A logical mechanism by which SNPs affect the pathophysiology of disease is through altering the expression of genes. Several studies have explored how SNPs alter expression of nearby genes (cis-eQTLs), but far fewer studies have explored distant effects (trans-eQTLs). This is likely due to the dramatic expansion of statistical tests required and the limited interpretability of results. We hypothesize that distant effects seen in trans-eQTLs are propagated or mediated by biological pathways. To investigate this hypothesis, we performed a focused trans-eQTL analysis on SNPs with known cis-effects by applying Signaling Pathway Impact Analysis (SPIA) to two independent datasets that have both genotype and gene-expression data. Fifteen SNP-Pathway associations were identified and replicated after correction for multiple testing. Given our requirement that all SNPs have cis-effects we performed conditional analyses to determine the effect of the cis-gene expression on our SNP-Pathway associations. Additionally, we annotated these results for functional elements from the ENCODE project to determine biological plausibility and generalizability. In summary, we identify trans-eQTL effects within the context of biological pathways that replicate across multiple ethnic populations.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-07162014-192116 |
| Date | 17 July 2014 |
| Creators | Wiley, Laura Katherine |
| Contributors | Joshua C Denny, William S Bush, Josh F Peterson |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-07162014-192116/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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