Co-expression patterns define epigenetic regulators associated with neurological dysfunction

Coding variants in genes encoding for epigenetic regulators are an emerging cause of neurological dysfunction and cancer. However, a systematic effort to identify disease candidates within the human epigenetic machinery (EM) has not been performed, and it is unclear whether features exist that distinguish between variation-intolerant and variation-tolerant EM genes, and between EM genes associated with neurological dysfunction versus cancer. Here, we rigorously define a set of 295 human genes with a direct role in epigenetic regulation (writers, erasers, remodelers, readers). Systematic exploration of these genes reveals that while individual enzymatic functions are always mutually exclusive, readers often also exhibit enzymatic activity as well (dual function EM genes). We find that the majority of EM genes are very intolerant to loss-of-function variation, even when compared to the dosage sensitive group of transcription factors. Using this strategy, we identify 103 novel EM disease candidates. We show that the intolerance to loss-of-function variation is driven by the protein domains encoding the epigenetic function, strongly suggesting that disease is caused by a perturbed chromatin state. Unexpectedly, we also describe a large subset of EM genes that are co-expressed within multiple tissues. This subset is almost exclusively populated by extremely variation-intolerant EM genes, and shows enrichment for dual function EM genes. It is also highly enriched for genes associated with neurological dysfunction, even when accounting for dosage sensitivity, but not for cancer-associated EM genes. These findings prioritize novel disease candidate EM genes, and suggest that the co-expression itself may play a functional role in normal neurological homeostasis.