The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index.
Candidate Causal Regulatory Effects by Integration of Expression QTLs with Complex Trait Genetic Associations
Open accessAbstract
The recent success of genome-wide association studies (GWAS) is now followed by the challenge to determine how the reported susceptibility variants mediate complex traits and diseases. Expression quantitative trait loci (eQTLs) have been implicated in disease associations through overlaps between eQTLs and GWAS signals. However, the abundance of eQTLs and the strong correlation structure (LD) in the genome make it likely that some of these overlaps are coincidental and not driven by the same functional variants. In the present study, we propose an empirical methodology, which we call Regulatory Trait Concordance (RTC) that accounts for local LD structure and integrates eQTLs and GWAS results in order to reveal the subset of association signals that are due to cis eQTLs. We simulate genomic regions of various LD patterns with both a single or two causal variants and show that our score outperforms SNP correlation metrics, be they statistical (r(2)) or historical (D'). Following the observation of a significant abundance of regulatory signals among currently published GWAS loci, we apply our method with the goal to prioritize relevant genes for each of the respective complex traits. We detect several potential disease-causing regulatory effects, with a strong enrichment for immunity-related conditions, consistent with the nature of the cell line tested (LCLs). Furthermore, we present an extension of the method in trans, where interrogating the whole genome for downstream effects of the disease variant can be informative regarding its unknown primary biological effect. We conclude that integrating cellular phenotype associations with organismal complex traits will facilitate the biological interpretation of the genetic effects on these traits.
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Cites
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Self-citationRelative Impact of Nucleotide and Copy Number Variation on Gene Expression Phenotypes
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Self-citationGenetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma
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Cited by
The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans
The GTEx Consortium, Ardlie, K. G., Deluca, D. S., Segrè, A. V., Sullivan, T. J., Young, T. R., Gelfand, E. T., Trowbridge, C. A., Maller, J. B., Tukiainen, T., et al. (2015) · Science · doi:10.1126/science.1262110 · Cited by 5,062
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Integrative approaches for large-scale transcriptome-wide association studies
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Transcriptome and genome sequencing uncovers functional variation in humans
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Metadata
- Authors
- Nica, A. C., Montgomery, S. B., Dimas, A. S., Stranger, B. E., Beazley, C., Barroso, I., & Dermitzakis, E. T.
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-04-01
- Volume
- 6
- Issue
- 4
- Pages
- e1000895
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- OpenAlex
- W2164531600
- Cited by
- 445
- References
- 28
- FWCI
- 17.44
- Type
- journal article
- Language
- en
- Open access
- gold
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- Nica, A. C., Montgomery, S. B., Dimas, A. S., Stranger, B. E., Beazley, C., Barroso, I., & Dermitzakis, E. T. (2010). Candidate Causal Regulatory Effects by Integration of Expression QTLs with Complex Trait Genetic Associations. PLoS Genetics. https://doi.org/10.1371/journal.pgen.1000895
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