Long-read assembly reveals vast transcriptional complexity in the placenta associated with metabolic and endocrine function.

The placenta is critical for fetal development and mediates effects of pregnancy complications on offspring metabolic health yet remains poorly characterized in genomic studies. Existing transcriptomic analyses rely on adult tissue reference annotations, overlooking developmentally important splicing diversity. Using largest-in-class long-read RNA-seq (n = 72), we create a comprehensive placental transcriptome reference identifying 37,661 high-confidence isoforms (14,985 previously unannotated) across 12,302 genes (2,759 previously unannotated). Contrary to characterizations of the placenta as a transcriptomic void, we find transcriptional breadth and complexity comparable to adult tissues, with high splicing diversity of obesity- and growth-related gene transcripts, including 108 distinct CSH1 (placental lactogen) isoforms. Applying this reference to short-read RNA-seq from diverse populations (n = 352) reduced inferential uncertainty in isoform quantification by approximately 30%. We find placental transcription mediated 36% of gestational diabetes mellitus effects on birth weight, with ancestry-specific effects including previously unannotated CSH1 isoforms mediating larger effects in European (24.4%) than Asian (13.4%) populations. These findings illustrate the importance of tissue-matched, long-read annotations for isoform-resolved transcriptomics.