Background: Epidemiological studies have linked low birth weight to psychiatric disorders, including substance use disorders. Genomic analyses suggest a role of placental physiology on psychiatric risk. We investigated whether this association is causally related to impaired trophoblast function. Methods: We conducted a two-sample summary-data Mendelian randomization study using as instrumental variables genetic variants strongly associated with birth weight, whose effect is exerted through the fetal genome, and are located near genes with differential expression in trophoblasts. Eight psychiatric and substance use disorders with > 10,000 samples were included as outcomes. The inverse variance weighted method was used as the main analysis and several sensitivity analyses were performed for those significant results. Results: The inverse variance weighted estimate, based on 14 instrumental variables, revealed an association, after correction for multiple tests, between birth weight and broadly-defined depression (beta=-0.165, 95% CI=-0.282 to -0.047, P=0.0059). Sensitivity analyses revealed absence of heterogeneity in the effect of instrumental variables, confirmed by leave-one-out analysis, MR_Egger intercept and MR_PRESSO. The effect was consistent using robust methods. Reverse causality was not detected. The effect was specifically linked to genetic variants near genes involved in trophoblast physiology instead of genes with fetal effect on birth weight or involved in placenta development. Conclusion: Impaired trophoblast functioning, probably leading to reduced fetal brain oxygen and nutrient supply, is causally related to broadly-defined depression. Considering the therapeutic potential of some agents to treat fetal growth restriction, further research on the effect of trophoblast physiology on mental disorders may have future implications in prevention.

The authors have declared no competing interest.

This work was supported by Instituto de Salud Carlos III (ISCIII), under grant numbers PI20/00802 (Fondo de Investigación en Salud-FIS, cofounded by FEDER), and RD21/0009/0011 (ISCIII-Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS)-Red de Investigación en Atencion Primaria de Adicciones (RIAPAd)).

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All the data used in this work are de-identified summary statistics data made publicly available after approval by the respective institutional ethical committees of the different consortia. The GWAS summary statistics used for this study can be found in the deCODE genetics (https://www.decode.com/summarydata/) and the Psychiatric Genomics Consortium (https://pgc.unc.edu/for-researchers/download-results/).

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