Systematic association mapping identifies NELL1 as a novel IBD disease gene.
Crohn disease (CD), a sub-entity of inflammatory bowel disease (IBD), is a complex polygenic disorder. Although recent studies have successfully identified CD-associated genetic variants, these susceptibility loci explain only a fraction of the heritability of the disease. Here, we report on a multi-stage genome-wide scan of 393 German CD cases and 399 controls. Among the 116,161 single-nucleotide polymorphisms tested, an association with the known CD susceptibility gene NOD2, the 5q31 haplotype, and the recently reported CD locus at 5p13.1 was confirmed. In addition, SNP rs1793004 in the gene encoding nel-like 1 precursor (NELL1, chromosome 11p15.1) showed a consistent disease-association in independent German population- and family-based samples (942 cases, 1082 controls, 375 trios). Subsequent fine mapping and replication in an independent sample of 454 French/Canadian CD trios supported the authenticity of the NELL1 association. Further confirmation in a large German ulcerative colitis (UC) sample indicated that NELL1 is a ubiquitous IBD susceptibility locus (combined p<10(-6); OR = 1.66, 95% CI: 1.30-2.11). The novel 5p13.1 locus was also replicated in the French/Canadian sample and in an independent UK CD patient panel (453 cases, 521 controls, combined p<10(-6) for SNP rs1992660). Several associations were replicated in at least one independent sample, point to an involvement of ITGB6 (upstream), GRM8 (downstream), OR5V1 (downstream), PPP3R2 (downstream), NM_152575 (upstream) and HNF4G (intron).
Institute for Clinical Molecular Biology, Christian-Albrechts University Kiel, Kiel, Germany.
Andre
A
Franke
Jochen
J
Hampe
Philip
P
Rosenstiel
Christian
C
Becker
Florian
F
Wagner
Robert
R
Häsler
Randall D
RD
Little
Klaus
K
Huse
Andreas
A
Ruether
Tobias
T
Balschun
Michael
M
Wittig
Abdou
A
Elsharawy
Gabriele
G
Mayr
Mario
M
Albrecht
Natalie J
NJ
Prescott
Clive M
CM
Onnie
Hélène
H
Fournier
Tim
T
Keith
Uwe
U
Radelof
Matthias
M
Platzer
Christopher G
CG
Mathew
Monika
M
Stoll
Michael
M
Krawczak
Peter
P
Nürnberg
Stefan
S
Schreiber
D002135:Calcium-Binding Proteins; D002874:Chromosome Mapping; D003093:Colitis, Ulcerative / Q000235:genetics; D003424:Crohn Disease / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D014018:Tissue Distribution
D002135:Calcium-Binding Proteins; C104144:NELL1 protein, human; D009419:Nerve Tissue Proteins