Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Human and Statistical Genetics


English (en)

Date of Award

January 2010

Degree Type


Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Louis Muglia


Preterm birth: PTB) is a leading cause of mortality and disease burden globally; however, determinants of human parturition remain largely uncharacterized, making prediction and prevention of difficult. Genetic studies are one way in which we can attempt to better understand this disorder. We first sought to develop a model for the genetic influences on PTB to facilitate gene discovery. Study of standard measures of familial aggregation, the sibling risk ratio and the sibling-sibling odds ratio, and segregation analyses of gestational age, a quantitative proxy for preterm birth, lend support to a genetic component contributing to birth timing, since preterm deliveries cluster in families and models in which environmental factors alone contribute to gestational age are strongly rejected. Analyses of gestational age attributed to the infant support a model in which mother's genome and/or maternally-inherited genes acting in the fetus are largely responsible for birth timing. We also aimed to discover specific genes associated with PTB by screening genes selected based on an evolutionary-motivated filter, rather than known parturition physiology. Because humans are born developmentally less mature than other mammals, birth timing mechanisms may differ between humans and model organisms that have been typically studied; as a result, we screened 150 genes, selected because of their rapid evolution along the human lineage. A screen of over 8000 SNPs in 165 Finnish preterm and 163 control mothers identified an enrichment of variants in FSHRassociated with PTB and prompted further study of the gene. Additionally, PLA2G4C, identified as the gene with the most statistically significant evidence for rapid evolution that was also included in a list of preterm birth candidate genes, was examined further. Three SNPs in PLA2G4C and one SNP in FSHR were statistically significant across populations after multiple testing corrections. Additional work to identify variants in these genes with functional effects was also initiated, including comparisons of prostaglandin metabolite levels among genotype classes for significantly associated SNPs in PLA2G4C and sequencing of FSHR to identify functional coding variants. Together, these experiments better characterize the nature of genetic influences on PTB and support the role of PLA2G4C and FSHR in PTB.



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