An SNP linkage scan identifies significant Crohn's disease loci on chromosomes 13q13.3 and, in Jewish families, on 1p35.2 and 3q29.
Inflammatory bowel disease (IBD) is a complex genetic disorder of two major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC), with increased risk in Ashkenazi Jews. Twelve genome-wide linkage screens have identified multiple loci, but these screens have been of modest size and have used low-density microsatellite markers. We, therefore, performed a high-density single-nucleotide polymorphism (SNP) genome-wide linkage study of 993 IBD multiply affected pedigrees (25% Jewish ancestry) that contained 1709 IBD-affected relative pairs, including 919 CD-CD pairs and 312 UC-UC pairs. We identified a significant novel CD locus on chromosome 13p13.3 (peak logarithm of the odds (LOD) score=3.98) in all pedigrees, significant linkage evidence on chromosomes 1p35.1 (peak LOD score=3.5) and 3q29 (peak LOD score=3.19) in Jewish CD pedigrees, and suggestive loci for Jewish IBD on chromosome 10q22 (peak LOD score=2.57) and Jewish UC on chromosome 2q24 (peak LOD score=2.69). Nominal or greater linkage evidence was present for most previously designated IBD loci (IBD1-9), notably, IBD1 for CD families at chromosome 16q12.1 (peak LOD score=4.86) and IBD6 in non-Jewish UC families at chromosome 19p12 (peak LOD score=2.67). This study demonstrates the ability of high information content adequately powered SNP genome-wide linkage studies to identify loci not observed in multiple microsatellite-based studies in smaller cohorts.
Shugart
Y Y
YY
Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21231, USA.
Silverberg
M S
MS
Duerr
R H
RH
Taylor
K D
KD
Wang
M-H
MH
Zarfas
K
K
Schumm
L P
LP
Bromfield
G
G
Steinhart
A H
AH
Griffiths
A M
AM
Kane
S V
SV
Barmada
M M
MM
Rotter
J I
JI
Mei
L
L
Bernstein
C N
CN
Bayless
T M
TM
Langelier
D
D
Cohen
A
A
Bitton
A
A
Rioux
J D
JD
Cho
J H
JH
Brant
S R
SR
D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D003093:Colitis, Ulcerative / Q000453:epidemiology / Q000235:genetics; D003424:Crohn Disease / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D007585:Jews / Q000235:genetics*; D008126:Lod Score; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics
D005819:Genetic Markers