One caveat is that a gene-wide approach requires at least some of the true association signals to be located within the (arbitrarily) derived boundaries of genes. Our analysis showing an excess in observed association signals within genes but not in sequences beyond gene boundaries supports the view that such a gene-centric enrichment does occur, thereby providing an rationale for targeting the immediate vicinity of genes for analysis. This may be intuitively obvious by analogy with simpler genetic disorders, but with respect to complex diseases, there has been little empirical support for such a strategy. Analogous analyses in multiple phenotypes with genes defined incrementally by adding additional flanking sequence might better define optimal (on average) locations for such endeavours.
