title: Extended haplotype association study in Crohn's disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3.
abstract: The Ashkenazi Jewish population has a several-fold higher prevalence of Crohn's disease (CD) compared with non-Jewish European ancestry populations and has a unique genetic history. Haplotype association is critical to CD etiology in this population, most notably at NOD2, in which three causal, uncommon and conditionally independent NOD2 variants reside on a shared background haplotype. We present an analysis of extended haplotypes that showed significantly greater association to CD in the Ashkenazi Jewish population compared with a non-Jewish population (145 haplotypes and no haplotypes with P-value <10(-3), respectively). Two haplotype regions, one each on chromosomes 16 and 21, conferred increased disease risk within established CD loci. We performed exome sequencing of 55 Ashkenazi Jewish individuals and follow-up genotyping focused on variants in these two regions. We observed Ashkenazi Jewish-specific nominal association at R755C in TRPM2 on chromosome 21. Within the chromosome 16 region, R642S of HEATR3 and rs9922362 of BRD7 showed genome-wide significance. Expression studies of HEATR3 demonstrated a positive role in NOD2-mediated NF-κB signaling. The BRD7 signal showed conditional dependence with only the downstream rare CD-causal variants in NOD2, but not with the background haplotype; this elaborates NOD2 as a key illustration of synthetic association.
authors.affiliation: Section of Digestive Diseases, Department of Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.forename: K Y
authors.initials: KY
authors.lastname: Hui
authors.forename: A
authors.initials: A
authors.lastname: Gusev
authors.forename: N
authors.initials: N
authors.lastname: Warner
authors.forename: S M E
authors.initials: SM
authors.lastname: Ng
authors.forename: J
authors.initials: J
authors.lastname: Ferguson
authors.forename: M
authors.initials: M
authors.lastname: Choi
authors.forename: A
authors.initials: A
authors.lastname: Burberry
authors.forename: C
authors.initials: C
authors.lastname: Abraham
authors.forename: L
authors.initials: L
authors.lastname: Mayer
authors.forename: R J
authors.initials: RJ
authors.lastname: Desnick
authors.forename: C J
authors.initials: CJ
authors.lastname: Cardinale
authors.forename: H
authors.initials: H
authors.lastname: Hakonarson
authors.forename: M
authors.initials: M
authors.lastname: Waterman
authors.forename: Y
authors.initials: Y
authors.lastname: Chowers
authors.forename: A
authors.initials: A
authors.lastname: Karban
authors.forename: S R
authors.initials: SR
authors.lastname: Brant
authors.forename: M S
authors.initials: MS
authors.lastname: Silverberg
authors.forename: P K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: S
authors.initials: S
authors.lastname: Katz
authors.forename: R P
authors.initials: RP
authors.lastname: Lifton
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.forename: G
authors.initials: G
authors.lastname: Nuñez
authors.forename: I
authors.initials: I
authors.lastname: Pe'er
authors.forename: I
authors.initials: I
authors.lastname: Peter
authors.forename: J H
authors.initials: JH
authors.lastname: Cho
mesh_terms: D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D003424:Crohn Disease / Q000235:genetics*; D005091:Exons / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D057809:HEK293 Cells; D006239:Haplotypes; D006801:Humans; D007585:Jews / Q000235:genetics*; D016015:Logistic Models; D020125:Mutation, Missense; D016328:NF-kappa B / Q000235:genetics*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D034622:RNA Interference; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics*; D000092468:Bromodomain Containing Proteins
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D016328:NF-kappa B; D053473:Nod2 Signaling Adaptor Protein; D011506:Proteins; C485694:BRD7 protein, human; D000092468:Bromodomain Containing Proteins; C586434:HEATR3 protein, human; C429018:NOD2 protein, human