IDENTIFICATION OF NOVEL SUSCEPTIBILITY LOCI FOR INFLAMMATORY BOWEL-DISEASE ON CHROMOSOMES 1Q, 3Q, AND 4Q - EVIDENCE FOR EPISTASIS BETWEEN 1P AND IBD1

The idiopathic inflammatory bowel diseases, Crohn's disease (CD) and u lcerative colitis (UC), are chronic, frequently disabling diseases of the intestines. Segregation analyses, twin concordance, and ethnic dif ferences 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 link age at 3q for all families (multipoint logarithm of the odds score (ML od) = 2.29, P = 5.7 x 10(-4)), with greatest significance for non-Ashk enazim 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 subs et of mixed families (containing one member with CD and another with U C), evidence for linkage was observed on chromosome Iq (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 regi on of chromosome 16 (MLod = 1.69, P = 2.6 x 10(-3)), particularly amon g Ashkenazim (MLod = 1.51, P = 7.8 x 10(-3)); however, positive MLod s cores were observed over a very broad region of chromosome 16. Further more, evidence for epistasis between IBD1 and chromosome Ip,vas observ ed. Thirteen additional loci demonstrated nominal (MLod > 1.0, P < 0.0 16) evidence for linkage. This screen pro,ides strong evidence that th ere are several major susceptibility loci contributing to the genetic risk for CD and UC.