A genome-wide homozygosity association study identifies runs of homozygosity associated with rheumatoid arthritis in the human major histocompatibility complex
Rheumatoid arthritis (RA) is a chronic inflammatory disorder with a polygenic mode of inheritance. This study examined the hypothesis that runs of homozygosity (ROHs) play a recessive-acting role in the underlying RA genetic mechanism and identified RA-associated ROHs. Ours is the first genome-wide...
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| description | Rheumatoid arthritis (RA) is a chronic inflammatory disorder with a polygenic mode of inheritance. This study examined the hypothesis that runs of homozygosity (ROHs) play a recessive-acting role in the underlying RA genetic mechanism and identified RA-associated ROHs. Ours is the first genome-wide homozygosity association study for RA and characterized the ROH patterns associated with RA in the genomes of 2,000 RA patients and 3,000 normal controls of the Wellcome Trust Case Control Consortium. Genome scans consistently pinpointed two regions within the human major histocompatibility complex region containing RA-associated ROHs. The first region is from 32,451,664 bp to 32,846,093 bp (-log10(p)>22.6591). RA-susceptibility genes, such as HLA-DRB1, are contained in this region. The second region ranges from 32,933,485 bp to 33,585,118 bp (-log10(p)>8.3644) and contains other HLA-DPA1 and HLA-DPB1 genes. These two regions are physically close but are located in different blocks of linkage disequilibrium, and ∼40% of the RA patients' genomes carry these ROHs in the two regions. By analyzing homozygote intensities, an ROH that is anchored by the single nucleotide polymorphism rs2027852 and flanked by HLA-DRB6 and HLA-DRB1 was found associated with increased risk for RA. The presence of this risky ROH provides a 62% accuracy to predict RA disease status. An independent genomic dataset from 868 RA patients and 1,194 control subjects of the North American Rheumatoid Arthritis Consortium successfully validated the results obtained using the Wellcome Trust Case Control Consortium data. In conclusion, this genome-wide homozygosity association study provides an alternative to allelic association mapping for the identification of recessive variants responsible for RA. The identified RA-associated ROHs uncover recessive components and missing heritability associated with RA and other autoimmune diseases. |
| doi_str_mv | 10.1371/journal.pone.0034840 |
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This study examined the hypothesis that runs of homozygosity (ROHs) play a recessive-acting role in the underlying RA genetic mechanism and identified RA-associated ROHs. Ours is the first genome-wide homozygosity association study for RA and characterized the ROH patterns associated with RA in the genomes of 2,000 RA patients and 3,000 normal controls of the Wellcome Trust Case Control Consortium. Genome scans consistently pinpointed two regions within the human major histocompatibility complex region containing RA-associated ROHs. The first region is from 32,451,664 bp to 32,846,093 bp (-log10(p)>22.6591). RA-susceptibility genes, such as HLA-DRB1, are contained in this region. The second region ranges from 32,933,485 bp to 33,585,118 bp (-log10(p)>8.3644) and contains other HLA-DPA1 and HLA-DPB1 genes. These two regions are physically close but are located in different blocks of linkage disequilibrium, and ∼40% of the RA patients' genomes carry these ROHs in the two regions. By analyzing homozygote intensities, an ROH that is anchored by the single nucleotide polymorphism rs2027852 and flanked by HLA-DRB6 and HLA-DRB1 was found associated with increased risk for RA. The presence of this risky ROH provides a 62% accuracy to predict RA disease status. An independent genomic dataset from 868 RA patients and 1,194 control subjects of the North American Rheumatoid Arthritis Consortium successfully validated the results obtained using the Wellcome Trust Case Control Consortium data. In conclusion, this genome-wide homozygosity association study provides an alternative to allelic association mapping for the identification of recessive variants responsible for RA. The identified RA-associated ROHs uncover recessive components and missing heritability associated with RA and other autoimmune diseases.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0034840</identifier><identifier>PMID: 22536334</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Arthritis ; Arthritis, Rheumatoid - genetics ; Autoimmune diseases ; Biology ; Biometrics ; Case-Control Studies ; Chromosome Mapping ; Computer Simulation ; Consortia ; Discriminant analysis ; Disease ; Disease susceptibility ; DNA Copy Number Variations ; Drb1 protein ; Gene Amplification ; Gene Deletion ; Gene mapping ; Genes ; Genetic aspects ; Genetic Heterogeneity ; Genetics ; Genome-Wide Association Study ; Genomes ; Genomics ; Heritability ; Histocompatibility antigen HLA ; HLA antigens ; Homozygosity ; Homozygote ; Humans ; Inflammatory diseases ; Linkage Disequilibrium ; Major Histocompatibility Complex ; Mathematics ; Medical research ; Medicine ; Models, Genetic ; Mutation ; Patients ; Polygenic inheritance ; Polymorphism ; Polymorphism, Single Nucleotide ; Power ; Principal components analysis ; Rheumatoid arthritis ; Rheumatoid factor ; Science ; Single nucleotide polymorphisms ; Single-nucleotide polymorphism ; Studies</subject><ispartof>PloS one, 2012-04, Vol.7 (4), p.e34840</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Yang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Yang et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-e0202c9ae1ff0409d995cb0a055bac288afc152c2ebbd075b7f6a4ae31733dd63</citedby><cites>FETCH-LOGICAL-c692t-e0202c9ae1ff0409d995cb0a055bac288afc152c2ebbd075b7f6a4ae31733dd63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335047/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335047/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22536334$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Cherny, Stacey</contributor><creatorcontrib>Yang, Hsin-Chou</creatorcontrib><creatorcontrib>Chang, Lun-Ching</creatorcontrib><creatorcontrib>Liang, Yu-Jen</creatorcontrib><creatorcontrib>Lin, Chien-Hsing</creatorcontrib><creatorcontrib>Wang, Pei-Li</creatorcontrib><title>A genome-wide homozygosity association study identifies runs of homozygosity associated with rheumatoid arthritis in the human major histocompatibility complex</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Rheumatoid arthritis (RA) is a chronic inflammatory disorder with a polygenic mode of inheritance. This study examined the hypothesis that runs of homozygosity (ROHs) play a recessive-acting role in the underlying RA genetic mechanism and identified RA-associated ROHs. Ours is the first genome-wide homozygosity association study for RA and characterized the ROH patterns associated with RA in the genomes of 2,000 RA patients and 3,000 normal controls of the Wellcome Trust Case Control Consortium. Genome scans consistently pinpointed two regions within the human major histocompatibility complex region containing RA-associated ROHs. The first region is from 32,451,664 bp to 32,846,093 bp (-log10(p)>22.6591). RA-susceptibility genes, such as HLA-DRB1, are contained in this region. The second region ranges from 32,933,485 bp to 33,585,118 bp (-log10(p)>8.3644) and contains other HLA-DPA1 and HLA-DPB1 genes. These two regions are physically close but are located in different blocks of linkage disequilibrium, and ∼40% of the RA patients' genomes carry these ROHs in the two regions. By analyzing homozygote intensities, an ROH that is anchored by the single nucleotide polymorphism rs2027852 and flanked by HLA-DRB6 and HLA-DRB1 was found associated with increased risk for RA. The presence of this risky ROH provides a 62% accuracy to predict RA disease status. An independent genomic dataset from 868 RA patients and 1,194 control subjects of the North American Rheumatoid Arthritis Consortium successfully validated the results obtained using the Wellcome Trust Case Control Consortium data. In conclusion, this genome-wide homozygosity association study provides an alternative to allelic association mapping for the identification of recessive variants responsible for RA. The identified RA-associated ROHs uncover recessive components and missing heritability associated with RA and other autoimmune diseases.</description><subject>Analysis</subject><subject>Arthritis</subject><subject>Arthritis, Rheumatoid - genetics</subject><subject>Autoimmune diseases</subject><subject>Biology</subject><subject>Biometrics</subject><subject>Case-Control Studies</subject><subject>Chromosome Mapping</subject><subject>Computer Simulation</subject><subject>Consortia</subject><subject>Discriminant analysis</subject><subject>Disease</subject><subject>Disease susceptibility</subject><subject>DNA Copy Number Variations</subject><subject>Drb1 protein</subject><subject>Gene Amplification</subject><subject>Gene Deletion</subject><subject>Gene mapping</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic Heterogeneity</subject><subject>Genetics</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Heritability</subject><subject>Histocompatibility antigen HLA</subject><subject>HLA antigens</subject><subject>Homozygosity</subject><subject>Homozygote</subject><subject>Humans</subject><subject>Inflammatory diseases</subject><subject>Linkage Disequilibrium</subject><subject>Major Histocompatibility Complex</subject><subject>Mathematics</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Models, Genetic</subject><subject>Mutation</subject><subject>Patients</subject><subject>Polygenic inheritance</subject><subject>Polymorphism</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Power</subject><subject>Principal components analysis</subject><subject>Rheumatoid arthritis</subject><subject>Rheumatoid factor</subject><subject>Science</subject><subject>Single nucleotide polymorphisms</subject><subject>Single-nucleotide 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genome-wide homozygosity association study identifies runs of homozygosity associated with rheumatoid arthritis in the human major histocompatibility complex</title><author>Yang, Hsin-Chou ; Chang, Lun-Ching ; Liang, Yu-Jen ; Lin, Chien-Hsing ; Wang, Pei-Li</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-e0202c9ae1ff0409d995cb0a055bac288afc152c2ebbd075b7f6a4ae31733dd63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Analysis</topic><topic>Arthritis</topic><topic>Arthritis, Rheumatoid - genetics</topic><topic>Autoimmune diseases</topic><topic>Biology</topic><topic>Biometrics</topic><topic>Case-Control Studies</topic><topic>Chromosome Mapping</topic><topic>Computer Simulation</topic><topic>Consortia</topic><topic>Discriminant analysis</topic><topic>Disease</topic><topic>Disease susceptibility</topic><topic>DNA Copy Number Variations</topic><topic>Drb1 protein</topic><topic>Gene Amplification</topic><topic>Gene Deletion</topic><topic>Gene mapping</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genetic Heterogeneity</topic><topic>Genetics</topic><topic>Genome-Wide Association Study</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Heritability</topic><topic>Histocompatibility antigen HLA</topic><topic>HLA antigens</topic><topic>Homozygosity</topic><topic>Homozygote</topic><topic>Humans</topic><topic>Inflammatory diseases</topic><topic>Linkage Disequilibrium</topic><topic>Major Histocompatibility Complex</topic><topic>Mathematics</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Models, Genetic</topic><topic>Mutation</topic><topic>Patients</topic><topic>Polygenic inheritance</topic><topic>Polymorphism</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Power</topic><topic>Principal components analysis</topic><topic>Rheumatoid arthritis</topic><topic>Rheumatoid 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one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Hsin-Chou</au><au>Chang, Lun-Ching</au><au>Liang, Yu-Jen</au><au>Lin, Chien-Hsing</au><au>Wang, Pei-Li</au><au>Cherny, Stacey</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A genome-wide homozygosity association study identifies runs of homozygosity associated with rheumatoid arthritis in the human major histocompatibility complex</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-04-20</date><risdate>2012</risdate><volume>7</volume><issue>4</issue><spage>e34840</spage><pages>e34840-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Rheumatoid arthritis (RA) is a chronic inflammatory disorder with a polygenic mode of inheritance. This study examined the hypothesis that runs of homozygosity (ROHs) play a recessive-acting role in the underlying RA genetic mechanism and identified RA-associated ROHs. Ours is the first genome-wide homozygosity association study for RA and characterized the ROH patterns associated with RA in the genomes of 2,000 RA patients and 3,000 normal controls of the Wellcome Trust Case Control Consortium. Genome scans consistently pinpointed two regions within the human major histocompatibility complex region containing RA-associated ROHs. The first region is from 32,451,664 bp to 32,846,093 bp (-log10(p)>22.6591). RA-susceptibility genes, such as HLA-DRB1, are contained in this region. The second region ranges from 32,933,485 bp to 33,585,118 bp (-log10(p)>8.3644) and contains other HLA-DPA1 and HLA-DPB1 genes. These two regions are physically close but are located in different blocks of linkage disequilibrium, and ∼40% of the RA patients' genomes carry these ROHs in the two regions. By analyzing homozygote intensities, an ROH that is anchored by the single nucleotide polymorphism rs2027852 and flanked by HLA-DRB6 and HLA-DRB1 was found associated with increased risk for RA. The presence of this risky ROH provides a 62% accuracy to predict RA disease status. An independent genomic dataset from 868 RA patients and 1,194 control subjects of the North American Rheumatoid Arthritis Consortium successfully validated the results obtained using the Wellcome Trust Case Control Consortium data. In conclusion, this genome-wide homozygosity association study provides an alternative to allelic association mapping for the identification of recessive variants responsible for RA. The identified RA-associated ROHs uncover recessive components and missing heritability associated with RA and other autoimmune diseases.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22536334</pmid><doi>10.1371/journal.pone.0034840</doi><tpages>e34840</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Analysis Arthritis Arthritis, Rheumatoid - genetics Autoimmune diseases Biology Biometrics Case-Control Studies Chromosome Mapping Computer Simulation Consortia Discriminant analysis Disease Disease susceptibility DNA Copy Number Variations Drb1 protein Gene Amplification Gene Deletion Gene mapping Genes Genetic aspects Genetic Heterogeneity Genetics Genome-Wide Association Study Genomes Genomics Heritability Histocompatibility antigen HLA HLA antigens Homozygosity Homozygote Humans Inflammatory diseases Linkage Disequilibrium Major Histocompatibility Complex Mathematics Medical research Medicine Models, Genetic Mutation Patients Polygenic inheritance Polymorphism Polymorphism, Single Nucleotide Power Principal components analysis Rheumatoid arthritis Rheumatoid factor Science Single nucleotide polymorphisms Single-nucleotide polymorphism Studies |
| title | A genome-wide homozygosity association study identifies runs of homozygosity associated with rheumatoid arthritis in the human major histocompatibility complex |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-18T23%3A43%3A16IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20genome-wide%20homozygosity%20association%20study%20identifies%20runs%20of%20homozygosity%20associated%20with%20rheumatoid%20arthritis%20in%20the%20human%20major%20histocompatibility%20complex&rft.jtitle=PloS%20one&rft.au=Yang,%20Hsin-Chou&rft.date=2012-04-20&rft.volume=7&rft.issue=4&rft.spage=e34840&rft.pages=e34840-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0034840&rft_dat=%3Cgale_plos_%3EA477058701%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1324576751&rft_id=info:pmid/22536334&rft_galeid=A477058701&rft_doaj_id=oai_doaj_org_article_bec95bbec90a44dc9afa3414b3fa3a8c&rfr_iscdi=true |