Haplotype structure and association to Crohn's disease of CARD15 mutations in two ethnically divergent populations.
Current debate focuses on the relevance of linkage disequilibrium (LD), ethnicity and underlying haplotype structure to the search for genes involved in complex disorders. The recently described association between single nucleotide polymorphisms (SNPs) of the CARD15 (NOD2) gene and Crohn's disease (CD) in populations of north-European descent provides a test case that we have subjected to detailed SNP haplotype based analyses. We examined 23 SNPs spanning 290 kb, including CARD15, in large North-European and Korean samples of patients with Crohn's disease and normal controls. In Europeans we confirmed that the three disease-associated SNPs occur independently but share a common background haplotype. This suggests a common origin and the possibility of an undiscovered more strongly predisposing mutation. Korean CD patients present a phenotype identical to the European patients and have not previously been screened for CARD15. The three disease-associated SNPs were absent and there was no evidence of association between CARD15 and CD. Consequently, the disease-associated mutations in the Europeans, which are rare, have arisen recently (after the Asian-European split). Our results highlight important issues relevant to mapping the genes that predispose to complex disorders. First, although ethnically divergent populations may present identical phenotypes they do not necessarily share the same set of predisposing genes. Second, although single-locus tests of association showed consistent association with markers throughout the gene, pair-wise LD between markers (r(2) and D') yielded very little information about actual disease-association. Third, a population comparative approach allowed refining of the marker set through the examination of shared polymorphisms and common LD-groups. This approach, in conjunction with the examination of the mutational steps in a haplotype network, allows unambiguous identification of the potentially causative mutations.
Croucher
Peter J P
PJ
1st Department of Medicine, Christian-Albrechts-University, Kiel, Germany.
Mascheretti
Silvia
S
Hampe
Jochen
J
Huse
Klaus
K
Frenzel
Henning
H
Stoll
Monika
M
Lu
Tim
T
Nikolaus
Susanna
S
Yang
Suk-Kyun
SK
Krawczak
Michael
M
Kim
Won Ho
WH
Schreiber
Stefan
S
D044466:Asian People / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D015331:Cohort Studies; D003424:Crohn Disease / Q000453:epidemiology / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005828:Genetics, Population; D005858:Germany / Q000453:epidemiology; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007723:Korea / Q000453:epidemiology; D015810:Linkage Disequilibrium; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein; D020641:Polymorphism, Single Nucleotide; D006113:United Kingdom / Q000453:epidemiology; D044465:White People / Q000235:genetics
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein