Layered genetic control of DNA methylation and gene expression: a locus of multiple sclerosis in healthy individuals
DNA methylation may contribute to the etiology of complex genetic disorders through its impact on genome integrity and gene expression; it is modulated by DNA-sequence variants, named methylation quantitative trait loci (meQTLs). Most meQTLs influence methylation of a few CpG dinucleotides within sh...
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| Veröffentlicht in: | Human molecular genetics 2015-10, Vol.24 (20), p.5733-5745 |
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| container_title | Human molecular genetics |
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| creator | Shin, Jean Bourdon, Celine Bernard, Manon Wilson, Michael D Reischl, Eva Waldenberger, Melanie Ruggeri, Barbara Schumann, Gunter Desrivieres, Sylvane Leemans, Alexander Abrahamowicz, Michal Leonard, Gabriel Richer, Louis Bouchard, Luigi Gaudet, Daniel Paus, Tomas Pausova, Zdenka |
| description | DNA methylation may contribute to the etiology of complex genetic disorders through its impact on genome integrity and gene expression; it is modulated by DNA-sequence variants, named methylation quantitative trait loci (meQTLs). Most meQTLs influence methylation of a few CpG dinucleotides within short genomic regions ( |
| doi_str_mv | 10.1093/hmg/ddv294 |
| format | Article |
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Most meQTLs influence methylation of a few CpG dinucleotides within short genomic regions (<3 kb). Here, we identified a layered genetic control of DNA methylation at numerous CpGs across a long 300 kb genomic region. This control involved a single long-range meQTL and multiple local meQTLs. The long-range meQTL explained up to 75% of variance in methylation of CpGs located over extended areas of the 300 kb region. The meQTL was identified in four samples (P = 2.8 × 10(-17), 3.1 × 10(-31), 4.0 × 10(-71) and 5.2 × 10(-199)), comprising a total of 2796 individuals. The long-range meQTL was strongly associated not only with DNA methylation but also with mRNA expression of several genes within the 300 kb region (P = 7.1 × 10(-18)-1.0 × 10(-123)). The associations of the meQTL with gene expression became attenuated when adjusted for DNA methylation (causal inference test: P = 2.4 × 10(-13)-7.1 × 10(-20)), indicating coordinated regulation of DNA methylation and gene expression. Further, the long-range meQTL was found to be in linkage disequilibrium with the most replicated locus of multiple sclerosis, a disease affecting primarily the brain white matter. In middle-aged adults free of the disease, we observed that the risk allele was associated with subtle structural properties of the brain white matter found in multiple sclerosis (P = 0.02). In summary, we identified a long-range meQTL that controls methylation and expression of several genes and may be involved in increasing brain vulnerability to multiple sclerosis.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddv294</identifier><identifier>PMID: 26220975</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Adolescent ; Adult ; Aged ; Alleles ; Chromosomes, Human, Pair 6 ; CpG Islands ; DNA Methylation ; Female ; Gene Expression Regulation ; Genetic Predisposition to Disease ; Genomics ; Humans ; Linkage Disequilibrium ; Male ; Middle Aged ; Multiple Sclerosis - genetics ; Quantitative Trait Loci</subject><ispartof>Human molecular genetics, 2015-10, Vol.24 (20), p.5733-5745</ispartof><rights>The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.</rights><rights>The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c411t-7c4ba99121ea600fce13164ca1887c3ff53a9fcde16dbff01226f628144cd753</citedby><cites>FETCH-LOGICAL-c411t-7c4ba99121ea600fce13164ca1887c3ff53a9fcde16dbff01226f628144cd753</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26220975$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shin, Jean</creatorcontrib><creatorcontrib>Bourdon, Celine</creatorcontrib><creatorcontrib>Bernard, Manon</creatorcontrib><creatorcontrib>Wilson, Michael D</creatorcontrib><creatorcontrib>Reischl, Eva</creatorcontrib><creatorcontrib>Waldenberger, Melanie</creatorcontrib><creatorcontrib>Ruggeri, Barbara</creatorcontrib><creatorcontrib>Schumann, Gunter</creatorcontrib><creatorcontrib>Desrivieres, Sylvane</creatorcontrib><creatorcontrib>Leemans, Alexander</creatorcontrib><creatorcontrib>Abrahamowicz, Michal</creatorcontrib><creatorcontrib>Leonard, Gabriel</creatorcontrib><creatorcontrib>Richer, Louis</creatorcontrib><creatorcontrib>Bouchard, Luigi</creatorcontrib><creatorcontrib>Gaudet, Daniel</creatorcontrib><creatorcontrib>Paus, Tomas</creatorcontrib><creatorcontrib>Pausova, Zdenka</creatorcontrib><creatorcontrib>SYS Consortium</creatorcontrib><creatorcontrib>IMAGEN Consortium</creatorcontrib><creatorcontrib>the IMAGEN Consortium</creatorcontrib><creatorcontrib>the SYS Consortium</creatorcontrib><title>Layered genetic control of DNA methylation and gene expression: a locus of multiple sclerosis in healthy individuals</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>DNA methylation may contribute to the etiology of complex genetic disorders through its impact on genome integrity and gene expression; it is modulated by DNA-sequence variants, named methylation quantitative trait loci (meQTLs). Most meQTLs influence methylation of a few CpG dinucleotides within short genomic regions (<3 kb). Here, we identified a layered genetic control of DNA methylation at numerous CpGs across a long 300 kb genomic region. This control involved a single long-range meQTL and multiple local meQTLs. The long-range meQTL explained up to 75% of variance in methylation of CpGs located over extended areas of the 300 kb region. The meQTL was identified in four samples (P = 2.8 × 10(-17), 3.1 × 10(-31), 4.0 × 10(-71) and 5.2 × 10(-199)), comprising a total of 2796 individuals. The long-range meQTL was strongly associated not only with DNA methylation but also with mRNA expression of several genes within the 300 kb region (P = 7.1 × 10(-18)-1.0 × 10(-123)). The associations of the meQTL with gene expression became attenuated when adjusted for DNA methylation (causal inference test: P = 2.4 × 10(-13)-7.1 × 10(-20)), indicating coordinated regulation of DNA methylation and gene expression. Further, the long-range meQTL was found to be in linkage disequilibrium with the most replicated locus of multiple sclerosis, a disease affecting primarily the brain white matter. In middle-aged adults free of the disease, we observed that the risk allele was associated with subtle structural properties of the brain white matter found in multiple sclerosis (P = 0.02). In summary, we identified a long-range meQTL that controls methylation and expression of several genes and may be involved in increasing brain vulnerability to multiple sclerosis.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Alleles</subject><subject>Chromosomes, Human, Pair 6</subject><subject>CpG Islands</subject><subject>DNA Methylation</subject><subject>Female</subject><subject>Gene Expression Regulation</subject><subject>Genetic Predisposition to Disease</subject><subject>Genomics</subject><subject>Humans</subject><subject>Linkage Disequilibrium</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Multiple Sclerosis - genetics</subject><subject>Quantitative Trait Loci</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU9v1DAQxS0EokvLhQ-AfERIoR7bcWIOSFX5U6QVvfRuee3xrpETL3GyYr89rrZUcOtpRjM_Pc2bR8gbYB-AaXG5G7aX3h-4ls_ICqRiDWe9eE5WTCvZKM3UGXlVyk_GQEnRvSRnXHHOdNeuyLy2R5zQ0y2OOEdHXR7nKSeaA_3844oOOO-Oyc4xj9SOJ4zi7_2EpdTZR2ppym4p9_ywpDnuE9LiEk65xELjSHdoU9WorY-H6BebygV5EWrB1w_1nNx9_XJ3fdOsb799v75aN04CzE3n5MZqDRzQKsaCQxDVgbPQ950TIbTC6uA8gvKbEBhwroLiPUjpfNeKc_LpJLtfNgN6h9WZTWY_xcFOR5NtNP9vxrgz23wwsu1BMVEF3j0ITPnXgmU2QywOU7Ij5qUY6HinOt0BfwIKSgupWlXR9yfU1R-VCcPjRcDMfaCmBmpOgVb47b8eHtG_CYo_sc2fsQ</recordid><startdate>20151015</startdate><enddate>20151015</enddate><creator>Shin, Jean</creator><creator>Bourdon, Celine</creator><creator>Bernard, Manon</creator><creator>Wilson, Michael D</creator><creator>Reischl, Eva</creator><creator>Waldenberger, Melanie</creator><creator>Ruggeri, Barbara</creator><creator>Schumann, Gunter</creator><creator>Desrivieres, Sylvane</creator><creator>Leemans, Alexander</creator><creator>Abrahamowicz, Michal</creator><creator>Leonard, Gabriel</creator><creator>Richer, Louis</creator><creator>Bouchard, Luigi</creator><creator>Gaudet, Daniel</creator><creator>Paus, Tomas</creator><creator>Pausova, Zdenka</creator><general>Oxford University Press</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>7X8</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20151015</creationdate><title>Layered genetic control of DNA methylation and gene expression: a locus of multiple sclerosis in healthy individuals</title><author>Shin, Jean ; Bourdon, Celine ; Bernard, Manon ; Wilson, Michael D ; Reischl, Eva ; Waldenberger, Melanie ; Ruggeri, Barbara ; Schumann, Gunter ; Desrivieres, Sylvane ; Leemans, Alexander ; Abrahamowicz, Michal ; Leonard, Gabriel ; Richer, Louis ; Bouchard, Luigi ; Gaudet, Daniel ; Paus, Tomas ; Pausova, Zdenka</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c411t-7c4ba99121ea600fce13164ca1887c3ff53a9fcde16dbff01226f628144cd753</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Alleles</topic><topic>Chromosomes, Human, Pair 6</topic><topic>CpG Islands</topic><topic>DNA Methylation</topic><topic>Female</topic><topic>Gene Expression Regulation</topic><topic>Genetic Predisposition to Disease</topic><topic>Genomics</topic><topic>Humans</topic><topic>Linkage Disequilibrium</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Multiple Sclerosis - genetics</topic><topic>Quantitative Trait Loci</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shin, Jean</creatorcontrib><creatorcontrib>Bourdon, Celine</creatorcontrib><creatorcontrib>Bernard, Manon</creatorcontrib><creatorcontrib>Wilson, Michael D</creatorcontrib><creatorcontrib>Reischl, Eva</creatorcontrib><creatorcontrib>Waldenberger, Melanie</creatorcontrib><creatorcontrib>Ruggeri, Barbara</creatorcontrib><creatorcontrib>Schumann, Gunter</creatorcontrib><creatorcontrib>Desrivieres, Sylvane</creatorcontrib><creatorcontrib>Leemans, Alexander</creatorcontrib><creatorcontrib>Abrahamowicz, Michal</creatorcontrib><creatorcontrib>Leonard, Gabriel</creatorcontrib><creatorcontrib>Richer, Louis</creatorcontrib><creatorcontrib>Bouchard, Luigi</creatorcontrib><creatorcontrib>Gaudet, Daniel</creatorcontrib><creatorcontrib>Paus, Tomas</creatorcontrib><creatorcontrib>Pausova, Zdenka</creatorcontrib><creatorcontrib>SYS Consortium</creatorcontrib><creatorcontrib>IMAGEN Consortium</creatorcontrib><creatorcontrib>the IMAGEN Consortium</creatorcontrib><creatorcontrib>the SYS Consortium</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shin, Jean</au><au>Bourdon, Celine</au><au>Bernard, Manon</au><au>Wilson, Michael D</au><au>Reischl, Eva</au><au>Waldenberger, Melanie</au><au>Ruggeri, Barbara</au><au>Schumann, Gunter</au><au>Desrivieres, Sylvane</au><au>Leemans, Alexander</au><au>Abrahamowicz, Michal</au><au>Leonard, Gabriel</au><au>Richer, Louis</au><au>Bouchard, Luigi</au><au>Gaudet, Daniel</au><au>Paus, Tomas</au><au>Pausova, Zdenka</au><aucorp>SYS Consortium</aucorp><aucorp>IMAGEN Consortium</aucorp><aucorp>the IMAGEN Consortium</aucorp><aucorp>the SYS Consortium</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Layered genetic control of DNA methylation and gene expression: a locus of multiple sclerosis in healthy individuals</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum Mol Genet</addtitle><date>2015-10-15</date><risdate>2015</risdate><volume>24</volume><issue>20</issue><spage>5733</spage><epage>5745</epage><pages>5733-5745</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><abstract>DNA methylation may contribute to the etiology of complex genetic disorders through its impact on genome integrity and gene expression; it is modulated by DNA-sequence variants, named methylation quantitative trait loci (meQTLs). Most meQTLs influence methylation of a few CpG dinucleotides within short genomic regions (<3 kb). Here, we identified a layered genetic control of DNA methylation at numerous CpGs across a long 300 kb genomic region. This control involved a single long-range meQTL and multiple local meQTLs. The long-range meQTL explained up to 75% of variance in methylation of CpGs located over extended areas of the 300 kb region. The meQTL was identified in four samples (P = 2.8 × 10(-17), 3.1 × 10(-31), 4.0 × 10(-71) and 5.2 × 10(-199)), comprising a total of 2796 individuals. The long-range meQTL was strongly associated not only with DNA methylation but also with mRNA expression of several genes within the 300 kb region (P = 7.1 × 10(-18)-1.0 × 10(-123)). The associations of the meQTL with gene expression became attenuated when adjusted for DNA methylation (causal inference test: P = 2.4 × 10(-13)-7.1 × 10(-20)), indicating coordinated regulation of DNA methylation and gene expression. Further, the long-range meQTL was found to be in linkage disequilibrium with the most replicated locus of multiple sclerosis, a disease affecting primarily the brain white matter. In middle-aged adults free of the disease, we observed that the risk allele was associated with subtle structural properties of the brain white matter found in multiple sclerosis (P = 0.02). In summary, we identified a long-range meQTL that controls methylation and expression of several genes and may be involved in increasing brain vulnerability to multiple sclerosis.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>26220975</pmid><doi>10.1093/hmg/ddv294</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Adolescent Adult Aged Alleles Chromosomes, Human, Pair 6 CpG Islands DNA Methylation Female Gene Expression Regulation Genetic Predisposition to Disease Genomics Humans Linkage Disequilibrium Male Middle Aged Multiple Sclerosis - genetics Quantitative Trait Loci |
| title | Layered genetic control of DNA methylation and gene expression: a locus of multiple sclerosis in healthy individuals |
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