Functional genomics in autoimmune diseases

Abstract

Associations between genetic loci and increased susceptibility to autoimmune disease have been well characterized, however, translating this knowledge into mechanistic insight and patient benefit remains a challenge. While improvements in the precision, completeness and accuracy of our genetic understanding of autoimmune diseases will undoubtedly be helpful, meeting this challenge will require two interlinked problems to be addressed: first which of the highly correlated variants at an individual locus is responsible for increased disease risk, and second what are the downstream effects of this variant. Given that the majority of loci are thought to affect non-coding regulatory elements, the second question is often reframed as what are the target gene(s) and pathways affected by causal variants. Currently, these questions are being addressed using a wide variety of novel techniques and datasets. In many cases, these approaches are complementary and it is likely that the most accurate picture will be generated by consolidating information relating to transcription, regulatory activity, chromatin accessibility, chromatin conformation and readouts from functional experiments, such as genome editing and reporter assays. It is clear that it will be necessary to gather this information from disease relevant cell types and conditions and that by doing so our understanding of disease etiology will be improved. This review is focused on the field of autoimmune disease functional genomics with a particular focus on the most exciting and significant research to be published within the last couple of years.

Fine mapping with epigenetic information and 3D structure

“…These studies and many others [ 93 , 94 ] exemplify how 3D chromatin structure can aid the functional interrogation of GWAS loci. However, Hi-C methods often lack resolution to characterize individual enhancer-promoter interactions at sufficient depth since interaction maps are constrained by the restriction enzyme used, typically HindIII .…”

Global climate change, diet, and the complex relationship between human host and microbiome: Towards an integrated picture

“…Specific genetic variants that are often associated with increased risk of, for example, cancer, might be significant only insofar as they are coupled with associated (micro)environmental factors. [170,171] This is important given the healthcare industry's rapid evolution. Patient-tailored treatments that follow a decontextualized identification and prediction of disease-susceptibility loci should be avoided unless non-genetic and environment-driven changes are also taken into account.…”

Functional genomics in primary T cells and monocytes identifies mechanisms by which genetic susceptibility loci influence systemic sclerosis risk

“…These regulatory elements can interact with genes often located hundreds of kilobases away, bypassing in many cases nearby genes (16). Thus, the current challenge remains in linking disease-associated regions with the genes that they affect, in the specific cell types involved, in order to pinpoint to the mechanisms and the biological pathways implicated in genetically susceptible patients (17). In this regard, many techniques to analyze the three-dimensional genome architecture have emerged, such as chromosome conformation capture (3C) (18,19), that can help us annotate these genetic variants.…”

“…Thus, the current challenge remains in linking disease-associated regions with the genes that they affect, in the specific cell types involved, in order to pinpoint to the mechanisms and the biological pathways implicated in genetically susceptible patients (17). In this regard, many techniques to analyze the three-dimensional genome architecture have emerged, such as chromosome conformation capture (3C) (18,19), that can help us annotate these genetic variants.…”