Genetics of spontaneous idiopathic preterm birth: exploration of maternal and fetal genomes
McElroy, Jude James
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.