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The architecture of...
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Nica, Alexandra C
(author)
The architecture of gene regulatory variation across multiple human tissues : the MuTHER study.
- Article/chapterEnglish2011
Publisher, publication year, extent ...
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2011-02-03
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Public Library of Science (PLoS),2011
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printrdacarrier
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LIBRIS-ID:oai:DiVA.org:uu-275702
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-275702URI
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https://doi.org/10.1371/journal.pgen.1002003DOI
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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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.
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Parts, Leopold
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Glass, Daniel
(author)
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Nisbet, James
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Barrett, Amy
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Sekowska, Magdalena
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Travers, Mary
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Potter, Simon
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Grundberg, Elin
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Small, Kerrin
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Hedman, Asa K
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Bataille, Veronique
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Tzenova Bell, Jordana
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Surdulescu, Gabriela
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Dimas, Antigone S
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Ingle, Catherine
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Nestle, Frank O
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di Meglio, Paola
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Min, Josine L
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Wilk, Alicja
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Hammond, Christopher J
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Hassanali, Neelam
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Yang, Tsun-Po
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Montgomery, Stephen B
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O'Rahilly, Steve
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Lindgren, Cecilia M
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Zondervan, Krina T
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Soranzo, Nicole
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Barroso, Inês
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Durbin, Richard
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Ahmadi, Kourosh
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Deloukas, Panos
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McCarthy, Mark I
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Dermitzakis, Emmanouil T
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Spector, Timothy D
(author)
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In:PLOS Genetics: Public Library of Science (PLoS)7:21553-73901553-7404
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Nica, Alexandra ...
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Parts, Leopold
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Glass, Daniel
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Nisbet, James
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Barrett, Amy
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Sekowska, Magdal ...
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show more...
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Travers, Mary
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Potter, Simon
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Grundberg, Elin
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Small, Kerrin
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Hedman, Asa K
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Bataille, Veroni ...
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Tzenova Bell, Jo ...
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Surdulescu, Gabr ...
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Dimas, Antigone ...
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Ingle, Catherine
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Nestle, Frank O
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di Meglio, Paola
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Min, Josine L
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Wilk, Alicja
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Hammond, Christo ...
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Hassanali, Neela ...
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Yang, Tsun-Po
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Montgomery, Step ...
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O'Rahilly, Steve
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Lindgren, Cecili ...
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Zondervan, Krina ...
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Soranzo, Nicole
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Barroso, Inês
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Durbin, Richard
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Ahmadi, Kourosh
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Deloukas, Panos
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McCarthy, Mark I
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Dermitzakis, Emm ...
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Spector, Timothy ...
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PLOS Genetics
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Uppsala University