Original ResearchFull Report: Basic and Translational—Alimentary TractA Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF
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Human Subjects
Written informed consent for genetic analyses was obtained from all subjects through the respective Institutional Review Boards from the contributing institutions (Supplementary Table 1). Resected terminal ileal tissues and blood samples from Crohn’s patients were obtained after written informed consent under the guidelines of the Human Investigations Committee (Institutional Review Board) of the Icahn School of Medicine at Mount Sinai. IBD patients had diagnoses confirmed at each recruiting
Exome Sequencing and Association Studies
Exome sequencing detected a total of 371 frameshift mutations in 47 CD patients and 3 controls with full AJ ancestry.19 Of these, 224 mutations passed the Illumina design filters for custom content and were added to the HumanExome beadchip. Using this array, we performed association analyses in 1477 unrelated CD cases and 2614 independent healthy controls passing quality filters with full AJ ancestry genetically validated using PCA (discovery cohort). Sequencing 94 independent chromosomes would
Conclusions
In this study, we surveyed the role of uncommon frameshift mutations in Ashkenazi Jewish CD. For most common variants reported in GWAS, the genetic architecture among Ashkenazim is similar to non-Jewish European ancestry populations, with similar directions of risk alleles observed for the large majority of loci.19 Rare variant analyses focused on Jewish populations may be particularly fruitful because of the higher CD prevalence and unique population history of the Ashkenazim. Although the
Acknowledgments
The authors thank the patients who participated in this study and the staff that assisted in their recruitment. The authors appreciate the sample contribution of The Charles Bronfman Institute for Personalized Medicine’s Biobank at Mount Sinai. The Flow Cytometry CORE at the Icahn School of Medicine at Mount Sinai provided training, consultation, and technical assistance for CyTOF and flow cytometry. Microscopy was performed at the Microscopy CORE at the Icahn School of Medicine at Mount Sinai.
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Conflicts of interest The authors disclose no conflicts.
Funding Supported by the National Institutes of Health (DK092235), Inflammatory Bowel Disease Genetics Consortium (DK062429), Genetic Research Center at the Icahn School of Medicine (DK062422), New York Crohn’s Foundation, Consortium ancillary RO1 (DK099097) and U01 (DK062431), Inflammatory Bowel Disease Genetic Research Chair, RO1 (DK062420) and RO1 (CA141743), the Atran Foundation, and the Sanford J. Grossman Charitable Trust. Researchers at University College of London were funded by the Wellcome Trust, Charles Wolfson Charitable Trust, and the Irwin Joffe Memorial Fellowship. Inflammatory bowel disease Research at Cedars-Sinai is supported by U.S. Public Health Service grant PO1 (DK046763) and the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Research Funds. Project investigators are supported by The Helmsley Charitable Trust (D.P.B.M.), The European Union (D.P.B.M.), The Crohn's and Colitis Foundation of America (D.P.B.M.), The Joshua L. and Lisa Z. Greer Chair in Inflammatory Bowel Disease Genetics (D.P.B.M.), and grants DK062413, DK046763-19, AI067068, and HS021747 (D.P.B.M.).
Author names in bold designate shared co-first authorship.
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Authors share co-first authorship.