Discovery of rare ancestry-specific variants in the fetal genome that confer risk of preterm premature rupture of membranes (PPROM) and preterm birth

Bhavi P Modi,Maria E Teves,Timothy P York,Jiang Liyu,Hardik I Parikh,Rewa Kulkarni,Roberto Romero,Jerome F Strauss

doi:10.1186/s12881-018-0696-4

Abstract

BackgroundPreterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth, a complication that is more common in African Americans. Attempts to identify genetic loci associated with preterm birth using genome-wide association studies (GWAS) have only been successful with large numbers of cases and controls, and there has yet to be a convincing genetic association to explain racial/ethnic disparities. Indeed, the search for ancestry-specific variants associated with preterm birth has led to the conclusion that spontaneous preterm birth could be the consequence of multiple rare variants. The hypothesis that preterm birth is due to rare genetic variants that would go undetected in standard GWAS has been explored in the present study. The detection and validation of these rare variants present challenges because of the low allele frequency. However, some success in the identification of fetal loci/genes associated with preterm birth using whole genome sequencing and whole exome sequencing (WES) has recently been reported. While encouraging, this is currently an expensive technology, and methods to leverage the sequencing data to quickly identify and cost-effectively validate variants are needed.MethodsWe developed a WES data analysis strategy based on neonatal genomic DNA from PPROM cases and term controls that was unencumbered by preselection of candidate genes, and capable of identifying variants in African Americans worthy of focused evaluation to establish statistically significant associations.ResultsWe describe this approach and the identification of damaging nonsense variants of African ancestry in the DEFB1 and MBL2 genes that encode anti-microbial proteins that presumably defend the fetal membranes from infectious agents. Our approach also enabled us to rule out a likely contribution of a predicted damaging nonsense variant in the METTL7B gene.ConclusionsOur findings support the notion that multiple rare population-specific variants in the fetal genome contribute to preterm birth associated with PPROM.

Highlights

Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth, a complication that is more common in African Americans
Efforts to identify ancestry-specific variants using genome-wide association studies (GWAS) approaches have led to the conclusion that spontaneous preterm birth is likely to be the consequence of multiple common variants or rare variants not detected by GWAS [6]
We detected more than 800 different nonsense variants in the discovery whole exome sequencing (WES) sample of PPROM cases and term controls, approximately 33% of which were unique to PPROM, the majority of which occurred in only one PPROM case, and 30% of the variant types were unique to term controls, with the majority occurring in one term control (Table 1) The remaining approximately one third of the nonsense variants occurred both in PPROM cases and controls, and not unexpectedly were nonsense variants with the highest allele frequency, suggesting that these variants might be tolerated and do not contribute to PPROM risk

Summary

Introduction

Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth, a complication that is more common in African Americans. Attempts to identify genetic loci associated with gestational age at delivery and preterm birth using genome-wide association studies (GWAS) have only been successful with large numbers of cases and controls (see reference [5] for a review). These studies have not identified genes that could account for increased preterm births in African-Americans. This is not a surprising conclusion since GWAS is based the “common disease-common variant” hypothesis, positing that a significant proportion of the variance of common diseases are attributable to DNA variants that are present in > 1–5% of the population, and that there are many of these DNA variants, each contributing a small amount to the total risk to a particular disease [5]

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