Multiple sclerosis (MS) is characterized as a neurodegenerative autoimmune disease. This clinically complex disease has provided great challenges for geneticists over the years. With the advent of genome-wide association studies (GWAS), the strong genetic component associated with MS is finally beginning to be characterized. One of the first discoveries to emerge in this new era was the association with rs6897932 in the interleukin-7 receptor alpha chain (IL7RA) gene. The goal of the work presented in this dissertation was to identify additional genes that increase ones susceptibility to MS. Our studies involved examining genes in the extended biological pathway related to IL7RA to identify novel associations. Through this approach, we identified two additional novel gene regions that are likely associated with MS. These results help to further delineate the genetic architecture of MS and validate our pathway approach as an effective method to identify novel associations associated in a complex disease.
We began our investigation with a discovery screen containing SNPs from 73 genes with putative functional relationships to IL7RA and subsequently genotyped 7,865 single nucleotide polymorphism (SNPs) in and around these genes. Two of the gene regions examined, IL7 and SOCS1, had significantly associated SNPs that further replicated in an independent case-control dataset with joint p-values reaching 8.29x10-5 and 3.48x10-7, respectively, exceeding the threshold for experiment-wide significance. Our results also implicated two additional novel gene regions that are likely to be associated with MS: PRKCE with p-values reaching 3.47x10-4 and BCL2 with p-values reaching 4.32x10-4. The TYK2 gene, which emerged in our analysis, also has recently been associated with MS in other studies.
The work presented in this dissertation confirmed two novel regions and implicated several others that need further examination as MS disease loci. Thus, using the pathway approach in conjunction with large datasets and dense genotyping, the etiology of MS is finally starting to be dissected. By building on the knowledge of these gene effects, these studies will hopefully result in further understanding of the pathogenesis of MS.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-12032009-161131 |
| Date | 07 December 2009 |
| Creators | Zuvich, Rebecca Lynn |
| Contributors | Subramanian Sriram, Dana Crawford, Marylyn Ritchie, Michael Rock, Jonathan Haines |
| 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-12032009-161131/ |
| Rights | unrestricted, 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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