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CONTEXT: Elevated body mass index (BMI) in pregnancy is associated with adverse maternal and fetal outcomes. The placental transcriptome may elucidate molecular mechanisms underlying these associations.OBJECTIVE: We examined the association of 1st trimester maternal BMI with the placental transcriptome in Gen3G prospective cohort.METHODS: We enrolled participants at 5-16 weeks of gestation and measured height and weight. We collected placenta samples at delivery. We performed whole genome RNA sequencing using Illumina HiSeq 4000 and aligned RNA sequences based on the GTEx v8 pipeline. We conducted differential gene expression analysis of over 15,000 genes from 450 placental samples and report the change in normalized gene expression per 1-unit increase in log2 BMI (kg/m2) as a continuous variable using Limma Voom. We adjusted models for maternal age, fetal sex, gestational age at delivery, gravidity, and surrogate variables accounting for technical variability. We compared participants with BMI of 18.5-24.9 mg/kg2 (N = 257) vs. those with obesity (BMI ≥30 kg/m2, N = 82) in secondary analyses.RESULTS: Participants had a mean ± SD age of 28.2 ± 4.4 years and BMI of 25.4 ± 5.5 kg/m2 in early pregnancy. Higher maternal BMI was associated with lower placental expression of EPYC (slope = -1.94, FDR-adjusted P = 7.3 × 10-6 for continuous BMI; log2 fold change = -1.35, FDR-adjusted P = 3.4 × 10-3 for BMI ≥30 vs. BMI 18.5-24.9 kg/m2) and with higher placental expression of IGFBP6, CHRDL1, and CXCL13 after adjustment for covariates and accounting for multiple testing (FDR < 0.05).CONCLUSIONS: Our genome-wide transcriptomic study revealed novel genes potentially implicated in placental biologic response to higher maternal BMI in early pregnancy.