Protein interaction networks define the genetic architecture of preterm birth

Abstract

The likely genetic architecture of complex diseases is that subgroups of patients share variants in genes in specific networks sufficient to express a shared phenotype. We combined high throughput sequencing with advanced bioinformatic approaches to identify such subgroups of patients with variants in shared networks. We performed targeted sequencing of patients with 2 or 3 generations of preterm birth on genes, gene sets and haplotype blocks that were highly associated with preterm birth. We analyzed the data using a multi-sample, protein–protein interaction (PPI) tool to identify significant clusters of patients associated with preterm birth. We identified shared protein interaction networks among preterm cases in two statistically significant clusters, p < 0.001. We also found two small control-dominated clusters. We replicated these data on an independent, large birth cohort. Separation testing showed significant similarity scores between the clusters from the two independent cohorts of patients. Canonical pathway analysis of the unique genes defining these clusters demonstrated enrichment in inflammatory signaling pathways, the glucocorticoid receptor, the insulin receptor, EGF and B-cell signaling, These results support a genetic architecture defined by subgroups of patients that share variants in genes in specific networks and pathways which are sufficient to give rise to the disease phenotype.

The “Bad Father”: Paternal Role in Biology of Pregnancy and in Birth Outcome

“…The hypothesis contemplated concerns the delicate balance between pro- and anticoagulant factors at the feto-placental interface, therefore the phenomena of fibrin deposition and infarction could arise either from the maternal or fetal side, or from both. The expression of certain paternally derived allelic variants in the trophoblast involved in immune regulation or vascular remodeling has also been linked to adverse pregnancy outcomes associated with abnormal placentation [ 27 , 28 ]. The presence of microthrombi in the chorio-decidual capillaries could, in fact, compromise the physiological anchoring of the villi and lead to the phenomena ranging from activating the coagulatory “cascade” to the thrombosis of vessels in the umbilical cord or multiple placental infarcts.…”