Identifying dysregulated regions in amyotrophic lateral sclerosis through chromatin accessibility outliers

The high heritability of ALS and similar rare diseases contrasts with their low molecular diagnosis rate post-genetic testing, pointing to potential undiscovered genetic factors. Chromatin accessibility assays quantify the activity of functional elements genome-wide, offering invaluable insights into dysregulated regions. In this research, we introduced EpiOut, a computational toolbox to identify outliers in chromatin accessibility. These outliers represent dysregulated regions where chromatin accessibility uniquely diverges from the population baseline in a single or few samples. Annotation of accessible regions with histone ChIP-seq and Hi-C indicates that outliers are concentrated in functional loci, especially among promoters interacting with active enhancers. Across different omics levels, outliers are robustly replicated, and chromatin accessibility outliers are reliable predictors of gene expression outliers and aberrant protein levels. For example, 59% of gene expression outliers can be linked to aberration in chromatin accessibility. When promoter accessibility does not align with gene expression, our results indicate that molecular aberrations are more likely to be linked to post-transcriptional regulation rather than transcriptional regulation. Our findings demonstrate that the outlier detection paradigm can uncover dysregulated regions in rare diseases. EpiOut is open-sourced and freely available at github.com/uci-cbcl/EpiOut.