Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis.
Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.
Montreal Heart Institute, Research Center, Montreal, Quebec, Canada.
Mélissa
M
Beaudoin
Philippe
P
Goyette
Gabrielle
G
Boucher
Ken Sin
KS
Lo
Manuel A
MA
Rivas
Christine
C
Stevens
Azadeh
A
Alikashani
Martin
M
Ladouceur
David
D
Ellinghaus
Leif
L
Törkvist
Gautam
G
Goel
Caroline
C
Lagacé
Vito
V
Annese
Alain
A
Bitton
Jakob
J
Begun
Steve R
SR
Brant
Francesca
F
Bresso
Judy H
JH
Cho
Richard H
RH
Duerr
Jonas
J
Halfvarson
Dermot P B
DP
McGovern
Graham
G
Radford-Smith
Stefan
S
Schreiber
Philip L
PL
Schumm
Yashoda
Y
Sharma
Mark S
MS
Silverberg
Rinse K
RK
Weersma
Mauro
M
D'Amato
Severine
S
Vermeire
Andre
A
Franke
Guillaume
G
Lettre
Ramnik J
RJ
Xavier
Mark J
MJ
Daly
John D
JD
Rioux
D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D002170:Canada; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics* / Q000473:pathology; D005006:Ethnicity; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D018123:Receptors, Interleukin / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D053468:CARD Signaling Adaptor Proteins; C505855:CARD9 protein, human; C515500:IL23R protein, human; D018123:Receptors, Interleukin; C587047:RNF186 protein, human; D044767:Ubiquitin-Protein Ligases