Mapping genetic susceptibility to preterm birth: Analysis of Utah pedigrees using shared genomic segment analysis

Abstract

Background: Spontaneous preterm birth (SPTB) is the leading cause of neonatal morbidity and mortality. It is a final common pathway for multiple etiologies, some of which are well known while others likely remain to be identified. There is a genetic component to SPTB, but genetic mechanisms remain poorly defined. Well-characterized family-based studies may aid in identifying genetic contributors to SPTB. Objective: To identify inherited risk variants for SPTB using large pedigrees. Study Design: Using the Utah Population Database (UPDB), which links a 4.5 million-person genealogy to state birth certificate and fetal death records, we identified large pedigrees containing multiple women with early SPTB (<34 weeks’ gestation). We reviewed birth certificate data to exclude those with maternal and fetal diagnoses associated with iatrogenic preterm birth, resulting in 74 large multiplex pedigrees for early SPTB. Women with any SPTB (<37 weeks) within these early SPTB pedigrees were invited to participate. Enrolled women underwent comprehensive clinical phenotyping with review of primary medical records. Seven pedigrees, each containing at least 3 sampled women with SPTB, were the focus of this genetic study. High-density single-nucleotide polymorphism genotyping was conducted in maternal peripheral blood samples from women in the seven pedigrees. Shared genomic segment (SGS) analysis was performed to identify genome-wide significant chromosomal regions shared in excess by women with SPTB. Results: We identified two genome-wide significant regions. In single-pedigree SGS analyses, a 1.75 Mb genome-wide significant region at 8q24.23 was shared by 5 out of 6 women with SPTB in a single large pedigree (false positive rate per genome, µ=0.028). In duo-pedigree analysis, this region showed overlapping evidence with a second pedigree. The shared 1.05 Mb 8q24.23 locus had a more extreme false-positive rate (µ=0.0019). and contains FAM135Band KHDRBS3 genes, which have previously been implicated in oncogenesis and ovarian cancer. Duo-pedigree SGS analysis also identified a second genome-wide significant 67 kb locus at 12q21.1-q21.2 that was shared by all SPTB cases in two independent pedigrees (µ=0.01). The intersecting region at 12q21.1-q21.2 contains genes (CAPS2; KCNC2) implicated in vascular-related complications of pregnancy and preterm labor. Conclusion: We identified two risk loci for SPTB using shared genomic segments analysis in large multiplex pedigrees. Identification of genes associated with SPTB may provide novel therapeutic targets for prevention and treatment to prolong pregnancy and improve outcomes.