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).
Franke
Andre
A
Institute for Clinical Molecular Biology, Christian-Albrechts University Kiel, Kiel, Germany.
Hampe
Jochen
J
Rosenstiel
Philip
P
Becker
Christian
C
Wagner
Florian
F
Häsler
Robert
R
Little
Randall D
RD
Huse
Klaus
K
Ruether
Andreas
A
Balschun
Tobias
T
Wittig
Michael
M
Elsharawy
Abdou
A
Mayr
Gabriele
G
Albrecht
Mario
M
Prescott
Natalie J
NJ
Onnie
Clive M
CM
Fournier
Hélène
H
Keith
Tim
T
Radelof
Uwe
U
Platzer
Matthias
M
Mathew
Christopher G
CG
Stoll
Monika
M
Krawczak
Michael
M
Nürnberg
Peter
P
Schreiber
Stefan
S
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