A genome screen of systemic lupus erythematosus using affected-relative-pair linkage analysis with covariates demonstrates genetic heterogeneity
Systemic lupus erythematosus (SLE) appears to be the consequence of complex genetics and of only partly understood environmental contributions. Previous work by ourselves and by others has established genetic effects on 1q, 2q, 4p, 6p, and 16p using SLE as the phenotype. However, individual SLE affe...
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| creator | Olson, J M Song, Y Dudek, D M Moser, K L Kelly, J A Bruner, G R Downing, K J Berry, C K James, J A Harley, J B |
| description | Systemic lupus erythematosus (SLE) appears to be the consequence of complex genetics and of only partly understood environmental contributions. Previous work by ourselves and by others has established genetic effects on 1q, 2q, 4p, 6p, and 16p using SLE as the phenotype. However, individual SLE affecteds are extraordinarily different from one another by clinical and laboratory measures. This variation may have a genetic basis; if so, it is advantageous to incorporate measures of between-family clinical variability as covariates in a genetic linkage analysis of affected relative pairs (ARPs) to allow for locus heterogeneity. This approach was applied to genome scan marker data from 160 pedigrees multiplex for SLE and containing 202 ARPs. Because the number of potential covariates was large, we used both ad hoc methods and formal principal components analysis to construct four composite covariates using the SLE classification criteria plus age of onset, ethnicity, and sex. Linkage analysis without covariates has detected evidence for linkage at 1q22–24, 2q37, 4p16, 12p12–11, and 17p13. Linkage analysis with these covariates uncovered linkage at 13p11, 17q11–25, and 20q12 and greatly improved evidence for linkage at 1q22–24, 2q37, 12p12–11, and 17p13. Follow-up analysis identified the original variables contributing to locus heterogeneity in each of these locations. In conclusion, allowing for locus heterogeneity through the incorporation of covariates in linkage analysis is a useful way to dissect the genetic contributions to SLE and uncover new genetic effects. |
| doi_str_mv | 10.1038/sj.gene.6363860 |
| format | Article |
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Previous work by ourselves and by others has established genetic effects on 1q, 2q, 4p, 6p, and 16p using SLE as the phenotype. However, individual SLE affecteds are extraordinarily different from one another by clinical and laboratory measures. This variation may have a genetic basis; if so, it is advantageous to incorporate measures of between-family clinical variability as covariates in a genetic linkage analysis of affected relative pairs (ARPs) to allow for locus heterogeneity. This approach was applied to genome scan marker data from 160 pedigrees multiplex for SLE and containing 202 ARPs. Because the number of potential covariates was large, we used both ad hoc methods and formal principal components analysis to construct four composite covariates using the SLE classification criteria plus age of onset, ethnicity, and sex. Linkage analysis without covariates has detected evidence for linkage at 1q22–24, 2q37, 4p16, 12p12–11, and 17p13. Linkage analysis with these covariates uncovered linkage at 13p11, 17q11–25, and 20q12 and greatly improved evidence for linkage at 1q22–24, 2q37, 12p12–11, and 17p13. Follow-up analysis identified the original variables contributing to locus heterogeneity in each of these locations. In conclusion, allowing for locus heterogeneity through the incorporation of covariates in linkage analysis is a useful way to dissect the genetic contributions to SLE and uncover new genetic effects.</description><identifier>ISSN: 1466-4879</identifier><identifier>EISSN: 1476-5470</identifier><identifier>DOI: 10.1038/sj.gene.6363860</identifier><identifier>PMID: 12215896</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Analysis of Variance ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Epidemiology ; Female ; full-paper ; Gene Expression ; Genetic analysis ; Genetic diversity ; Genetic Heterogeneity ; Genetic Linkage ; Genomes ; Health services ; Human Genetics ; Humans ; Immunology ; Linkage analysis ; Lod Score ; Lupus ; Lupus Erythematosus, Systemic - genetics ; Male ; Models, Genetic ; Phenotypes ; Principal components analysis ; Public health ; Systemic lupus erythematosus</subject><ispartof>Genes and immunity, 2002-10, Vol.3 (S1), p.S5-S12</ispartof><rights>Macmillan Publishers Limited 2002</rights><rights>Copyright Nature Publishing Group Oct 2002</rights><rights>Macmillan Publishers Limited 2002.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c476t-c757406667f6227a7f44a9907d7d4617e202ffe07bc16bd0819a1f85192732773</citedby><cites>FETCH-LOGICAL-c476t-c757406667f6227a7f44a9907d7d4617e202ffe07bc16bd0819a1f85192732773</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/sj.gene.6363860$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/sj.gene.6363860$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27922,27923,41486,42555,51317</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12215896$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Olson, J M</creatorcontrib><creatorcontrib>Song, Y</creatorcontrib><creatorcontrib>Dudek, D M</creatorcontrib><creatorcontrib>Moser, K L</creatorcontrib><creatorcontrib>Kelly, J A</creatorcontrib><creatorcontrib>Bruner, G R</creatorcontrib><creatorcontrib>Downing, K J</creatorcontrib><creatorcontrib>Berry, C K</creatorcontrib><creatorcontrib>James, J A</creatorcontrib><creatorcontrib>Harley, J B</creatorcontrib><title>A genome screen of systemic lupus erythematosus using affected-relative-pair linkage analysis with covariates demonstrates genetic heterogeneity</title><title>Genes and immunity</title><addtitle>Genes Immun</addtitle><addtitle>Genes Immun</addtitle><description>Systemic lupus erythematosus (SLE) appears to be the consequence of complex genetics and of only partly understood environmental contributions. Previous work by ourselves and by others has established genetic effects on 1q, 2q, 4p, 6p, and 16p using SLE as the phenotype. However, individual SLE affecteds are extraordinarily different from one another by clinical and laboratory measures. This variation may have a genetic basis; if so, it is advantageous to incorporate measures of between-family clinical variability as covariates in a genetic linkage analysis of affected relative pairs (ARPs) to allow for locus heterogeneity. This approach was applied to genome scan marker data from 160 pedigrees multiplex for SLE and containing 202 ARPs. Because the number of potential covariates was large, we used both ad hoc methods and formal principal components analysis to construct four composite covariates using the SLE classification criteria plus age of onset, ethnicity, and sex. Linkage analysis without covariates has detected evidence for linkage at 1q22–24, 2q37, 4p16, 12p12–11, and 17p13. Linkage analysis with these covariates uncovered linkage at 13p11, 17q11–25, and 20q12 and greatly improved evidence for linkage at 1q22–24, 2q37, 12p12–11, and 17p13. Follow-up analysis identified the original variables contributing to locus heterogeneity in each of these locations. In conclusion, allowing for locus heterogeneity through the incorporation of covariates in linkage analysis is a useful way to dissect the genetic contributions to SLE and uncover new genetic effects.</description><subject>Analysis of Variance</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Epidemiology</subject><subject>Female</subject><subject>full-paper</subject><subject>Gene Expression</subject><subject>Genetic analysis</subject><subject>Genetic diversity</subject><subject>Genetic Heterogeneity</subject><subject>Genetic Linkage</subject><subject>Genomes</subject><subject>Health services</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Immunology</subject><subject>Linkage analysis</subject><subject>Lod Score</subject><subject>Lupus</subject><subject>Lupus Erythematosus, Systemic - genetics</subject><subject>Male</subject><subject>Models, Genetic</subject><subject>Phenotypes</subject><subject>Principal components analysis</subject><subject>Public health</subject><subject>Systemic lupus erythematosus</subject><issn>1466-4879</issn><issn>1476-5470</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqFkk1v1DAQhiMEoh9w5gSyqASnbG0nGdvHquJLqsQFzpE3mex6SeLF47TKv-An47ALlZAKJ3s0z7zvzGiy7IXgK8ELfUm71QZHXEEBhQb-KDsVpYK8KhV_vPwB8lIrc5KdEe04FyDAPM1OhJSi0gZOsx9XLAn4ARk1AXFkvmM0U8TBNayf9hMxDHPc4mCjpxRN5MYNs12HTcQ2D9jb6G4x31sXWO_Gb3aDzI62n8kRu3Nxyxp_a4OzEYm1OPiRYvgVLJ3HZLPFiMEvkYvzs-xJZ3vC58f3PPv6_t2X64_5zecPn66vbvImDRjzRlWq5ACgOpBSWdWVpTWGq1a1JQiFksvUI1frRsC65VoYKzpdCSNVIZUqzrO3B9198N8npFgPjhrsezuin6jWKumaquSJfPNPUkkOldHVf0GhQRTAZQIv_gJ3fgppZ1RLKIWSFZSQqNcPUkJrMFIunpcHqAmeKGBX74MbbJhrwevlRGra1ctq6-OJpIpXR9lpPWB7zx9vIgH8AFBKjRsM974Pa748lIw2TgH_aP7O_wQhKdOo</recordid><startdate>20021001</startdate><enddate>20021001</enddate><creator>Olson, J M</creator><creator>Song, Y</creator><creator>Dudek, D M</creator><creator>Moser, K L</creator><creator>Kelly, J A</creator><creator>Bruner, G R</creator><creator>Downing, K J</creator><creator>Berry, C K</creator><creator>James, J A</creator><creator>Harley, J B</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20021001</creationdate><title>A genome screen of systemic lupus erythematosus using affected-relative-pair linkage analysis with covariates demonstrates genetic heterogeneity</title><author>Olson, J M ; Song, Y ; Dudek, D M ; Moser, K L ; Kelly, J A ; Bruner, G R ; Downing, K J ; Berry, C K ; James, J A ; Harley, J B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c476t-c757406667f6227a7f44a9907d7d4617e202ffe07bc16bd0819a1f85192732773</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Analysis of Variance</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>Epidemiology</topic><topic>Female</topic><topic>full-paper</topic><topic>Gene Expression</topic><topic>Genetic analysis</topic><topic>Genetic diversity</topic><topic>Genetic Heterogeneity</topic><topic>Genetic Linkage</topic><topic>Genomes</topic><topic>Health services</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Immunology</topic><topic>Linkage analysis</topic><topic>Lod Score</topic><topic>Lupus</topic><topic>Lupus Erythematosus, Systemic - genetics</topic><topic>Male</topic><topic>Models, Genetic</topic><topic>Phenotypes</topic><topic>Principal components analysis</topic><topic>Public health</topic><topic>Systemic lupus erythematosus</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Olson, J M</creatorcontrib><creatorcontrib>Song, Y</creatorcontrib><creatorcontrib>Dudek, D M</creatorcontrib><creatorcontrib>Moser, K L</creatorcontrib><creatorcontrib>Kelly, J A</creatorcontrib><creatorcontrib>Bruner, G R</creatorcontrib><creatorcontrib>Downing, K J</creatorcontrib><creatorcontrib>Berry, C K</creatorcontrib><creatorcontrib>James, J A</creatorcontrib><creatorcontrib>Harley, J B</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection (ProQuest)</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Genes and immunity</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Olson, J M</au><au>Song, Y</au><au>Dudek, D M</au><au>Moser, K L</au><au>Kelly, J A</au><au>Bruner, G R</au><au>Downing, K J</au><au>Berry, C K</au><au>James, J A</au><au>Harley, J B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A genome screen of systemic lupus erythematosus using affected-relative-pair linkage analysis with covariates demonstrates genetic heterogeneity</atitle><jtitle>Genes and immunity</jtitle><stitle>Genes Immun</stitle><addtitle>Genes Immun</addtitle><date>2002-10-01</date><risdate>2002</risdate><volume>3</volume><issue>S1</issue><spage>S5</spage><epage>S12</epage><pages>S5-S12</pages><issn>1466-4879</issn><eissn>1476-5470</eissn><abstract>Systemic lupus erythematosus (SLE) appears to be the consequence of complex genetics and of only partly understood environmental contributions. Previous work by ourselves and by others has established genetic effects on 1q, 2q, 4p, 6p, and 16p using SLE as the phenotype. However, individual SLE affecteds are extraordinarily different from one another by clinical and laboratory measures. This variation may have a genetic basis; if so, it is advantageous to incorporate measures of between-family clinical variability as covariates in a genetic linkage analysis of affected relative pairs (ARPs) to allow for locus heterogeneity. This approach was applied to genome scan marker data from 160 pedigrees multiplex for SLE and containing 202 ARPs. Because the number of potential covariates was large, we used both ad hoc methods and formal principal components analysis to construct four composite covariates using the SLE classification criteria plus age of onset, ethnicity, and sex. Linkage analysis without covariates has detected evidence for linkage at 1q22–24, 2q37, 4p16, 12p12–11, and 17p13. Linkage analysis with these covariates uncovered linkage at 13p11, 17q11–25, and 20q12 and greatly improved evidence for linkage at 1q22–24, 2q37, 12p12–11, and 17p13. Follow-up analysis identified the original variables contributing to locus heterogeneity in each of these locations. In conclusion, allowing for locus heterogeneity through the incorporation of covariates in linkage analysis is a useful way to dissect the genetic contributions to SLE and uncover new genetic effects.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>12215896</pmid><doi>10.1038/sj.gene.6363860</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Analysis of Variance Biomedical and Life Sciences Biomedicine Cancer Research Epidemiology Female full-paper Gene Expression Genetic analysis Genetic diversity Genetic Heterogeneity Genetic Linkage Genomes Health services Human Genetics Humans Immunology Linkage analysis Lod Score Lupus Lupus Erythematosus, Systemic - genetics Male Models, Genetic Phenotypes Principal components analysis Public health Systemic lupus erythematosus |
| title | A genome screen of systemic lupus erythematosus using affected-relative-pair linkage analysis with covariates demonstrates genetic heterogeneity |
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