Integrating Multi-Omics with environmental data for precision health: A novel analytic framework and case study on prenatal mercury induced childhood fatty liver disease

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• dc.contributor.author Goodrich, Jesse A.
• dc.contributor.author Stratakis, Nikos
• dc.contributor.author Maitre, Léa
• dc.contributor.author Bustamante Pineda, Mariona
• dc.contributor.author Basagaña Flores, Xavier
• dc.contributor.author Urquiza, José M.
• dc.contributor.author Vrijheid, Martine
• dc.contributor.author Conti, David V.
• dc.date.accessioned 2024-11-20T07:36:12Z
• dc.date.available 2024-11-20T07:36:12Z
• dc.date.issued 2024
• dc.description.abstract Background: Precision Health aims to revolutionize disease prevention by leveraging information across multiple omic datasets (multi-omics). However, existing methods generally do not consider personalized environmental risk factors (e.g., environmental pollutants). Objective: To develop and apply a precision health framework which combines multiomic integration (including early, intermediate, and late integration, representing sequential stages at which omics layers are combined for modeling) with mediation approaches (including high-dimensional mediation to identify biomarkers, mediation with latent factors to identify pathways, and integrated/quasi-mediation to identify high-risk subpopulations) to identify novel biomarkers of prenatal mercury induced metabolic dysfunction-associated fatty liver disease (MAFLD), elucidate molecular pathways linking prenatal mercury with MAFLD in children, and identify high-risk children based on integrated exposure and multiomics data. Methods: This prospective cohort study used data from 420 mother-child pairs from the Human Early Life Exposome (HELIX) project. Mercury concentrations were determined in maternal or cord blood from pregnancy. Cytokeratin 18 (CK-18; a MAFLD biomarker) and five omics layers (DNA Methylation, gene transcription, microRNA, proteins, and metabolites) were measured in blood in childhood (age 6-10 years). Results: Each standard deviation increase in prenatal mercury was associated with a 0.11 [95% confidence interval: 0.02-0.21] standard deviation increase in CK-18. High dimensional mediation analysis identified 10 biomarkers linking prenatal mercury and CK-18, including six CpG sites and four transcripts. Mediation with latent factors identified molecular pathways linking mercury and MAFLD, including altered cytokine signaling and hepatic stellate cell activation. Integrated/quasi-mediation identified high risk subgroups of children based on unique combinations of exposure levels, omics profiles (driven by epigenetic markers), and MAFLD. Conclusions: Prenatal mercury exposure is associated with elevated liver enzymes in childhood, likely through alterations in DNA methylation and gene expression. Our analytic framework can be applied across many different fields and serve as a resource to help guide future precision health investigations.
• dc.description.sponsorship This manuscript was primarily supported by the National Institute of Environmental Health Sciences of the National Institutes of Health, United States, grant K01ES036193. Additional funding for this research came from the National Institutes of Health, United States, including the National Institute of Environmental Health Sciences (P30ES007048, R21ES029681), the National Human Genome Research Institute (U01HG013288), the National Cancer Institute (P01CA196569; P30CA014089, U19CA214253, U01CA164973), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR084040). The research was further supported by the European Community’s Seventh Framework Programme [FP7/2007–2013] under grant agreement no. 308333 [the HELIX project], and by the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 874583 [ATHLETE]. Born in Bradford (BiB) study received core infrastructure funding from the Wellcome Trust (WT101597MA), a joint grant from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) (MR/N024397/1), and NIHR Applied Research Collaboration for Yorkshire and Humber (NIHR200166). The views expressed in this publication are those of the author(s) and not necessarily those of the different funding bodies, including the National Institutes of Health, the National Institute for Health Research, the Department of Health and Social Care, or the Wellcome Trust.
• dc.format.mimetype application/pdf
• dc.identifier.citation Goodrich JA, Wang H, Jia Q, Stratakis N, Zhao Y, Maitre L, et al. Integrating Multi-Omics with environmental data for precision health: A novel analytic framework and case study on prenatal mercury induced childhood fatty liver disease. Environ Int. 2024 Aug;190:108930. DOI: 10.1016/j.envint.2024.108930
• dc.identifier.doi http://dx.doi.org/10.1016/j.envint.2024.108930
• dc.identifier.issn 0160-4120
• dc.identifier.uri http://hdl.handle.net/10230/68746
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Environ Int. 2024 Aug;190:108930
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/308333
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/874583
• dc.rights © 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Bioinformatics
• dc.subject.keyword Biomarkers
• dc.subject.keyword Epigenetics
• dc.subject.keyword Multiomics
• dc.subject.keyword Precision health
• dc.subject.keyword Prenatal exposures
• dc.title Integrating Multi-Omics with environmental data for precision health: A novel analytic framework and case study on prenatal mercury induced childhood fatty liver disease
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion