Threshold-dependent models77 postulate that disease is more likely to arise in individuals who have extreme values of underlying endophenotypes78,79. In many cases, causal common variants associated with a continuous endophenotype have been associated with disease [eg80–82], and in some cases these have been confirmed by in vitro biochemical assays for structural and regulatory effects [eg83–85]. eQTL analysis shows that gene expression and splicing are heavily influenced by common variants, possibly for the majority of transcripts86–88. To ignore these data is to deny that such transcriptional and metabolic variation is relevant to disease. It is of course possible that disease represents a discrete phase shift (in gene expression profiles, for example) that takes the organism outside the normal range of continuous variation. Thus, tumor samples have discrete transcriptome profile differences89,90, and it is not obvious that the normal variability is relevant to pathology. Similarly, at least some cortex samples from autistic brains converge on a common transcriptional profile91. By contrast, various blood disorders have been shown to correlate with extreme values for the major vectors of modules of gene expression92. More
