Identification of novel susceptibility loci for inflammatory bowel disease on chromosomes 1p, 3q, and 4q: evidence for epistasis between 1p and IBD1

Abstract

The idiopathic inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC), are chronic, frequently disabling diseases of the intestines. Segregation analyses, twin concordance, and ethnic differences in familial risks have established that CD and UC are complex, non-Mendelian, related genetic disorders. We performed a genome-wide screen using 377 autosomal markers, on 297 CD, UC, or mixed relative pairs from 174 families, 37% Ashkenazim. We observed evidence for linkage at 3q for all families (multipoint logarithm of the odds score (MLod) = 2.29, P = 5.7 x 10(-4)), with greatest significance for non-Ashkenazim Caucasians (MLod = 3.39, P = 3.92 x 10(-5)), and at chromosome 1p (MLod = 2.65, P = 2.4 x 10(-4)) for all families. In a limited subset of mixed families (containing one member with CD and another with UC), evidence for linkage was observed on chromosome 4q (MLod = 2.76, P = 1.9 x 10(-4)), especially among Ashkenazim. There was confirmatory evidence for a CD locus, overlapping IBD1, in the pericentromeric region of chromosome 16 (MLod = 1.69, P = 2.6 x 10(-3)), particularly among Ashkenazim (MLod = 1.51, P = 7.8 x 10(-3)); however, positive MLod scores were observed over a very broad region of chromosome 16. Furthermore, evidence for epistasis between IBD1 and chromosome 1p was observed. Thirteen additional loci demonstrated nominal (MLod > 1.0, P < 0.016) evidence for linkage. This screen provides strong evidence that there are several major susceptibility loci contributing to the genetic risk for CD and UC.

Figure 1

Multipoint nonparametric linkage analysis of all families, CD-only families, mixed (families containing at least one or more member with a diagnosis of CD and one or more member with a diagnosis of UC, or any member with indeterminate idiopathic colitis) and UC-only families. The all-families curves reflect the combined contributions of the CD-only families, UC-only families, and mixed families. Map distances were taken from the Weber screening set 8.0. Multipoint analysis was performed by using a modified version of genehunter (25). Information content was 0.48, SD 0.07. ∗, regions implicated in Hugot et al.’s genome-wide screen (16). +, regions implicated in Satsangi et al.’s genome-wide screen (20). MHC, major histocompatibility complex.

Figure 2

Analysis of CD-only families on chromosome 16, conditioned on results from the region of maximal MLod on chromosome 1p. MLod curves of all CD families (A), CD families with positive NPL scores (25) (B), and negative (25) scores on chromosome 1p (C). IBD1, interpolated region of linkage described by Hugot et al. (16).