FROM PLACENTA TO BRAIN: GWAS OF PLACENTAL EFFICIENCY LINKS EARLY REGULATION TO PSYCHIATRIC RISK

The placenta is increasingly understood as more than a mere transient support organ: it is a dynamic regulator of fetal development with potential long-term consequences for brain and mental health. This perspective motivates a framework for neuro-placentomics, in which placental genomic architecture is considered an integral part of the biology shaping early neurodevelopment. In this symposium presentation, I will present findings from the first genome-wide association study of placental efficiency (PLE), as measured by the birthweight-to-placental-weight ratio, in 63,894 term singleton births from the Norwegian Mother, Father and Child Cohort Study (MoBa). Across offspring and maternal genomes, we identified multiple genome-wide significant loci, with TSNAX-DISC1 consistently implicated across analyses. Comparative analyses showed that PLE shared substantial genetic architecture with placental weight, but much less with birth weight, suggesting that it captures distinct aspects of placental adaptation rather than fetal growth alone. Functional analyses revealed enrichment of monoaminergic pathways, particularly norepinephrine uptake and transport, alongside broader chromatin- and chromosome-related regulatory functions. Mapped genes such as SLC6A2, SLC22A2, and SLC22A3 further implicated placental regulation of monoamine signaling. Importantly, tissue-expression analyses demonstrated significant enrichment in placental tissue, which was not observed for placental weight or birth weight, supporting a biologically distinct placental signal. Together, these findings suggest that PLE indexes a genomic architecture tied to placental regulatory function, including mechanisms that may shape fetal monoaminergic environments during sensitive stages of brain development. To extend these findings beyond discovery genomics, we examined latent polygenic dimensions of placental efficiency in psychosis-spectrum cohorts. While overall polygenic scores showed no main effects on case-control status, specific polygenic dimensions revealed sex-dependent associations with psychosis risk. Moreover, genetic propensity for placental efficiency was associated with brain volume in severe mental illness, particularly in schizophrenia, suggesting that placentally relevant genomic variation may have downstream effects on adult brain structure. These findings further suggest that placentally informed polygenic dimensions may improve etiological specificity within broad clinical diagnoses by helping identify biologically distinct subgroups, particularly when considering sex-dependent effects. These findings support the emergence of neuro-placentomics as a framework for understanding how placental biology and neurodevelopment intersect. In this view, the placenta is not only a mediator of growth, but also a regulatory interface through which genetic influences on neurotransmission, neurodevelopment, and environmental adaptation may become embedded early in life. By linking placental genomic variation to pathways relevant for neural development, brain structure, and psychiatric vulnerability, this work provides a foundation for integrating early developmental biology into psychiatric genetics. More broadly, this framework may help identify biologically informed subtypes within heterogeneous psychiatric disorders and improve our understanding of how risk for mental illness emerges across the lifecourse.