Genome-wide association study identifies a novel maternal gene × stress interaction associated with spontaneous...

Maternal stress is potentially a modifiable risk factor for spontaneous preterm birth (sPTB). However, epidemiologic findings on the maternal stress-sPTB relationship have been inconsistent.

To investigate whether the maternal stress-sPTB associations may be modified by genetic susceptibility, we performed genome-wide gene × stress interaction analyses in 1490 African-American women from the Boston Birth cohort who delivered term (n = 1033) or preterm (n = 457) infants. Genotyping was performed using Illumina HumanOmni 2.5 array. Replication was performed using data from the NICHD genomic and Proteomic Network (GPN) for PTB research.

rs35331017, a T-allele insertion/deletion polymorphism in the protein-tyrosine phosphatase receptor Type D (PTPRD) gene, was the top hit that interacted significantly with maternal lifetime stress on risk of sPTB (P_G × E = 4.7 × 10^-8). We revealed a dose-responsive association between degree of stress and risk of sPTB in mothers carrying the insertion/insertion genotype, but an inverse association was observed in mothers carrying the heterozygous or deletion/deletion genotypes. This interaction was replicated in African-American (P_G × E = 0.088) and Caucasian mothers (P_G × E = 0.023) from the GPN study.

We demonstrated a significant maternal PTPRD × stress interaction on sPTB risk. This finding, if further confirmed, may provide new insight into individual susceptibility to stress-induced sPTB.

This was the first preterm study to demonstrate a significant genome-wide gene-stress interaction in African Americans, specifically, PTPRD gene variants can interact with maternal perceived stress to affect risk of spontaneous preterm birth. The PTPRD × maternal stress interaction was demonstrated in African Americans and replicated in both African Americans and Caucasians from the GPN study. Our findings highlight the importance of considering genetic susceptibility in assessing the role of maternal stress on spontaneous preterm birth.