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

• Authors: Ariadna Cilleros-Portet, Biocruces-Bizkaia Health Research Institute and University of the Basque Country (UPV/EHU), Leioa, Spain; Corina Lesseur, Icahn School of Medicine at Mount Sinai; Sergi Marí, Biocruces-Bizkaia Health Research Institute and University of the Basque Country (UPV/EHU), Leioa, Spain; Marta Cosin-Tomas, Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III; Manuel Lozano, FISABIO-Universitat Jaume I-Universitat de Valéncia,; Amala Irizar, Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III; Amber Burt, Emory University; Iraia García-Santisteban, Biocruces-Bizkaia Health Research Institute and University of the Basque Country (UPV/EHU), Leioa, Spain; Diego Gsrrido Martín, Universitat de Barcelona (UB); Geòrgia Escaramís, Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III; Alba Hernangomez-Laderas, Biocruces-Bizkaia Health Research Institute and University of the Basque Country (UPV/EHU), Leioa, Spain; Raquel Soler-Blasco, Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III; Charles E Breeze, University College London; Bárbara P Gonzalez-Garcia, Biocruces-Bizkaia Health Research Institute and University of the Basque Country (UPV/EHU), Leioa, Spain; Loreto Santa-Marina, Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III; Jia Chen, Icahn School of Medicine at Mount Sinai; Sabrina Llop, Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III; Mariana F Fernández, Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III; Martine Vrijhed, ISGlobal, Barcelona, Spain; Jesús Ibarluzea, Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III; Mònica Guxens, ISGlobal, Barcelona, Spain; Carmen Marsit, Emory University; Mariona Bustamante, Emory University; Jose Ramon Bilbao, Biocruces-Bizkaia Health Research Institute and University of the Basque Country (UPV/EHU), Leioa, Spain; Nora Fernandez-Jimenez, Biocruces-Bizkaia Health Research Institute and University of the Basque Country (UPV/EHU), Leioa, Spain
• Journal Title: medRxiv
• Publisher: medRxiv | 2023-03-08
• Type of Work: Article | Preprint: Prior to Peer Review
• Publisher DOI: http://doi.org/10.1101/2023.03.07.23286905
• Subjects: Anthropology, Physical; Biology, Animal Physiology; Health Sciences, Public Health; Health Sciences, Toxicology
• Keywords: schizophrenia; neuropsychiatric disorders

Abstract

Increasing evidence supports the role of placenta in neurodevelopment and potentially, in the later onset of neuropsychiatric disorders. Recently, methylation quantitative trait loci (mQTL) and interaction QTL (iQTL) maps have proven useful to understand SNP-genome wide association study (GWAS) relationships, otherwise missed by conventional expression QTLs. In this context, we propose that part of the genetic predisposition to complex neuropsychiatric disorders acts through placental DNA methylation (DNAm). We constructed the first public placental cis -mQTL database including nearly eight million mQTLs calculated in 368 fetal placenta DNA samples from the INMA project, ran cell type- and gestational age-imQTL models and combined those data with the summary statistics of the largest GWAS on 10 neuropsychiatric disorders using Summary-based Mendelian Randomization (SMR) and colocalization. Finally, we evaluated the influence of the DNAm sites identified on placental gene expression in the RICHS cohort. We found that placental cis -mQTLs are highly enriched in placenta-specific active chromatin regions, and useful to map the etiology of neuropsychiatric disorders at prenatal stages. Specifically, part of the genetic burden for schizophrenia, bipolar disorder and major depressive disorder confers risk through placental DNAm. The potential causality of several of the observed associations is reinforced by secondary association signals identified in conditional analyses, regional pleiotropic methylation signals associated to the same disorder, and cell type- imQTLs, additionally associated to the expression levels of relevant immune genes in placenta. In conclusion, the genetic risk of several neuropsychiatric disorders could operate, at least in part, through DNAm and associated gene expression in placenta.