Pathway analysis methods typically assume that the gene scores used to define pathway enrichment are independent. However, functionally related genes often cluster on the genome and harbor SNPs in LD, leading to correlated gene scores that violate this assumption. To circumvent this problem, we check for a given pathway if any of its genes that cluster physically close on the chromosome are in LD. If so, for the calculation of the pathway score, we consider a single entity (a so-called fusion-gene) consisting of all the SNPs of the gene cluster. We then replace the genes in the cluster by this fusion-gene and calculate its gene score, but only for the calculation of the score for this particular pathway. The pathway score is then computed from the p-values of independent pathway genes and fusion genes that integrate the associational signals from dependent pathway genes (Fig 1B). In this way, the LD structure of neighbouring pathway genes is taken into account. Our gene scoring method facilitates this approach because it is sufficiently fast and scalable for recomputing the scores of all fusion genes.
