Genetics of Inflammatory Bowel Diseases

In this review, we provide an update on genome-wide association studies (GWAS) in inflammatory bowel disease (IBD). In addition, we summarize progress in defining the functional consequences of associated alleles for coding and noncoding genetic variation. In the small minority of loci where major association signals correspond to non-synonymous variation, we summarize studies defining their functional effects and implications for therapeutic targeting. Importantly, the large majority of GWAS-associated loci involve noncoding variation, many of which modulate levels of gene expression. Recent expression quantitative trait loci (eQTL) studies have established that the expression of most human genes is regulated by noncoding genetic variations. Significant advances in defining the epigenetic landscape have demonstrated that IBD GWAS signals are highly enriched within cell-specific active enhancer marks. Studies in European ancestry populations have dominated the landscape of IBD genetics studies, but increasingly, studies in Asian and African-American populations are being reported. Common variation accounts for only a modest fraction of the predicted heritability and the role of rare genetic variation of higher effects (ie, odds ratios markedly deviating from 1) is increasingly being identified through sequencing efforts. These sequencing studies have been particularly productive in more severe very early onset cases. A major challenge in IBD genetics will be harnessing the vast array of genetic discovery for clinical utility through emerging precision medical initiatives. In this article, we discuss the rapidly evolving area of direct-to-consumer genetic testing and the current utility of clinical exome sequencing, especially in very early onset, severe IBD cases. We summarize recent progress in the pharmacogenetics of IBD with respect to partitioning patient responses to anti-TNF and thiopurine therapies. Highly collaborative studies across research centers and across subspecialties and disciplines will be required to fully realize the promise of genetic discovery in IBD.