Original ResearchFull Report: Clinical—Alimentary TractAssociation Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies
Section snippets
Study Subjects
We captured the exomes of 42 German patients with CD, one HapMap trio,6 and 3 unrelated German healthy control subjects by means of the NimbleGen 2.1M Human Exome Array (Madison, WI), followed by Illumina Genome Analyzer (San Diego, CA) resequencing (Supplementary Figures 1 and 2 and Supplementary Table 1). For detailed information on the whole-exome enrichment and sequencing process and sequence read alignment, variant calling, and annotation, see Supplementary Notes. Follow-up genotyping of
Discovery of Low-Frequency Variants Using Whole-Exome Sequencing
In total, we identified 117,957 SNVs in our 48 subjects with CD, including 59,076 coding and splice site SNVs (Supplementary Tables 2 and 3). The overall SNV analysis workflow of our study is shown in Supplementary Figure 3. To pinpoint a small subset of functionally important SNVs from the large amount of genetic variation, we developed a software tool for SNV annotation, categorization, and filtering named snpActs (Supplementary Table 4 and Supplementary Notes).
Results of Association Testing
Two missense SNPs,
Discussion
The outcomes of the present study highlight the importance of detailed multifaceted analyses to extend genetic insights beyond those derived from GWAS alone. By conducting whole-exome sequencing followed by rare variant analysis, as well as detailed expression and functional studies, we have substantially advanced understanding of a previously defined GWAS locus and have identified a new CD susceptibility gene that further emphasizes the contribution of autophagy and NF-κB pathways to the
Acknowledgments
The authors thank all subjects with CD or UC and their families, control subjects, and clinicians for their participation; Tanja Wesse, Tanja Henke, Sanaz Sedghpour Sabet, Sandra Greve, and Ilona Urbach for expert technical help; and the International IBD Genetics Consortium for providing summary statistics of the CD and UC meta-analyses through their website (http://www.ibdgenetics.org).
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2021, Biochimica et Biophysica Acta - General SubjectsCitation Excerpt :The findings will provide a more nuanced understanding of the role autophagy adaptors play, which is critical given their relationship to human diseases. Mutations to OPTN have been linked to ALS and POAG, whereas missense mutations in p62 have been identified in Paget's disease of bone, frontotemporal lobar degradation, and ALS [133], and associations between NDP52 and Crohn's disease have been reported [134]. Although it remains to be determined if the onset of these disease states is linked to the ubiquitin and/or autophagy machinery, research into the molecular functions of autophagy adaptors and their recently-identified novel binding partners will provide new insights for therapeutic and pharmacological approaches.
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Conflicts of interest The authors disclose no conflicts.
Funding Supported by Deutsche Forschungsgemeinschaft (DFG) grant FR 2821/2-1 and research fellowship Ti 640 1-1, the SFB 877 subproject B9, the German Ministry of Education and Research through the National Genome Research Network, the PopGen biobank (http://www.popgen.de), and the National Institutes of Health (grant GM069373). The project received infrastructure support through the DFG Clusters of Excellence “Inflammation at Interfaces” and “Multimodal Computing and Interaction.” S. Brand is supported by DFG grant BR1912/6-1 and by the Else-Kröner-Fresenius-Stiftung (stipend 2010_EKES.32). The authors acknowledge use of material from the British 1958 Birth Cohort DNA collection, funded by Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02 (http://www.b58cgene.sgul.ac.uk/). The authors also acknowledge the participation of all Cambridge BioResource subjects and staff (http://www.cambridgebioresource.org.uk/); the National Institute for Health Research Biomedical Research Centre awards to Guy’s & St Thomas’ National Health Service Trust/King’s College London and to Addenbrooke’s Hospital/University of Cambridge School of Clinical Medicine; the Wellcome Trust Case Control Consortium, a seed grant from the San Diego Center for Systems Biology (to A. Till and S. Subramani), National Institutes of Health grant 1R01CA141743-01 (principal investigator: R. H. Duerr), the University of Pittsburgh Genomics and Proteomics Core Laboratories for the ImmunoChip genotyping services, and DFG grants ZE 814/4-1 and ZE 814/5-1 (to S. Zeissig). M. D’Amato received support from the Swedish Research Council (VR).
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Authors share co-first authorship.