Sex-specific placental gene expression signatures of small for gestational age at birth

Abstract

Introduction: Small for gestational age at birth (SGA), often a consequence of placental dysfunction, is a risk factor for neonatal morbidity and later life cardiometabolic diseases. There are sex differences in placental gene expression and fetal growth. Here, we investigated sex-specific associations between gene expression in human placenta measured using RNA sequencing and SGA status using data from ethnic diverse pregnant women in the NICHD Fetal Growth Studies cohort (n = 74).

Methods: Gene expression measures were obtained using RNA-Sequencing and differential gene expression between SGA (birthweight <10th percentile) and appropriate for gestational age (AGA: ≥10th and <90th percentile) was tested separately in males (12 SGA and 27 AGA) and females (9 SGA and 26 AGA) using a weighted mean of log ratios method with adjustment for mode of delivery and ethnicity.

Results: At 5% false discovery rate (FDR), we identified 40 differentially expressed genes (DEGs) related to SGA status among males (95% up- and 5% down-regulated) and 314 DEGs among females (32.5% up- and 67.5% down-regulated). Seven female-specific DEGs overlapped with known imprinted genes (AXL, CYP24A1, GPR1, PLAGL1, CMTM1, DLX5, LY6D). The DEGs in males were significantly enriched for immune response and inflammation signaling pathways whereas the DEGs in females were enriched for organ development signaling pathways (FDR<0.05). Sex-combined analysis identified no additional DEGs, rather 98% of the sex-specific DEGs were no longer significant and the remaining 2% were attenuated.

Discussion: This study revealed sex-specific human placental gene expression changes and molecular pathways associated with SGA and underscored that unravelling the pathogenesis of SGA warrants consideration of fetal sex as a biological variable.

Trial registration: https://www.

Clinicaltrials: gov, Unique identifier: NCT00912132.

Keywords: Developmental origins of health and disease; Human placenta; Pregnancy; Sexual dimorphism; Small for gestational age.

Conflict of interest statement

Competing interests

The authors declare that they have no competing interests.

Published by Elsevier Ltd.

Figures

Figure 1.. Volcano plot depicting distribution of associations between placental gene expression and small for gestational age weight at birth.

A. male-specific, and B. female-specific. Shown in blue are differentially expressed genes (FDR-adjusted P-value

Figure 2.. Comparison of sex-stratified and sex-combined associations for seven genes associated with small for gestational age in both sex-specific and sex-combined analyses.

Data on sex-combined analysis is denoted by sky-blue bubbles, female-specific analysis by golden bubbles, and male-specific analysis by green bubbles. The larger the size of a bubble, the higher the strength of significance (−log10(adjusted P-values)). IFNG is missing in female-specific analysis because it was filtered out during quality control.

Figure 3.. Functional pathway comparison.

The circle plot represents enriched functional pathways in males and females with adjusted P-value