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The Architecture of Gene Regulatory Variation across Multiple Human Tissues: The MuTHER Study
Open accessAbstract
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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Cites
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Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets
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Multi-omics approaches to disease
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Metadata
- Authors
- Nica, A. C., Parts, L., Glass, D., Nisbet, J., Barrett, A., Sekowska, M., Travers, M., Potter, S., Grundberg, E., Small, K., Hedman, Å. K., Bataille, V., Tzenova Bell, J., Surdulescu, G., Dimas, A. S., Ingle, C., Nestle, F. O., di Meglio, P., Min, J. L., Wilk, A., Hammond, C. J., Hassanali, N., Yang, T.-P., Montgomery, S. B., O'Rahilly, S., Lindgren, C. M., Zondervan, K. T., Soranzo, N., Barroso, I., Durbin, R., Ahmadi, K., Deloukas, P., McCarthy, M. I., Dermitzakis, E. T., Spector, T. D., & The MuTHER Consortium
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-02-03
- Volume
- 7
- Issue
- 2
- Pages
- e1002003
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- OpenAlex
- W1972698844
- Cited by
- 394
- References
- 12
- FWCI
- 37.64
- Type
- journal article
- Language
- en
- Open access
- gold
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- Nica, A. C., Parts, L., Glass, D., Nisbet, J., Barrett, A., Sekowska, M., Travers, M., Potter, S., Grundberg, E., Small, K., Hedman, Å. K., Bataille, V., Tzenova Bell, J., Surdulescu, G., Dimas, A. S., Ingle, C., Nestle, F. O., di Meglio, P., Min, J. L., . . . The MuTHER Consortium. (2011). The Architecture of Gene Regulatory Variation across Multiple Human Tissues: The MuTHER Study. PLoS Genetics. https://doi.org/10.1371/journal.pgen.1002003
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