Autoimmune diseases — connecting risk alleles with molecular traits of the immune system

• Published in: Nature reviews. Genetics Vol. 17; no. 3; pp. 160 - 174
• Main Authors: Gutierrez-Arcelus, Maria, Rich, Stephen S., Raychaudhuri, Soumya
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2016; Nature Publishing Group
• Subjects: 631/208/205/2138; 631/208/2489/144; 631/208/726/649; 631/208/729/743; 631/250/38; Agriculture; Alleles; Animal Genetics and Genomics; Autoimmune Diseases - epidemiology; Autoimmune Diseases - genetics; Autoimmunity; Autoimmunity - genetics; Biomedicine; Cancer Research; Chromosome Mapping; Disease susceptibility; Epigenesis, Genetic; Gene Function; Genetic aspects; Genetic Loci - genetics; Genetic Predisposition to Disease; Genetic Variation; Genomics; Health aspects; Human Genetics; Humans; Identification and classification; Immune System - physiology; Immunophenotyping; Medicin och hälsovetenskap; Models, Molecular; Phenotype; Prevalence; Quantitative trait loci; review-article; Risk; Risk factors
• ISSN: 1471-0056; 1471-0064; 1471-0064
• DOI: 10.1038/nrg.2015.33

Key Points Autoimmune diseases affect approximately 8–9% of the world population. There are no cures and only limited therapies exist to treat symptoms. Hundreds of genomic susceptibility loci have been discovered but, despite progress in fine-mapping causal genes and variant identification, the genetic mechanisms that trigger autoimmunity are largely unknown. Most risk variants that are likely to be causal are in non-coding sequences, particularly in regulatory regions known to be active in immune cell types; it is therefore crucial to understand how enhancers and their targets affect gene regulation and immune function. As a wider compendium of transcriptomic and epigenomic profiles for human immune cell types and cell states is built, we will be able to further pinpoint the conditions under which most risk variants may be exerting their effect. Profiling of immunophenotypes, such as signalling response, immune cell abundances and serum cytokine levels (among others), in thousands of individuals may help identify the key immune functions and interactions involved in autoimmunity risk. When the key immunophenotypes have been identified, longitudinal studies will be essential for revealing the causal relationships among intermediate phenotypes and elucidating the sequence of events that lead to autoimmunity. Genome-wide approaches have advanced the study into mechanisms triggering autoimmunity. This Review illustrates how this has been achieved for twelve common autoimmune diseases, and discusses recent functional genomics approaches that have the potential to help define key immune molecular traits, cell types and cell states. Genome-wide strategies have driven the discovery of more than 300 susceptibility loci for autoimmune diseases. However, for almost all loci, understanding of the mechanisms leading to autoimmunity remains limited, and most variants that are likely to be causal are in non-coding regions of the genome. A critical next step will be to identify the in vivo and ex vivo immunophenotypes that are affected by risk variants. To do this, key cell types and cell states that are implicated in autoimmune diseases will need to be defined. Functional genomic annotations from these cell types and states can then be used to resolve candidate genes and causal variants. Together with longitudinal studies, this approach may yield pivotal insights into how autoimmunity is triggered.