Our finding that specific mitochondria-related gene sets functionally implicated in T2D are not enriched for associations could be due to several reasons, of potential relevance also to the study of other diseases: (i) The fraction of causal genes in the given gene set, while considerable, may not be significantly higher than the total fraction of causal genes in the genome (especially relevant to gene permutation analysis); (ii) The causal variants may be spread across a large number of biological processes or there may be allelic heterogeneity in the population, making it hard to detect clustering of associations into pathways; (iii) Causal genes for certain phenotypes may cluster in small pathways, which are more sensitive to individual gene score fluctuations than large pathways; (iv) The relevant pathways or sets of functionally related genes may have not yet been tested; (v) By considering only variants within a given distance around each gene, potential signals from more distant transcriptional regulatory elements, such as enhancers or epigenetic marks, might be missed; future genome-wide maps of regulatory elements may be used to generate a discontinuous
