Placental genomics mediates genetic associations with complex health traits and disease

Bhattacharya et al., Nature Communications, 2022 asked which genes in the placenta carry genetic effects through to health traits across the life course, and which upstream regulators drive them. Using placental multi-omics from 272 pre-term infants in the Extremely Low Gestational Age Newborn Study, the authors trained models of placental expression enriched for distal variants and tested them against genome-wide association data for 40 traits. They found 248 gene-trait associations across 176 unique genes, most of them for body size, metabolic and neonatal traits, and placental expression explained a significant share of heritability for four early-life traits but for none of the later-life ones.

The analysis also produced a testable prediction: that EPS15, a regulatory protein gene highly expressed in placenta, holds down SPATA13 and FAM214A, two genes whose predicted placental expression tracks waist to hip ratio and whose association ran opposite to that of EPS15 itself. The authors tested that prediction directly with AUMsilence sdASOs against EPS15, added to the medium of human placenta-derived JEG-3 choriocarcinoma cells from a 500 μM stock to a final 20 μM for 24 hours, against no-addition and scramble oligonucleotide controls.

The prediction held. EPS15 fell by 50%, SPATA13 rose by 795% and FAM214A by 377%, all significant against the scramble control at an FDR-adjusted P below 0.10. RNA sequencing of the same cells showed the reach of the single knockdown: 650 genes lowered and 838 raised, with the lowered set enriched for cell cycle, proliferation and replication and the raised set for lipid processes, cell movement and extracellular organisation. The authors read this as evidence that placental genomic regulation shapes developmental programming, and as support for building mechanistic hypotheses that survive experimental test.