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

Judy H. Cho*, Dan L. Nicolae, Leslee H. Gold, Carter T. Fields, Michele C. Labuda, Patrick M. Rohal, Michael R. Pickles, Qin Li, Yifan Fu, Jasdeep S. Mann, Barbara S. Kirschner, Ethylin Wang Jabs, James Weber, Stephen B. Hanauer, Theodore M. Bayless, Steven R. Brant

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

335 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7502-7507
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number13
DOIs
StatePublished - Jun 23 1998

Keywords

  • Ashkenazim
  • Chromosome 16
  • Crohn's disease
  • Linkage analysis
  • Ulcerative colitis

ASJC Scopus subject areas

  • General

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