Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis
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{"title"=>"Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis", "type"=>"journal", "authors"=>[{"first_name"=>"Mélissa", "last_name"=>"Beaudoin", "scopus_author_id"=>"7005931661"}, {"first_name"=>"Philippe", "last_name"=>"Goyette", "scopus_author_id"=>"6602150099"}, {"first_name"=>"Gabrielle", "last_name"=>"Boucher", "scopus_author_id"=>"36553997600"}, {"first_name"=>"Ken Sin", "last_name"=>"Lo", "scopus_author_id"=>"36242156600"}, {"first_name"=>"Manuel A.", "last_name"=>"Rivas", "scopus_author_id"=>"25724653200"}, {"first_name"=>"Christine", "last_name"=>"Stevens", "scopus_author_id"=>"24178358100"}, {"first_name"=>"Azadeh", "last_name"=>"Alikashani", "scopus_author_id"=>"53063113200"}, {"first_name"=>"Martin", "last_name"=>"Ladouceur", "scopus_author_id"=>"7003291188"}, {"first_name"=>"David", "last_name"=>"Ellinghaus", "scopus_author_id"=>"57191919367"}, {"first_name"=>"Leif", "last_name"=>"Törkvist", "scopus_author_id"=>"57199512028"}, {"first_name"=>"Gautam", "last_name"=>"Goel", "scopus_author_id"=>"36145687300"}, {"first_name"=>"Caroline", "last_name"=>"Lagacé", "scopus_author_id"=>"13407815300"}, {"first_name"=>"Vito", "last_name"=>"Annese", "scopus_author_id"=>"7006533282"}, {"first_name"=>"Alain", "last_name"=>"Bitton", "scopus_author_id"=>"7003739389"}, {"first_name"=>"Jakob", "last_name"=>"Begun", "scopus_author_id"=>"7004230524"}, {"first_name"=>"Steve R.", "last_name"=>"Brant", "scopus_author_id"=>"57195257046"}, {"first_name"=>"Francesca", "last_name"=>"Bresso", "scopus_author_id"=>"8564927000"}, {"first_name"=>"Judy H.", "last_name"=>"Cho", "scopus_author_id"=>"55757802800"}, {"first_name"=>"Richard H.", "last_name"=>"Duerr", "scopus_author_id"=>"56861964200"}, {"first_name"=>"Jonas", "last_name"=>"Halfvarson", "scopus_author_id"=>"22937355800"}, {"first_name"=>"Dermot P.B.", "last_name"=>"McGovern", "scopus_author_id"=>"57198062236"}, {"first_name"=>"Graham", "last_name"=>"Radford-Smith", "scopus_author_id"=>"56567870100"}, {"first_name"=>"Stefan", "last_name"=>"Schreiber", "scopus_author_id"=>"55682654030"}, {"first_name"=>"Philip L.", "last_name"=>"Schumm", "scopus_author_id"=>"57192195690"}, {"first_name"=>"Yashoda", "last_name"=>"Sharma", "scopus_author_id"=>"55865917600"}, {"first_name"=>"Mark S.", "last_name"=>"Silverberg", "scopus_author_id"=>"57198315065"}, {"first_name"=>"Rinse K.", "last_name"=>"Weersma", "scopus_author_id"=>"55882202000"}, {"first_name"=>"Mauro", "last_name"=>"D'Amato", "scopus_author_id"=>"57197127590"}, {"first_name"=>"Severine", "last_name"=>"Vermeire", "scopus_author_id"=>"56998917000"}, {"first_name"=>"Andre", "last_name"=>"Franke", "scopus_author_id"=>"8243151300"}, {"first_name"=>"Guillaume", "last_name"=>"Lettre", "scopus_author_id"=>"36149864300"}, {"first_name"=>"Ramnik J.", "last_name"=>"Xavier", "scopus_author_id"=>"7006636647"}, {"first_name"=>"Mark J.", "last_name"=>"Daly", "scopus_author_id"=>"56463512500"}, {"first_name"=>"John D.", "last_name"=>"Rioux", "scopus_author_id"=>"57196639402"}, {"first_name"=>"Guy", "last_name"=>"Aumais", "scopus_author_id"=>"6603365475"}, {"first_name"=>"Edmond Jean", "last_name"=>"Bernard", "scopus_author_id"=>"7102852480"}, {"first_name"=>"Alain", "last_name"=>"Bitton", "scopus_author_id"=>"56217081800"}, {"first_name"=>"Albert", "last_name"=>"Cohen", "scopus_author_id"=>"57198878033"}, {"first_name"=>"Colette", "last_name"=>"Deslandres", "scopus_author_id"=>"6601995586"}, {"first_name"=>"Raymond", "last_name"=>"Lahaie", "scopus_author_id"=>"6701901376"}, {"first_name"=>"Pierre", "last_name"=>"Paré", "scopus_author_id"=>"7103044322"}, {"first_name"=>"John D.", "last_name"=>"Rioux", "scopus_author_id"=>"57196639403"}, {"first_name"=>"Steven R.", "last_name"=>"Brant", "scopus_author_id"=>"55851942216"}, {"first_name"=>"Judy H.", "last_name"=>"Cho", "scopus_author_id"=>"56833063300"}, {"first_name"=>"Richard H.", "last_name"=>"Duerr", "scopus_author_id"=>"57031608700"}, {"first_name"=>"Dermot P.B.", "last_name"=>"McGovern", "scopus_author_id"=>"55882243900"}, {"first_name"=>"John D.", "last_name"=>"Rioux", "scopus_author_id"=>"55651579500"}, {"first_name"=>"Mark S.", "last_name"=>"Silverberg", "scopus_author_id"=>"55121900100"}, {"first_name"=>"David", "last_name"=>"Ellinghaus", "scopus_author_id"=>"23666901100"}, {"first_name"=>"Andre", "last_name"=>"Franke", "scopus_author_id"=>"55619304234"}, {"first_name"=>"Stephan R.", "last_name"=>"Targan", "scopus_author_id"=>"7006874007"}, {"first_name"=>"Philip", "last_name"=>"Schumm", "scopus_author_id"=>"55681075900"}, {"first_name"=>"Paul", "last_name"=>"Rutgeerts", "scopus_author_id"=>"35926874100"}, {"first_name"=>"Severine", "last_name"=>"Vermeire", "scopus_author_id"=>"56676463400"}, {"first_name"=>"Mark S.", "last_name"=>"Silverberg", "scopus_author_id"=>"7005034547"}, {"first_name"=>"A. 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W.", "last_name"=>"Verspaget", "scopus_author_id"=>"7005772169"}, {"first_name"=>"Martine", "last_name"=>"de Vos", "scopus_author_id"=>"54790564700"}, {"first_name"=>"Thomas", "last_name"=>"Walters", "scopus_author_id"=>"12805551700"}, {"first_name"=>"Kai", "last_name"=>"Wang", "scopus_author_id"=>"55547130019"}, {"first_name"=>"Rinse K.", "last_name"=>"Weersma", "scopus_author_id"=>"8238994000"}, {"first_name"=>"David", "last_name"=>"Whiteman", "scopus_author_id"=>"14024933500"}, {"first_name"=>"Cisca", "last_name"=>"Wijmenga", "scopus_author_id"=>"7005273061"}], "year"=>2013, "source"=>"PLoS Genetics", "identifiers"=>{"pui"=>"369903993", "sgr"=>"84884683078", "issn"=>"15537390", "pmid"=>"24068945", "scopus"=>"2-s2.0-84884683078", "doi"=>"10.1371/journal.pgen.1003723", "isbn"=>"2222222222222"}, "id"=>"da8d579d-9818-32f4-bc6e-00663f7271b5", "abstract"=>"Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.", "link"=>"http://www.mendeley.com/research/deep-resequencing-gwas-loci-identifies-rare-variants-card9-il23r-rnf186-associated-ulcerative-coliti", "reader_count"=>136, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>2, "Librarian"=>1, "Researcher"=>48, "Student > Doctoral Student"=>5, "Student > Ph. D. Student"=>41, "Student > Postgraduate"=>6, "Other"=>5, "Student > Master"=>9, "Student > Bachelor"=>9, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>5}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>2, "Librarian"=>1, "Researcher"=>48, "Student > Doctoral Student"=>5, "Student > Ph. D. Student"=>41, "Student > Postgraduate"=>6, "Other"=>5, "Student > Master"=>9, "Student > Bachelor"=>9, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>5}, "reader_count_by_subject_area"=>{"Unspecified"=>9, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>11, "Agricultural and Biological Sciences"=>65, "Medicine and Dentistry"=>43, "Arts and Humanities"=>1, "Sports and Recreations"=>1, "Business, Management and Accounting"=>1, "Physics and Astronomy"=>1, "Psychology"=>1, "Social Sciences"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>43}, "Social Sciences"=>{"Social Sciences"=>1}, "Sports and Recreations"=>{"Sports and Recreations"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Psychology"=>{"Psychology"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>65}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>11}, "Unspecified"=>{"Unspecified"=>9}, "Environmental Science"=>{"Environmental Science"=>1}, "Arts and Humanities"=>{"Arts and Humanities"=>1}}, "reader_count_by_country"=>{"Netherlands"=>1, "United States"=>4, "Chile"=>1, "Switzerland"=>1, "Germany"=>1, "India"=>2}, "group_count"=>8}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1202774", "https://ndownloader.figshare.com/files/1202775", "https://ndownloader.figshare.com/files/1202776", "https://ndownloader.figshare.com/files/1202777", "https://ndownloader.figshare.com/files/1202778", "https://ndownloader.figshare.com/files/1202779", "https://ndownloader.figshare.com/files/1202780", "https://ndownloader.figshare.com/files/1202781", "https://ndownloader.figshare.com/files/1202782", "https://ndownloader.figshare.com/files/1202783", "https://ndownloader.figshare.com/files/1202784", "https://ndownloader.figshare.com/files/1202785", "https://ndownloader.figshare.com/files/1202786", "https://ndownloader.figshare.com/files/1202787", "https://ndownloader.figshare.com/files/1202788", "https://ndownloader.figshare.com/files/1202789", "https://ndownloader.figshare.com/files/1202790", "https://ndownloader.figshare.com/files/1202791", "https://ndownloader.figshare.com/files/1202792", "https://ndownloader.figshare.com/files/1202793", "https://ndownloader.figshare.com/files/1202794"], "description"=>"<div><p>Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (∼14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both <i>IL23R</i> and <i>CARD9</i>, previously identified from sequencing of CD loci, as well as identified a novel association in <i>RNF186</i>. With the exception of <i>CARD9</i> (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for <i>RNF186</i> and OR = 0.79 for <i>IL23R</i>). <i>RNF186</i> encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.</p></div>", "links"=>[], "tags"=>["resequencing", "GWAS", "loci", "identifies", "variants", "ulcerative", "colitis"], "article_id"=>798212, "categories"=>["Biological Sciences"], "users"=>["Mélissa Beaudoin", "Philippe Goyette", "Gabrielle Boucher", "Ken Sin Lo", "Manuel A. Rivas", "Christine Stevens", "Azadeh Alikashani", "Martin Ladouceur", "David Ellinghaus", "Leif Törkvist", "Gautam Goel", "Caroline Lagacé", "Vito Annese", "Alain Bitton", "Jakob Begun", "Steve R. Brant", "Francesca Bresso", "Judy H. Cho", "Richard H. Duerr", "Jonas Halfvarson", "Dermot P. B. McGovern", "Graham Radford-Smith", "Stefan Schreiber", "Philip L. Schumm", "Yashoda Sharma", "Mark S. Silverberg", "Rinse K. Weersma", "Mauro D'Amato", "Séverine Vermeire", "Andre Franke", "Guillaume Lettre", "Ramnik J. Xavier", "Mark J. Daly", "John D. Rioux"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1003723.s001", "https://dx.doi.org/10.1371/journal.pgen.1003723.s002", "https://dx.doi.org/10.1371/journal.pgen.1003723.s003", "https://dx.doi.org/10.1371/journal.pgen.1003723.s004", "https://dx.doi.org/10.1371/journal.pgen.1003723.s005", "https://dx.doi.org/10.1371/journal.pgen.1003723.s006", "https://dx.doi.org/10.1371/journal.pgen.1003723.s007", "https://dx.doi.org/10.1371/journal.pgen.1003723.s008", "https://dx.doi.org/10.1371/journal.pgen.1003723.s009", "https://dx.doi.org/10.1371/journal.pgen.1003723.s010", "https://dx.doi.org/10.1371/journal.pgen.1003723.s011", "https://dx.doi.org/10.1371/journal.pgen.1003723.s012", "https://dx.doi.org/10.1371/journal.pgen.1003723.s013", "https://dx.doi.org/10.1371/journal.pgen.1003723.s014", "https://dx.doi.org/10.1371/journal.pgen.1003723.s015", "https://dx.doi.org/10.1371/journal.pgen.1003723.s016", "https://dx.doi.org/10.1371/journal.pgen.1003723.s017", "https://dx.doi.org/10.1371/journal.pgen.1003723.s018", "https://dx.doi.org/10.1371/journal.pgen.1003723.s019", "https://dx.doi.org/10.1371/journal.pgen.1003723.s020", "https://dx.doi.org/10.1371/journal.pgen.1003723.s021"], "stats"=>{"downloads"=>11, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Deep_Resequencing_of_GWAS_Loci_Identifies_Rare_Variants_in_CARD9_IL23R_and_RNF186_That_Are_Associated_with_Ulcerative_Colitis/798212", "title"=>"Deep Resequencing of GWAS Loci Identifies Rare Variants in <i>CARD9</i>, <i>IL23R</i> and <i>RNF186</i> That Are Associated with Ulcerative Colitis", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-09-12 02:30:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/1202644"], "description"=>"<p>(A) <i>RNF186</i> encodes a protein with RING domain and two transmembrane domains. E3 ubiquitin-protein ligase activity is intrinsic to the RING domain. This domain contains the disease-coding variant (A64T). (B) <i>RNF186</i> expression response to <i>S. flexneri</i> in young mice (see also <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003723#pgen.1003723.s011\" target=\"_blank\">Figure S11</a>). (C) Network building steps. Network is generated by mining multiple sources of interaction databases in Metacore that span human protein-protein, protein-DNA, Protein-RNA and protein-compounds interactions. (D) Transcriptional regulation model for <i>RNF186</i>. IL1-beta and TGF-beta 1 decrease <i>HNF4A</i> mRNA expression <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003723#pgen.1003723-Caja1\" target=\"_blank\">[39]</a>–<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003723#pgen.1003723-Wang1\" target=\"_blank\">[41]</a>. Knockdown of retinoid X receptor, alpha (<i>RXRA</i>) down-regulates <i>HNF4A</i> gene expression; RXRA interacts with <i>HNF4A</i> gene <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003723#pgen.1003723-Tomaru1\" target=\"_blank\">[24]</a>. <i>HNF4A</i> is a direct target gene of caudal type homeobox 2 (CDX2); CDX2 increases <i>HNF4A</i> mRNA expression in intestinal epithelial cells <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003723#pgen.1003723-Boyd2\" target=\"_blank\">[42]</a>, <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003723#pgen.1003723-McKinneyFreeman1\" target=\"_blank\">[43]</a>. HNF4A binds promoter region of <i>HNF1A</i> and up-regulates its expression. HNF1A interacts with <i>RNF186</i> and regulates its transcription.</p>", "links"=>[], "tags"=>["characterization"], "article_id"=>798107, "categories"=>["Biological Sciences"], "users"=>["Mélissa Beaudoin", "Philippe Goyette", "Gabrielle Boucher", "Ken Sin Lo", "Manuel A. Rivas", "Christine Stevens", "Azadeh Alikashani", "Martin Ladouceur", "David Ellinghaus", "Leif Törkvist", "Gautam Goel", "Caroline Lagacé", "Vito Annese", "Alain Bitton", "Jakob Begun", "Steve R. Brant", "Francesca Bresso", "Judy H. Cho", "Richard H. Duerr", "Jonas Halfvarson", "Dermot P. B. McGovern", "Graham Radford-Smith", "Stefan Schreiber", "Philip L. Schumm", "Yashoda Sharma", "Mark S. Silverberg", "Rinse K. Weersma", "Mauro D'Amato", "Séverine Vermeire", "Andre Franke", "Guillaume Lettre", "Ramnik J. Xavier", "Mark J. Daly", "John D. Rioux"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003723.g001", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Functional_characterization_of_RNF186_/798107", "title"=>"Functional characterization of RNF186.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-09-12 02:30:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/1202645"], "description"=>"a<p>Positions from Human genome build 36.</p>b<p>Previously reported variant independently identified in the current study.</p>c<p>Minor allele frequencies estimates from combined case:control cohorts; actual allele frequencies can vary between cohorts.</p><p>UC, Ulcerative Colitis; HC, Healthy Controls; NA, data not available.</p>", "links"=>[], "tags"=>["variants", "ulcerative"], "article_id"=>798108, "categories"=>["Biological Sciences"], "users"=>["Mélissa Beaudoin", "Philippe Goyette", "Gabrielle Boucher", "Ken Sin Lo", "Manuel A. Rivas", "Christine Stevens", "Azadeh Alikashani", "Martin Ladouceur", "David Ellinghaus", "Leif Törkvist", "Gautam Goel", "Caroline Lagacé", "Vito Annese", "Alain Bitton", "Jakob Begun", "Steve R. Brant", "Francesca Bresso", "Judy H. Cho", "Richard H. Duerr", "Jonas Halfvarson", "Dermot P. B. McGovern", "Graham Radford-Smith", "Stefan Schreiber", "Philip L. Schumm", "Yashoda Sharma", "Mark S. Silverberg", "Rinse K. Weersma", "Mauro D'Amato", "Séverine Vermeire", "Andre Franke", "Guillaume Lettre", "Ramnik J. Xavier", "Mark J. Daly", "John D. Rioux"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1003723.t001", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Identification_of_rare_variants_associated_with_ulcerative_colitis_/798108", "title"=>"Identification of rare variants associated with ulcerative colitis.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-09-12 02:30:06"}

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Relative Metric

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