Genetics of Inflammatory Bowel Diseases

doi:10.1053/j.gastro.2015.08.001

Gastroenterology

Volume 149, Issue 5, October 2015, Pages 1163-1176.e2

https://doi.org/10.1053/j.gastro.2015.08.001 Get rights and content

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 nonsynonymous 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.

Section snippets

Genome-Wide Association Studies in IBD

The first genome-wide association studies (GWAS) using genome-wide single nucleotide polymorphism (SNP) chips were published in 2005.1, 2 The conceptual basis of GWAS is that most complex (ie, not single-gene Mendelian) genetic disorders are polygenic, being driven by multiple, common genetic polymorphisms. A key methodologic advance enabling GWAS was the development of genome-wide SNP chips that typed a relatively limited number of selected polymorphisms (less than 1 million SNPs for

Functional Consequences of Missense Alleles Associated With IBD

Because of the highly correlated nature of human genetic polymorphisms, association signals often span broad genomic regions including multiple genes and transcribed sequences. Thus far, it has often been difficult to assign the likely “causal gene” driving the association signal. The presence of maximal association signals corresponding to missense alleles within a gene in the region, especially when linked to functional studies demonstrating altered gene function, provides strong support for

Fine-Mapping Noncoding Genetic Variation: Integration of Expression and Epigenetic Data Implicates Cell Subtypes in Disease Pathogenesis

It has long been understood that disease-causing alleles are highly enriched for nonsynonymous, coding region variations that modulate protein structure and/or function.²⁶ However, for 80% to 90% of GWAS-identified loci, the maximal association signals do not include a nonsynonymous variant, instead being confined to noncoding variation. Presumably, much of this noncoding variation exerts its pathogenic effects through modulation of gene expression. Expression quantitative trait loci (eQTL)

Population Differences in IBD

Initially thought to be a disease that affected primarily populations of European ancestry, it is increasingly evident that IBD involves almost all racial and ethnic groups.⁴⁰ Our current understanding of IBD genetics is based on studies done primarily in populations of European ancestry, but increasingly, studies in non-European populations are being reported. Some studies have shown that disease markers identified in European ancestry populations may also be observed in admixed populations.

Common and Rare IBD Genetic Variations: Sequencing Studies In IBD

Variants that affect protein function are more likely to have greater penetrance and may be more amenable to functional studies. Because natural selection acts against variants, such as Mendelian or monogenic mutations that confer large effects on disease susceptibility, such mutations are usually of low to rare frequency (Figure 1). However, rare mutations of higher effects (ie, high odds ratios) are not only predicted to outnumber common variants in the human genome,⁵⁶ but could also explain

Genetics of Early Onset Cases of IBD

Whereas childhood onset IBD represents only 10% to 25% of all IBD cases, genetic research of pediatric IBD has contributed new knowledge and revealed unsuspected pathways. A substantial proportion of patients with monogenic diseases present with very early onset intestinal inflammation (at less than 10 years of age) that is reminiscent of very early onset IBD. There is also considerable overlap with primary immunodeficiencies and very early onset IBD (Table 2), a topic which has been reviewed

Clinical Applications and Genetic Testing

Of particular relevance to IBD genetics has been the launch of major initiatives in precision medicine involving prevention and treatment strategies that take individual variability into account.⁷⁵ Inflammatory bowel diseases, because of their heterogeneity with respect to natural history and response to therapy, are, arguably, the prototype immune-mediated disease for incorporating genetic parameters into everyday clinical practice. This, coupled with the very significant advances in

Future Directions

Advances in our understanding of the genetic variation underlying IBD, particularly in European ancestry individuals, have been spectacular and have provided an outstanding framework for basic and translational research. These advances have also generated significant challenges and posed many additional questions. From an ethical and scientific perspective, it is imperative that the resources applied to generating these datasets be applied to non-European ancestry populations. Large-scale

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Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract that might lead to progressive bowel damage and disability. The exact cause of Crohn's disease is unknown, but evidence points towards multifactorial events causing dysregulation of the innate immune system in genetically susceptible people. Commonly affecting the terminal ileum and proximal colon, Crohn's disease inflammation is often discontinuous and patchy, segmental, and transmural. Identification of characteristic findings on ileocolonoscopy and histology remains the diagnostic gold standard, but complete assessment involves laboratory abnormalities, including micronutrient deficiencies, cross-sectional imaging to identify transmural disease extent, severity and complications, and a psychosocial assessment. Treatment strategies for patients with Crohn's disease now go beyond achieving clinical remission to include deeper targets of endoscopic healing and consideration of adjunctive histological and transmural targets to alter disease progression potentially further. The use of early effective advanced therapies and development of therapies targeting alternative novel pathways with improved safety profiles have resulted in a new era of healing in Crohn's disease management. Future combination of advanced therapies with diet or other biological drugs and small molecules, together with improvements in tight control monitoring tools and predictive biomarkers might continue to improve outcomes for patients with Crohn's disease.
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Inflammatory bowel disease (IBD) is a chronic, relapsing intestinal disease. Elucidation of the pathogenic mechanisms of IBD requires high-throughput technologies (HTTs) to effectively obtain and analyze large amounts of data. Recently, HTTs have been widely used in IBD, including genomics, transcriptomics, proteomics, microbiomics, metabolomics and single-cell sequencing. When combined with endoscopy, the application of these technologies can provide an in-depth understanding on the alterations of intestinal microbe diversity and abundance, the abnormalities of signaling pathway-mediated immune responses and functionality, and the evaluation of therapeutic effects, improving the accuracy of early diagnosis and treatment of IBD. This review comprehensively summarizes the development and advancement of HTTs, and also highlights the challenges and future directions of these technologies in IBD research. Although HTTs have made striking breakthrough in IBD, more standardized methods and large-scale dataset processing are still needed to achieve the goal of personalized medicine.
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: Conflicts of interest The authors disclose no conflicts.

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ReviewGenomicsGenetics of Inflammatory Bowel Diseases

Section snippets

Genome-Wide Association Studies in IBD

Functional Consequences of Missense Alleles Associated With IBD

Fine-Mapping Noncoding Genetic Variation: Integration of Expression and Epigenetic Data Implicates Cell Subtypes in Disease Pathogenesis

Population Differences in IBD

Common and Rare IBD Genetic Variations: Sequencing Studies In IBD

Genetics of Early Onset Cases of IBD

Clinical Applications and Genetic Testing

Future Directions

Gastroenterology

J Biol Chem

Gastroenterology

Gastroenterology

Lancet

Immunity

Gastroenterology

Immunity

Am J Med Sci

Gastroenterology

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Genetics of Inflammatory Bowel Diseases