Extended haplotype association study in Crohn's disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3

W. Zhang, K. Y. Hui, A. Gusev, N. Warner, S. M.E. Ng, J. Ferguson, M. Choi, A. Burberry, C. Abraham, L. Mayer, R. J. Desnick, C. J. Cardinale, H. Hakonarson, M. Waterman, Y. Chowers, A. Karban, S. R. Brant, M. S. Silverberg, P. K. Gregersen, S. KatzR. P. Lifton, H. Zhao, G. Nuñez, I. Pe'er, I. Peter, J. H. Cho

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)310-316
Number of pages7
JournalGenes and immunity
Volume14
Issue number5
DOIs
StatePublished - Jul 2013

Keywords

  • Ashkenazi Jewish
  • Crohn's disease
  • Haplotype association
  • NF-κB signaling
  • Synthetic association

ASJC Scopus subject areas

  • Immunology
  • Genetics
  • Genetics(clinical)

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