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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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57760-3 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ariadna Cilleros-Portet |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-eeb98e98f77641ffab7b1f4eaab25dcd |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-eeb98e98f77641ffab7b1f4eaab25dcd2025-08-20T02:28:09ZengNature PortfolioNature Communications2041-17232025-03-0116112110.1038/s41467-025-57760-3Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disordersAriadna Cilleros-Portet0Corina Lesseur1Sergi Marí2Marta Cosin-Tomas3Manuel Lozano4Amaia Irizar5Amber Burt6Iraia García-Santisteban7Diego Garrido-Martín8Geòrgia Escaramís9Alba Hernangomez-Laderas10Raquel Soler-Blasco11Charles E. Breeze12Bárbara P. Gonzalez-Garcia13Loreto Santa-Marina14Jia Chen15Sabrina Llop16Mariana F. Fernández17Martine Vrijheid18Jesús Ibarluzea19Mònica Guxens20Carmen Marsit21Mariona Bustamante22Jose Ramon Bilbao23Nora Fernandez-Jimenez24Department of Genetics, Physical Anthropology and Animal Physiology, Biobizkaia Health Research Institute and University of the Basque Country (UPV/EHU)Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount SinaiDepartment of Genetics, Physical Anthropology and Animal Physiology, Biobizkaia Health Research Institute and University of the Basque Country (UPV/EHU)ISGlobalEpidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de ValènciaSpanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos IIIGangarosa Department of Environmental Health, Rollins School of Public Health, Emory UniversityDepartment of Genetics, Physical Anthropology and Animal Physiology, Biobizkaia Health Research Institute and University of the Basque Country (UPV/EHU)Department of Genetics, Microbiology and Statistics, Faculty of Biology, Universitat de Barcelona (UB)Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos IIIDepartment of Genetics, Physical Anthropology and Animal Physiology, Biobizkaia Health Research Institute and University of the Basque Country (UPV/EHU)Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos IIIUCL Cancer Institute, University College LondonDepartment of Genetics, Physical Anthropology and Animal Physiology, Biobizkaia Health Research Institute and University of the Basque Country (UPV/EHU)Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos IIIDepartment of Environmental Medicine and Public Health, Icahn School of Medicine at Mount SinaiSpanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos IIISpanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos IIIISGlobalSpanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos IIIISGlobalGangarosa Department of Environmental Health, Rollins School of Public Health, Emory UniversityISGlobalDepartment of Genetics, Physical Anthropology and Animal Physiology, Biobizkaia Health Research Institute and University of the Basque Country (UPV/EHU)Department of Genetics, Physical Anthropology and Animal Physiology, Biobizkaia Health Research Institute and University of the Basque Country (UPV/EHU)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.https://doi.org/10.1038/s41467-025-57760-3 |
| spellingShingle | 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 Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders Nature Communications |
| title | Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders |
| title_full | Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders |
| title_fullStr | Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders |
| title_full_unstemmed | Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders |
| title_short | Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders |
| title_sort | potentially causal associations between placental dna methylation and schizophrenia and other neuropsychiatric disorders |
| url | https://doi.org/10.1038/s41467-025-57760-3 |
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