title: Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease.
abstract: 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.
authors: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. rivas@broadinstitute.org
authors: Manuel A
authors: MA
authors: Rivas
authors: Mélissa
authors: M
authors: Beaudoin
authors: Agnes
authors: A
authors: Gardet
authors: Christine
authors: C
authors: Stevens
authors: Yashoda
authors: Y
authors: Sharma
authors: Clarence K
authors: CK
authors: Zhang
authors: Gabrielle
authors: G
authors: Boucher
authors: Stephan
authors: S
authors: Ripke
authors: David
authors: D
authors: Ellinghaus
authors: Noel
authors: N
authors: Burtt
authors: Tim
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authors: Fennell
authors: Andrew
authors: A
authors: Kirby
authors: Anna
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authors: Latiano
authors: Philippe
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authors: Goyette
authors: Todd
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authors: Green
authors: Jonas
authors: J
authors: Halfvarson
authors: Talin
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authors: Haritunians
authors: Joshua M
authors: JM
authors: Korn
authors: Finny
authors: F
authors: Kuruvilla
authors: Caroline
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authors: Lagacé
authors: Benjamin
authors: B
authors: Neale
authors: Ken Sin
authors: KS
authors: Lo
authors: Phil
authors: P
authors: Schumm
authors: Leif
authors: L
authors: Törkvist
authors: Marla C
authors: MC
authors: Dubinsky
authors: Steven R
authors: SR
authors: Brant
authors: Mark S
authors: MS
authors: Silverberg
authors: Richard H
authors: RH
authors: Duerr
authors: David
authors: D
authors: Altshuler
authors: Stacey
authors: S
authors: Gabriel
authors: Guillaume
authors: G
authors: Lettre
authors: Andre
authors: A
authors: Franke
authors: Mauro
authors: M
authors: D'Amato
authors: Dermot P B
authors: DP
authors: McGovern
authors: Judy H
authors: JH
authors: Cho
authors: John D
authors: JD
authors: Rioux
authors: Ramnik J
authors: RJ
authors: Xavier
authors: Mark J
authors: MJ
authors: Daly
mesh_terms: D016022:Case-Control Studies; D002460:Cell Line; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D012326:RNA Splicing; D018123:Receptors, Interleukin / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: C515500:IL23R protein, human; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D018123:Receptors, Interleukin