Genome-wide approach identifies a novel gene-maternal pre-pregnancy BMI interaction on preterm birth

Abstract

Preterm birth (PTB) contributes significantly to infant mortality and morbidity with lifelong impact. Few robust genetic factors of PTB have been identified. Such 'missing heritability' may be partly due to gene × environment interactions (G × E), which is largely unexplored. Here we conduct genome-wide G × E analyses of PTB in 1,733 African-American women (698 mothers of PTB; 1,035 of term birth) from the Boston Birth Cohort. We show that maternal COL24A1 variants have a significant genome-wide interaction with maternal pre-pregnancy overweight/obesity on PTB risk, with rs11161721 (P_{G × E}=1.8 × 10^-8; empirical P_{G × E}=1.2 × 10^-8) as the top hit. This interaction is replicated in African-American mothers (P_{G × E}=0.01) from an independent cohort and in meta-analysis (P_{G × E}=3.6 × 10^-9), but is not replicated in Caucasians. In adipose tissue, rs11161721 is significantly associated with altered COL24A1 expression. Our findings may provide new insight into the aetiology of PTB and improve our ability to predict and prevent PTB.

Figure 1. Manhattan and quantile-quantile (Q-Q) plots for genome-wide SNP interactions with pre-pregnancy BMI category on overall PTB as well as the locuszoom plot for the genomic region reaching genome-wide significance.

(a) Manhattan plot, (b) Q–Q plot for the genome-wide genotyped and/or imputed SNP interaction with pre-pregnancy BMI category and (c) the locuszoom plot for both genotyped and/or imputed SNPs located in the region at chromosome 1p22 that showed genome-wide significant interaction with pre-pregnancy BMI on overall PTB, in 1,586 African American mothers from the BBC. All analyses were performed using the conventional 1-degree of freedom interaction test based on the multiple logistic regression models, adjusted for genotyping batch, genetic ancestry, maternal age at delivery, parity and infant's gender.

Figure 2. The joint associations between rs11161721 in the COL24A1 gene and pre-pregnancy BMI on overall PTB risk.

Y axis reflects the OR and 95% confidence interval (CI) of overall PTB risk for each subgroup stratified by the genotype of rs11161721 and maternal pre-pregnancy BMI category, with normal weight mothers carrying the rs11161721-CC genotype as the reference group. This analysis was conducted based on the multiple logistic regression models, adjusted for genotyping batch, genetic ancestry, maternal age at delivery, parity and infant's gender. *P<0.05; **P<0.01; ***P<0.001, ****P<0.0001 when compared with the reference group. NW, normal weight; OB, obesity; OW, overweight.