Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders
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.
Authors
- Ariadna Cilleros‐Portet (ORCID: https://orcid.org/0000-0001-7564-6840)
- Carmen J. Marsit (ORCID: https://orcid.org/0000-0003-4566-150X)
- Mariana F. Fernández (ORCID: https://orcid.org/0000-0001-6417-8914)
- Diego Garrido-Martín (ORCID: https://orcid.org/0000-0002-4131-4458)
- Manuel Lozano (ORCID: https://orcid.org/0000-0003-2046-5959)
- Sergi Marí (ORCID: https://orcid.org/0000-0003-2023-195X)
- Sabrina Llop (ORCID: https://orcid.org/0000-0002-6784-4211)
- Corina Lesseur (ORCID: https://orcid.org/0000-0001-6744-6750)
- Marta Cosín‐Tomás (ORCID: https://orcid.org/0000-0001-5012-8983)
- Bárbara P. González‐García (ORCID: https://orcid.org/0000-0002-9287-6047)
- Nora Fernández‐Jiménez (ORCID: https://orcid.org/0000-0001-6307-0880)
- Loreto Santa‐Marina (ORCID: https://orcid.org/0000-0003-1405-9751)
- Geòrgia Escaramís (ORCID: https://orcid.org/0000-0002-5416-3177)
- Mariona Bustamante (ORCID: https://orcid.org/0000-0003-0127-2860)
- Iraia García‐Santisteban (ORCID: https://orcid.org/0000-0002-7912-385X)
- Mònica Guxens (ORCID: https://orcid.org/0000-0002-8624-0333)
- Amber Burt (ORCID: https://orcid.org/0000-0003-1813-6726)
- Raquel Soler-Blasco (ORCID: https://orcid.org/0000-0002-4603-6784)
- Jesús Ibarluzea (ORCID: https://orcid.org/0000-0002-6933-5373)
- Martine Vrijheid (ORCID: https://orcid.org/0000-0002-7090-1758)
- Alba Hernangomez‐Laderas (ORCID: https://orcid.org/0009-0001-9948-5399)
- Amaia Irizar (ORCID: https://orcid.org/0000-0003-0307-3558)
- José Ramón Bilbao (ORCID: https://orcid.org/0000-0002-3176-501X)
- Charles E. Breeze (ORCID: https://orcid.org/0000-0002-5294-915X)
- Jia Chen (ORCID: https://orcid.org/0000-0001-6597-8577)
Institutions
- Universitat Jaume I (ES)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Emory University (US)
- Universitat de València (ES)
- University of the Basque Country (ES)
- Universitat Pompeu Fabra (ES)
- Universidad de Granada (ES)
- Basque Government (ES)
- Instituto de Salud Carlos III (ES)
- Erasmus MC (NL)
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES)
- Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (ES)
- Instituto de Investigación Biosanitaria de Granada (ES)
- CRUK Lung Cancer Centre of Excellence (GB)
- Barcelona Institute for Global Health (ES)
- Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (ES)
- University College London (GB)
- Universitat de Barcelona (ES)
- Erasmus University Rotterdam (NL)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-14
- DOI
- https://doi.org/10.1038/s41467-025-57760-3
- Citations
- 13
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 10.48
Funders
- Instituto de Salud Carlos III