Multilevel effects of non-coding genetic variation on regulatory elements and chromatin organization

Disease-linked variants identified in GWAS studies are often located outside protein-coding genes, but the effects of these variants are poorly understood. In order to assess the effects of noncoding variants on gene expression regulation, we analyzed the interaction between genetic variation, epigenetic regulatory elements, 3D chromatin organization and gene expression. Between ten inbred rat strains, we find variability in regulatory elements, of which part can be linked with genetic variants inside these elements. Although the 3D chromatin organization is largely similar between strains, even around differentially expressed genes, there are differences in 3D organization that correspond with changes in regulatory elements. Moreover, we find that active chromatin domains that differ between strains are enriched for genetic variation, suggesting a genetic influence on chromatin organization. Our findings demonstrate that genetic variation influences multiple transcription regulatory components and that multilevel analyses are required to properly understand the functional effects of individual genetic variants.