Genetic studies of Crohn's disease: past, present and future

Abstract

The exact aetiology of Crohn's disease is unknown, though it is clear from early epidemiological studies that a combination of genetic and environmental risk factors contributes to an individual's disease susceptibility. Here, we review the history of gene-mapping studies of Crohn's disease, from the linkage-based studies that first implicated the NOD2 locus, through to modern-day genome-wide association studies that have discovered over 140 loci associated with Crohn's disease and yielded novel insights into the biological pathways underlying pathogenesis. We describe on-going and future gene-mapping studies that utilise next generation sequencing technology to pinpoint causal variants and identify rare genetic variation underlying Crohn's disease risk. We comment on the utility of genetic markers for predicting an individual's disease risk and discuss their potential for identifying novel drug targets and influencing disease management. Finally, we describe how these studies have shaped and continue to shape our understanding of the genetic architecture of Crohn's disease.

Keywords: Crohn's; Genetics; Genomics; Genotyping; Sequencing.

Fig. 1

The genetic architecture of Crohn's disease. Known Crohn's disease risk variants are plotted according to their minor allele frequency and odds ratio (OR) . The size of the circles represents the amount of variance in Crohn's disease liability explained by that variant. The red, blue and black lines represent the minimum OR and allele frequency for a locus for which a linkage study with 3000 individuals, GWAS with 3000 individuals and GWAS with 50,000 individuals respectively will have >80% statistical power to detect . P-value thresholds for power calculations were set to P < 10⁻⁴ for linkage and P <5 × 10⁻⁸ for GWAS. The dashed lines represents the allele frequency spectrum of variants that are typically poorly captured on GWAS microarrays (minor allele frequencies less than 1%).

Fig. 2

The Crohn's disease genome. Known Crohn's disease risk loci are shown according to their location on the long or short arms of chromosomes. The size of each locus indicates the proportion of variance in Crohn's disease liability explained by that locus . Several notable genes are marked. Parentheses next to gene names denote the number of independent risk variants within the locus. The number above each chromosome is the ratio of the total amount of variance explained by that chromosome vs the expected number given the chromosome's size. Sex chromosomes were excluded as no loci have been conclusively implicated, largely due to these chromosomes being overlooked from most GWAS.

Fig. 3

Proportion of noncoding, nonsynonymous and known eQTLs among known 140 Crohn's disease risk loci. A locus is labelled as nonsynonymous if the lead SNP is in high linkage disequilibrium (LD; r² > 0.8) with a nonsense or missense mutation. Similarly, loci with eQTLs were marked if the lead SNP is in high LD with a known eQTL in studies of liver, brain, fibroblasts, monocytes, T cells and lymphoblastoid cell lines .