Preterm birth in the United States is now 12%. Multiple genes, gene networks, variants have been associated with this disease. Using a custom database for preterm birth (dbPTB) with a refined set of genes extensively curated from literature and biological databases, we analyzed a GWAS of preterm birth for complete genotype data on nearly 2000 preterm and term mothers. We used both the curated genes and a genome-wide approach to carry out a pathway-based analysis. There were 19 significant pathways, which withstood FDR correction for multiple testing that were identified using both the curated genes and the genome-wide approach. The analysis based on the curated genes was more significant than genome-wide in 15 out of 19 pathways. This approach demonstrates the use of a validated set of genes, in the analysis of otherwise unsuccessful GWAS data, to identify gene-gene interactions in a way that enhances statistical power and discovery.
"However, in this dataset, gene variants with genome-wide statistical significance have not been found. Recent pathway-based, rather than gene-based, analyses using a custom database of genes curated from existing literature for preterm birth (dbPTB), have implicated several potentially relevant pathways that can be used to elucidate further gene-gene and gene-environment interactions [52,57]. Further meta-analysis with emerging new data from other groups should provide additional power for the detection of associations. "
[Show abstract][Hide abstract] ABSTRACT: Preterm birth (delivery at less than 37 weeks of gestation) is the leading cause of infant mortality worldwide. So far, the application of animal models to understand human birth timing has not substantially revealed mechanisms that could be used to prevent prematurity. However, with amassing data implicating an important role for genetics in the timing of the onset of human labor, the use of modern genomic approaches, such as genome-wide association studies, rare variant analyses using whole-exome or genome sequencing, and family-based designs, holds enormous potential. Although some progress has been made in the search for causative genes and variants associated with preterm birth, the major genetic determinants remain to be identified. Here, we review insights from and limitations of animal models for understanding the physiology of parturition, recent human genetic and genomic studies to identify genes involved in preterm birth, and emerging areas that are likely to be informative in future investigations. Further advances in understanding fundamental mechanisms, and the development of preventative measures, will depend upon the acquisition of greater numbers of carefully phenotyped pregnancies, large-scale informatics approaches combining genomic information with information on environmental exposures, and new conceptual models for studying the interaction between the maternal and fetal genomes to personalize therapies for mothers and infants. Information emerging from these advances will help us to identify new biomarkers for earlier detection of preterm labor, develop more effective therapeutic agents, and/or promote prophylactic measures even before conception.
Genome Medicine 04/2013; 5(4):34. DOI:10.1186/gm438 · 5.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This review describes how improvements in biometrical-genetic studies of twin kinships, half-sibships and cousinships have now demonstrated a sizeable fetal genetic and maternal genetic contribution to the spontaneous onset of labor. This is an important development since previous literature for the most part only reports an influence of the maternal genome. Current estimates of the percent of variation attributable to fetal genetic factors range from 11% to 35% while the range for the maternal genetic contribution is 13-20%. These same studies demonstrate an even larger influence of environmental sources over and above the influence of genetic sources and previously identified environmental risk factors. With these estimates in hand, a major goal for research on pregnancy duration is to identify specific allelic variation and environmental risk to account for this estimated genetic and environmental variation. A review of the current literature can serve as a guide for future research efforts.
American journal of obstetrics and gynecology 10/2013; 210(5). DOI:10.1016/j.ajog.2013.10.001 · 4.70 Impact Factor
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