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

Genes & Immunity volume 14, pages 310–316 (2013)Cite this article

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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.

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Acknowledgements

This work was supported by the National Institutes of Health (NIDDK U01 DK062429, U01 DK062422, R01 DK092235 and RC1 DK086800 to JHC, NIDDK F30 DK098927 and NIGMS T32 GM007205 to KYH and R01 DK77905 to CA), the New York Crohn’s Disease Foundation (LM, RJD and IP) and the Crohn’s and Colitis Foundation of America (KL2RR024138 to JHC).

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Author notes

  1. W Zhang and K Y Hui: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA

    W Zhang, K Y Hui, S M E Ng, J Ferguson, C Abraham & J H Cho

  2. Department of Epidemiology, Harvard University, Boston, MA, USA

    A Gusev

  3. Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA

    N Warner, A Burberry & G Nuñez

  4. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA

    M Choi, R P Lifton, H Zhao & J H Cho

  5. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA

    L Mayer, R J Desnick & I Peter

  6. Center for Applied Genomics, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    C J Cardinale & H Hakonarson

  7. Department of Gastroenterology, Rambam Health Care Campus, B. Rappaport, Institute for Research in the Medicine Science, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

    M Waterman, Y Chowers & A Karban

  8. Department of Medicine, Meyerhoff Inflammatory Bowel Disease Center, Johns Hopkins University School of Medicine, MD, Baltimore, USA

    S R Brant

  9. IBD Group, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

    M S Silverberg

  10. Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY, USA

    P K Gregersen

  11. North Shore University Hospital-Long Island, Jewish Hospital Systems, St. Francis Hospital, Great Neck, NY, USA

    S Katz

  12. Department of Epidemiology and Public Health, Yale School of Medicine, New Haven, CT, USA

    H Zhao

  13. Department of Computer Science, Columbia University, New York, NY, USA

    I Pe'er

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  1. W Zhang
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Correspondence to J H Cho.

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Zhang, W., Hui, K., Gusev, A. et al. Extended haplotype association study in Crohn’s disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3. Genes Immun 14, 310–316 (2013). https://doi.org/10.1038/gene.2013.19

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  • DOI: https://doi.org/10.1038/gene.2013.19

Keywords

  • haplotype association
  • Ashkenazi Jewish
  • Crohn’s disease
  • NF-κB signaling
  • synthetic association

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