Dissecting the genetics of complex inheritance: linkage disequilibrium mapping provides insight into Crohn disease

Abstract

Family studies for Crohn disease (CD) report extensive linkage on chromosome 16q and pinpoint NOD2 as a possible causative locus. However, linkage is also observed in families that do not bear the most frequent NOD2 causative mutations, but no other signals on 16q have been found so far in published genome-wide association studies. Our aim is to identify this missing genetic contribution. We apply a powerful genetic mapping approach to the Wellcome Trust Case-Control Consortium and the National Institute of Diabetes and Digestive and Kidney Diseases genome-wide association data on CD. This method takes into account the underlying structure of linkage disequilibrium (LD) by using genetic distances from LD maps and provides a location for the causal agent. We find genetic heterogeneity within the NOD2 locus and also show an independent and unsuspected involvement of the neighboring gene, CYLD. We find associations with the IRF8 region and the region containing CDH1 and CDH3, as well as substantial phenotypic and genetic heterogeneity for CD itself. The genes are known to be involved in inflammation and immune dysregulation. These findings provide insight into the genetics of CD and suggest promising directions for understanding disease heterogeneity. The application of this method thus paves the way for understanding complex inheritance in general, leading to the dissection of different pathways and ultimately, personalized treatment.

Figure 1

NOD2, CYLD, and Genetic Heterogeneity (A) Analysis of all patients (unstratified data); SNP data are grouped in two separate windows, covering either NOD2 or CYLD. The vertical lines are the estimated locations (Ŝ) for the windows including NOD2 alone and CYLD alone. The LD map, which plots LDUs (y axis) against physical distance (x axis), is shown for the region surrounding the estimates of Ŝ. (B) Stratified data are shown for carriers and noncarriers of the most frequent NOD2 causal variants. (B) includes SNPs for both genes (NOD2 and CYLD windows). See text for details on the stratification procedure. The SNPs rs17860491, rs17860492, and rs17860493 correspond to the reported functional SNPs in NOD2. This figure also depicts the position of a putative enhancer (see text).

Figure 2

Localization within the CDH3 and CDH1 Region The LD map, which plots HapMap LDUs (y axis) against kb (x axis), is shown for the region surrounding Ŝ. The red vertical arrow is the estimated location Ŝ for both data sets, but because of the very long LD block, the causal location(s) could reside anywhere in this block. The rs16260 is a functional SNP within this block and is located 365 nucleotides upstream of the transcription start site for CDH1. ^∗NIDDK data only contain ileal CD with the involvement of at least one extraileal intestinal location.

Figure 3

Localization within the IRF8 Region The LD map, which plots HapMap LDUs (y axis) against kb (x axis), is shown for the region surrounding the Ŝ. The red vertical arrow is the estimated location Ŝ. ^∗NIDDK data only contain ileal CD with an involvement of at least one extraileal intestinal location. Two SNPs have been identified for UC and MS in GWA meta-analyses.