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

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• dc.contributor.author Cilleros-Portet, Ariadna
• dc.contributor.author Cosín Tomàs, Marta
• dc.contributor.author Vrijheid, Martine
• dc.contributor.author Guxens Junyent, Mònica
• dc.contributor.author Bustamante Pineda, Mariona
• dc.contributor.author Fernandez-Jimenez, Nora
• dc.date.accessioned 2025-05-13T06:06:51Z
• dc.date.available 2025-05-13T06:06:51Z
• dc.date.issued 2025
• dc.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.
• dc.description.sponsorship We would like to acknowledge all the INMA and RICHS participants and researchers, for their kind collaboration and support. INMA-Gipuzkoa is funded by grants from Instituto de Salud Carlos III (PI06/0867 and PI09/00090, incl. FEDER funds), Department of Health of the Basque Government (2005111093), Provincial Government of Gipuzkoa (DFG06/002), and annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia, Azpeitia and Beasain). INMA-Sabadell was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176, PS09/00432, PI17/01225, PI17/01935, and CP18/00018), Fundació La Marató de TV3 (090430), and Generalitat de Catalunya-CIRIT (1999SGR 00241), the European Community’s Seventh Framework Program (FP7/2007-206) under grant agreement no 308333 (HELIX project), and from the European Joint Programming Initiative “A Healthy Diet for a Healthy Life” (JPI HDHL and Instituto de Salud Carlos III) under the grant agreement no AC18/00006 (NutriPROGRAM project). ISGlobal acknowledges support from the Spanish Ministry of Science and Innovation and the State Research Agency through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. INMA-Valencia is funded by Grants from UE (FP7-ENV-2011 cod 282957, HEALTH.2010.2.4.5-1, and H2020 No 874583, the ATHLETE project), the Ministry of Universities (CAS21/00008, Margarita Salas Grant MS21-133 and NextGeneration EU), Instituto de Salud Carlos III (FIS-FEDER: 13/1944, 16/1288, 17/00663, and 19/1338; FIS-FSE: 17/00260; Miguel Servet-FSE: MSII20/0006), CIBERESP, Generalitat Valenciana (BEST/2020/059, AICO/2020/285 and CIAICO/2021/132). The RICHS cohort is supported by the US National Institute of Environmental Health Sciences (U24 ES02507). M.C.-T. is funded by a Beatriu de Pinós Postdoctoral Contract awarded by Generalitat de Catalunya-AGAUR and European Commission- Horizon 2020 (2019 BP 00107). I.G.-S. is funded by the Basque Department of Health (SAN2020111043) and the Spanish Ministry of Equity (12-4-ID22) and the UPV/EHU Collaborative Projects (COLAB22/01). A.H.-L. is a predoctoral fellow supported by grant PRE-C-2020-0091 from the MCIN/AEI/10.13039/501100011033 and by ESF Investing in your future. B.P.G.-G. is supported by the Mexican National Council for Science and Technology grant 2021-000007-01EXTF-00209. M.F.F. is funded by the EU Commission (QLK4-1999-01422, QLK4-2002-00603, and CONTAMED FP7-ENV-212502) and the Consejería de Salud de la Junta de Andalucía (Grant number 0675/10). J.R.B. is funded by Research Grant PID2019-106382RB-I00 funded by MCIN/AEI/10.13039/501100011033. N.F.-J. is funded by research grants 2019/111085 from the Basque Department of Health, and PI21/01491 from the Instituto de Salud Carlos III (ISCIII), co-funded by the European Union.
• dc.format.mimetype application/pdf
• dc.identifier.citation Cilleros-Portet A, Lesseur C, Marí S, Cosin-Tomas M, Lozano M, Irizar A, et al. Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders. Nat Commun. 2025 Mar 14;16(1):2431. DOI: 10.1038/s41467-025-57760-3
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-025-57760-3
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/70362
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Commun. 2025 Mar 14;16(1):2431
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/308333
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/282957
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/874583
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/212502
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-106382RB-I00
• dc.rights © The Author(s) 2025, corrected publication 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword Development
• dc.subject.keyword DNA methylation
• dc.subject.keyword Epigenomics
• dc.subject.keyword Quantitative trait
• dc.subject.keyword Schizophrenia
• dc.title Potentially causal associations between placental DNA methylation and schizophrenia and other neuropsychiatric disorders
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion