Abstract
Over the course of the past decade, genome‐wide association studies (GWAS) have revolutionised our understanding of complex disease genetics. One of the diseases that has benefitted most from this technology has been Crohn's disease (CD), with the identification of autophagy, the IL‐17/IL‐23 axis and innate lymphoid cells as key players in CD pathogenesis. Our increasing understanding of the genetic architecture of CD has also highlighted how a failure to suppress aberrant immune responses may contribute to disease development – a realisation that is now being incorporated into the design of new treatments. However, despite these successes, a significant proportion of disease heritability remains unexplained. Similarly, most of the causal variants at associated loci have not yet been identified, and even fewer have been functionally characterised. Because of the inarguable rise in the incidence of CD in regions of the world that previously had low disease rates, GWAS studies will soon have to shift from a largely Caucasian focus to include populations from other ethnic backgrounds. Future studies should also move beyond conventional studies of disease susceptibility into phenotypically driven ‘within‐cases’ analyses in order to explore the role of genetics in other important aspects of disease biology. These studies are likely to include assessments of prognosis and/or response to treatments and may be critical if personalised medicine is ever to become a reality.
Highlights
Crohn’s disease (CD) and ulcerative colitis (UC), collectively termed Inflammatory Bowel Disease (IBD), are some of the most extensively and successfully studied diseases in complex disease genetics
Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australasian Society for Immunology Inc
While most IBD susceptibility loci are shared between CD and UC, it is notable that single nucleotide polymorphisms (SNPs) that are implicated in autophagy seem to be specific to CD, while SNPs that are located in, or near to, genes involved in epithelial barrier function tend to be more UC specific.[74]
Summary
Crohn’s disease (CD) and ulcerative colitis (UC), collectively termed Inflammatory Bowel Disease (IBD), are some of the most extensively and successfully studied diseases in complex disease genetics. In addition to highlighting pathways that are likely to be important in the development of CD, GWAS has provided insights into how the genetic architecture of CD relates to that of other autoimmune diseases.[16] For example, while most IBD susceptibility loci are shared between CD and UC, it is notable that SNPs that are implicated in autophagy seem to be specific to CD, while SNPs that are located in, or near to, genes involved in epithelial barrier function tend to be more UC specific.[74] Interesting overlaps have been noted in other nonintestinal diseases This is perhaps best exemplified by the IL-23/IL-17 axis, to which multiple autoimmune diseases have been linked, including psoriasis (SNPs in or near to IL23R, IL12B, TYK2 and STAT3), ankylosing spondylitis (SNPs in or near to IL23R, IL12B, TYK2 and JAK2) and multiple sclerosis (SNPs in or near to IL12B, IL12A, TYK2 and STAT3). Several studies have been performed to attempt to identify rare disease-associated variants, but without much 2018 | Vol 7 | e1001 Page 8
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