Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders

Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders

Abstract Increasing evidence supports the role of the placenta in neurodevelopment and in the onset of neuropsychiatric disorders. Recently, mQTL and iQTL maps have proven useful in understanding relationships between SNPs and GWAS that are not captured by eQTL. In this context, we propose that part...

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Main Authors: Ariadna Cilleros-Portet, Corina Lesseur, Sergi Marí, Marta Cosin-Tomas, Manuel Lozano, Amaia Irizar, Amber Burt, Iraia García-Santisteban, Diego Garrido-Martín, Geòrgia Escaramís, Alba Hernangomez-Laderas, Raquel Soler-Blasco, Charles E. Breeze, Bárbara P. Gonzalez-Garcia, Loreto Santa-Marina, Jia Chen, Sabrina Llop, Mariana F. Fernández, Martine Vrijheid, Jesús Ibarluzea, Mònica Guxens, Carmen Marsit, Mariona Bustamante, Jose Ramon Bilbao, Nora Fernandez-Jimenez
Format: Article
Language:English
Published: Nature Portfolio 2025-03-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-57760-3
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Summary:Abstract Increasing evidence supports the role of the placenta in neurodevelopment and in the onset of neuropsychiatric disorders. Recently, mQTL and iQTL maps have proven useful in understanding relationships between SNPs and GWAS that are not captured by eQTL. In this context, we propose that part of the genetic predisposition to complex neuropsychiatric disorders acts through placental DNA methylation. We construct a public placental cis-mQTL database including 214,830 CpG sites calculated in 368 fetal placenta DNA samples from the INMA project, and run cell type-, gestational age- and sex-imQTL models. We combine these data with summary statistics of GWAS on ten neuropsychiatric disorders using summary-based Mendelian randomization and colocalization. We also evaluate the influence of identified DNA methylation sites on placental gene expression in the RICHS cohort. We find that placental cis-mQTLs are enriched in placenta-specific active chromatin regions, and establish that part of the genetic burden for schizophrenia, bipolar disorder, and major depressive disorder confers risk through placental DNA methylation. The potential causality of several of the observed associations is reinforced by secondary association signals identified in conditional analyses, the involvement of cell type-imQTLs, and the correlation of identified DNA methylation sites with the expression levels of relevant genes in the placenta.
ISSN:2041-1723

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