Preterm birth (PTB), defined as live birth before 37 weeks completed gestation, is the leading cause of infant mortality worldwide. Despite this major public health concern, little is known about the pathogenesis of PTB. The limited insight into PTB is contributed to by the fact that the mechanism for normal parturition is not known in humans. A number of lines of evidence suggest that PTB has a genetic component such as PTB aggregating in families, segregation analysis and genetic modeling. Primarily through candidate gene studies, there have been a number of single nucleotide polymorphisms (SNPs) associated with PTB; however, contradictory evidence from replication studies exists, and none of these have large effect sizes or have implicated novel insight into the mechanism of birth timing and parturition.
The primary objective of this dissertation was to identify unidentified or unappreciated genetic variants responsible for the predisposition or pathogenesis of PTB. In order to investigate this hypothesis, we performed studies using a number of complementary approaches, which included genome-wide association studies (GWAS), exome array association, whole-exome sequence and pathway analysis. In addition to using a group of complementary methods, we also interrogated both maternal and fetal genomes for their potential role.
Our GWAS in mothers identified several SNPs associated with the dichotomous trait, PTB, and the quantitative trait gestational age. Additionally, when we used whole-exome sequencing and exome array association in mothers we identified the Kyoto Encyclopedia of Genes and Genomes (KEGG) complement and coagulation cascade to be implicated in PTB and found a robust association with coding region SNPs in complement receptor 1 (CR1). Finally, when we switched our interrogation to infant samples we observed a handful of robust associations with PTB and the quantitative traits gestational age and birth weight z-scores.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-06242013-162422 |
| Date | 17 July 2013 |
| Creators | McElroy, Jude James |
| Contributors | Dana C. Crawford, Michael R. DeBaun, Louis J. Muglia, Dan M. Roden, Scott M. Williams |
| 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-06242013-162422/ |
| 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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