The architecture of gene regulatory variation across multiple human tissues: the MuTHER study.
While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, an...
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Public Library of Science (PLoS)
2011-02-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002003&type=printable |
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| author | Alexandra C Nica Leopold Parts Daniel Glass James Nisbet Amy Barrett Magdalena Sekowska Mary Travers Simon Potter Elin Grundberg Kerrin Small Asa K Hedman Veronique Bataille Jordana Tzenova Bell Gabriela Surdulescu Antigone S Dimas Catherine Ingle Frank O Nestle Paola di Meglio Josine L Min Alicja Wilk Christopher J Hammond Neelam Hassanali Tsun-Po Yang Stephen B Montgomery Steve O'Rahilly Cecilia M Lindgren Krina T Zondervan Nicole Soranzo Inês Barroso Richard Durbin Kourosh Ahmadi Panos Deloukas Mark I McCarthy Emmanouil T Dermitzakis Timothy D Spector MuTHER Consortium |
| author_facet | Alexandra C Nica Leopold Parts Daniel Glass James Nisbet Amy Barrett Magdalena Sekowska Mary Travers Simon Potter Elin Grundberg Kerrin Small Asa K Hedman Veronique Bataille Jordana Tzenova Bell Gabriela Surdulescu Antigone S Dimas Catherine Ingle Frank O Nestle Paola di Meglio Josine L Min Alicja Wilk Christopher J Hammond Neelam Hassanali Tsun-Po Yang Stephen B Montgomery Steve O'Rahilly Cecilia M Lindgren Krina T Zondervan Nicole Soranzo Inês Barroso Richard Durbin Kourosh Ahmadi Panos Deloukas Mark I McCarthy Emmanouil T Dermitzakis Timothy D Spector MuTHER Consortium |
| author_sort | Alexandra C Nica |
| collection | DOAJ |
| description | While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis--MCTA) permits immediate replication of eQTLs using co-twins (93%-98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%-20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits. |
| format | Article |
| id | doaj-art-ed6d41d2e4874ff2b5d076c62e716ffe |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2011-02-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Genetics |
| spelling | doaj-art-ed6d41d2e4874ff2b5d076c62e716ffe2025-08-20T02:08:57ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-02-0172e100200310.1371/journal.pgen.1002003The architecture of gene regulatory variation across multiple human tissues: the MuTHER study.Alexandra C NicaLeopold PartsDaniel GlassJames NisbetAmy BarrettMagdalena SekowskaMary TraversSimon PotterElin GrundbergKerrin SmallAsa K HedmanVeronique BatailleJordana Tzenova BellGabriela SurdulescuAntigone S DimasCatherine IngleFrank O NestlePaola di MeglioJosine L MinAlicja WilkChristopher J HammondNeelam HassanaliTsun-Po YangStephen B MontgomerySteve O'RahillyCecilia M LindgrenKrina T ZondervanNicole SoranzoInês BarrosoRichard DurbinKourosh AhmadiPanos DeloukasMark I McCarthyEmmanouil T DermitzakisTimothy D SpectorMuTHER ConsortiumWhile there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis--MCTA) permits immediate replication of eQTLs using co-twins (93%-98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%-20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002003&type=printable |
| spellingShingle | Alexandra C Nica Leopold Parts Daniel Glass James Nisbet Amy Barrett Magdalena Sekowska Mary Travers Simon Potter Elin Grundberg Kerrin Small Asa K Hedman Veronique Bataille Jordana Tzenova Bell Gabriela Surdulescu Antigone S Dimas Catherine Ingle Frank O Nestle Paola di Meglio Josine L Min Alicja Wilk Christopher J Hammond Neelam Hassanali Tsun-Po Yang Stephen B Montgomery Steve O'Rahilly Cecilia M Lindgren Krina T Zondervan Nicole Soranzo Inês Barroso Richard Durbin Kourosh Ahmadi Panos Deloukas Mark I McCarthy Emmanouil T Dermitzakis Timothy D Spector MuTHER Consortium The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. PLoS Genetics |
| title | The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. |
| title_full | The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. |
| title_fullStr | The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. |
| title_full_unstemmed | The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. |
| title_short | The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. |
| title_sort | architecture of gene regulatory variation across multiple human tissues the muther study |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002003&type=printable |
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