Associations of placental lncRNA expression with maternal pre-pregnancy BMI and infant birthweight in two birth cohorts

Pre-pregnancy obesity (ppOB) is linked to pregnancy complications and abnormal fetal growth through placental mechanisms, and long non-coding RNAs (lncRNAs) may play an epigenetic role in these processes. We investigated overall and sex-specific associations of pre-pregnancy body mass index (ppBMI), ppOB, and birthweight with placental lncRNA transcripts in two birth cohorts. Study participants were mother-child dyads recruited to the CANDLE (Memphis, TN)(<i>n</i> = 725) and GAPPS (Seattle and Yakima, WA)(<i>n</i> = 159) cohorts. Maternal ppBMI was assessed at enrollment using interviewer-administered questionnaires. LncRNAs (1,077 and 1,033 for CANDLE and GAPPS, respectively) were sequenced from placental samples collected at birth. Placental lncRNA was regressed on ppBMI, ppOB (ppBMI ≥30kg/m²), or continuous birthweight in cohort-specific weighted linear models controlling for <i>a priori</i>-specified confounders and experimental variables. Potential effect modification by infant-sex was examined in sex-stratified analyses and models including BMI-infant-sex interaction terms. No lncRNA transcripts were significantly associated with ppBMI, ppOB, or birthweight in primary models. Among male infants in CANDLE, expression of three lncRNA transcripts (<i>ERVH48-1</i>, <i>AC139099.1</i>, <i>CEBPA-DT</i>) was associated with ppBMI and one transcript (<i>AC104083.1</i>) with birthweight. In GAPPS, ppBMI was associated with two lncRNA transcripts (<i>AP000879.1</i> and <i>AL365203.2</i>) among males, and birthweight was associated with 17 lncRNA transcripts (including <i>LINC02709</i>, <i>KANSL1-AS1, DANCR, EPB41L4A-AS1</i>, and <i>GABPB1-AS1</i>) among females. No BMI-infant-sex interactions were observed. Though many of these potential associations are for uncharacterized transcripts, several identified lncRNAs (e.g., <i>ERVH48-1</i> and <i>CEBPA-DT</i>) have been linked to pathways controlling cancer or placental growth, trophoblast differentiation, and gene expression. These associations warrant validation in future studies.