TY - JOUR
T1 - Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders
AU - Cilleros-Portet, Ariadna
AU - Lesseur, Corina
AU - Marí, Sergi
AU - Cosin-Tomas, Marta
AU - Lozano, Manuel
AU - Irizar, Amaia
AU - Burt, Amber
AU - García-Santisteban, Iraia
AU - Garrido-Martín, Diego
AU - Escaramís, Geòrgia
AU - Hernangomez-Laderas, Alba
AU - Soler-Blasco, Raquel
AU - Breeze, Charles E.
AU - Gonzalez-Garcia, Bárbara P.
AU - Santa-Marina, Loreto
AU - Chen, Jia
AU - Llop, Sabrina
AU - Fernández, Mariana F.
AU - Vrijheid, Martine
AU - Ibarluzea, Jesús
AU - Guxens, Mònica
AU - Marsit, Carmen
AU - Bustamante, Mariona
AU - Bilbao, Jose Ramon
AU - Fernandez-Jimenez, Nora
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105000172148
U2 - 10.1038/s41467-025-57760-3
DO - 10.1038/s41467-025-57760-3
M3 - Article
C2 - 40087310
AN - SCOPUS:105000172148
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2431
ER -