TY - JOUR
T1 - Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease
AU - Rivas, Manuel A.
AU - Beaudoin, Mélissa
AU - Gardet, Agnes
AU - Stevens, Christine
AU - Sharma, Yashoda
AU - Zhang, Clarence K.
AU - Boucher, Gabrielle
AU - Ripke, Stephan
AU - Ellinghaus, David
AU - Burtt, Noel
AU - Fennell, Tim
AU - Kirby, Andrew
AU - Latiano, Anna
AU - Goyette, Philippe
AU - Green, Todd
AU - Halfvarson, Jonas
AU - Haritunians, Talin
AU - Korn, Joshua M.
AU - Kuruvilla, Finny
AU - Lagacé, Caroline
AU - Neale, Benjamin
AU - Lo, Ken Sin
AU - Schumm, Phil
AU - Törkvist, Leif
AU - National Institute of Diabetes and Digestive Kidney Diseases Inflammatory Bowel Disease Genetics Consortium
AU - United Kingdom Inflammatory Bowel Disease Genetics Consortium
AU - International Inflammatory Bowel Disease Genetics Consortium
AU - Lawrance, Ian
AU - Dubinsky, Marla C.
AU - Brant, Steven R.
AU - Silverberg, Mark S.
AU - Duerr, Richard H.
AU - Altshuler, David
AU - Gabriel, Stacey
AU - Lettre, Guillaume
AU - Franke, Andre
AU - D'Amato, Mauro
AU - McGovern, Dermot P B
AU - Cho, Judy H.
AU - Rioux, John D.
AU - Xavier, Ramnik J.
AU - Daly, Mark J.
PY - 2011/11
Y1 - 2011/11
N2 - More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10 -16, odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.
AB - More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10 -16, odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.
UR - http://www.scopus.com/inward/record.url?scp=80054975975&partnerID=8YFLogxK
U2 - 10.1038/ng.952
DO - 10.1038/ng.952
M3 - Article
AN - SCOPUS:80054975975
SN - 1061-4036
VL - 43
SP - 1066
EP - 1073
JO - Nature Genetics
JF - Nature Genetics
IS - 11
ER -