology of cancer, cardiovascular, and immune‐mediated disease. Interactions among genes are defined as phenotypic effects that differ from those observed for independent contributions of each gene, usually detected by univariate logistic regression methods. Using a multivariate extension of linkage disequilibrium (LD), we have developed a new method, based on distances between sample covariance matrices for groups of single nucleotide polymorphisms (SNPs), to test for interaction effects of two groups of genes associated with a disease phenotype. Since a disease‐associated interacting locus will often be in LD with more than one marker in the region, a method that examines a set of markers in a region collectively can offer greater power than traditional methods. Our method effectively identifies interaction effects in simulated data, as well as in data on the genetic contributions to the risk for graft‐versus‐host disease following hematopoietic stem cell transplantation.