Abstract: The interactions between genetic and environmental risk factors contribute to the aetiology of complex human diseases. Genome-wide association studies (GWAS) have revealed that most of the genetic variants associated with complex diseases are located in the non-coding part of the genome, preferentially within enhancers. Enhancers are distal cis-regulatory elements composed of clusters of transcription factors binding sites that positively regulate the expression of their target genes. The generation of genome-wide maps for histone marks (e.g., H3K27ac), chromatin accessibility and transcription factor and coactivator (e.g., p300) binding profiles have enabled the identification of enhancers across many human cell types and tissues. Nonetheless, the functional and pathological consequences of the majority of disease-associated genetic variants located within enhancers seem to be rather minor under normal conditions, thus questioning their medical relevance. Here we propose that, due to the prevalence of enhancer redundancy, the pathological effects of many disease-associated non-coding genetic variants might be preferentially (or even only) manifested under environmental stress.

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