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

Wei Zhang; Ken Y Hui; Alexander Gusev; Neil Warner; Sok Meng Evelyn Ng; John Ferguson; Murim Choi; Aaron Burberry; Clara Abraham; Lloyd Mayer; Robert J Desnick; Christopher J Cardinale; Hakon Hakonarson; Matti Waterman; Yehuda Chowers; Amir Karban; Steven R Brant; Mark S Silverberg; Peter K Gregersen; Seymour Katz; Richard P Lifton; Hongyu Zhao; Gabriel Nuñez; Itsik Pe’er; Inga Peter; Judy H Cho

doi:10.1038/gene.2013.19

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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

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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

Wei Zhang, Ken Y Hui, Alexander Gusev, Neil Warner, Sok Meng Evelyn Ng, John Ferguson, Murim Choi, Aaron Burberry, Clara Abraham, Lloyd Mayer, …

Genes and immunity, Vol.14(5), pp.310-316

2013

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

PMCID: PMC3785105

PMID: 23615072

Abstract

Ashkenazi Jewish

Crohn’s disease

haplotype association

NF-κB signaling

synthetic association

The Ashkenazi Jewish population has a several-fold higher prevalence of Crohn’s disease compared to non-Jewish European ancestry populations and has a unique genetic history. Haplotype association is critical to Crohn’s disease 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 which showed significantly greater association to Crohn’s disease in the Ashkenazi Jewish population compared to 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 Crohn’s disease 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 Crohn’s disease-causal variants in NOD2 , but not with the background haplotype; this elaborates NOD2 as a key illustration of synthetic association.

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Title: Extended haplotype association study in Crohn’s disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3
Creators: Wei Zhang - Department of Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
Ken Y Hui - Department of Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
Alexander Gusev - Department of Epidemiology, Harvard University, Boston, MA, USA
Neil Warner - Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA
Sok Meng Evelyn Ng - Department of Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
John Ferguson - Department of Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
Murim Choi - Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
Aaron Burberry - Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA
Clara Abraham - Department of Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
Lloyd Mayer - Department of Genetics & Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA
Robert J Desnick - Department of Genetics & Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA
Christopher J Cardinale - Center for Applied Genomics, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
Hakon Hakonarson - Center for Applied Genomics, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
Matti Waterman - 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
Yehuda Chowers - 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
Amir Karban - 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
Steven R Brant - Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Department of Epidemiology, Johns Hopkins University
Mark S Silverberg - IBD Group, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
Peter K Gregersen - Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY, USA
Seymour Katz - North Shore University Hospital-Long Island, Jewish Hospital Systems, St. Francis Hospital, Great Neck, NY, USA
Richard P Lifton - Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
Hongyu Zhao - Department of Epidemiology and Public Health, Yale School of Medicine, New Haven, CT, USA
Gabriel Nuñez - Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, USA
Itsik Pe’er - Department of Epidemiology, Harvard University, Boston, MA, USA
Inga Peter - Department of Genetics & Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA
Judy H Cho - Department of Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
Publication Details: Genes and immunity, Vol.14(5), pp.310-316
Date published: 2013
Academic Unit: Medicine - Gastroenterology and Hepatology (RWJMS)
Language: English
Resource Type: Journal article
Identifiers: 991031666482304646