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The architecture of gene regulatory variation across multiple human tissues: the MuTHER study.
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2011 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 7, no 2Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2011. Vol. 7, no 2
National Category
Medical and Health Sciences Biological Sciences
URN: urn:nbn:se:uu:diva-275702DOI: 10.1371/journal.pgen.1002003PubMedID: 21304890OAI: oai:DiVA.org:uu-275702DiVA: diva2:900699
Available from: 2016-02-04 Created: 2016-02-04 Last updated: 2016-02-04

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Hedman, Asa K
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