Fine mapping of the IBD1 locus did not identify Crohn disease-associated NOD2 variants: implications for complex disease genetics.
Crohn disease (CD) is a chronic relapsing inflammatory condition of the gastrointestinal tract. Recently, polymorphisms in NOD2 (CARD15), a gene mapping to the chromosome 16 IBD1 susceptibility locus, have been associated with susceptibility to CD. One group identified the gene by using classic positional cloning methods. Here, we report linkage and fine mapping analyses using 27 microsatellite markers encompassing the IBD1 susceptibility locus in 131 CD affected sibling pairs, and a simplex family cohort. No evidence for linkage was observed, and microsatellite markers close to NOD2 did not show association. However, significant association was confirmed in 294 CD trios for the NOD2 variants Arg702Trp and Leu1007fsinsC. Our fine mapping study of the IBD1 locus did not enable us to identify NOD2 as a CD gene, despite the presence of association with disease-causing alleles. This study illustrates the difficulties facing microsatellite linkage and linkage disequilibrium mapping methods for identifying disease genes in complex traits.
van Heel
David A
DA
Gastroenterology Unit, University of Oxford, Oxford, UK. david.vanheel@well.ox.ac.uk
McGovern
Dermot P B
DP
Cardon
Lon R
LR
Dechairo
Bryan M
BM
Lench
Nicholas J
NJ
Carey
Alisoun H
AH
Jewell
Derek P
DP
D002352:Carrier Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16; D003424:Crohn Disease / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015810:Linkage Disequilibrium; D018895:Microsatellite Repeats; D053473:Nod2 Signaling Adaptor Protein
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein