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dc.contributor.authorHillary, RF
dc.contributor.authorMcCartney, DL
dc.contributor.authorSmith, HM
dc.contributor.authorBernabeu, E
dc.contributor.authorGadd, DA
dc.contributor.authorChybowska, AD
dc.contributor.authorCheng, Y
dc.contributor.authorMurphy, L
dc.contributor.authorWrobel, N
dc.contributor.authorCampbell, A
dc.contributor.authorWalker, RM
dc.contributor.authorHayward, C
dc.contributor.authorEvans, KL
dc.contributor.authorMcIntosh, AM
dc.contributor.authorMarioni, RE
dc.date.accessioned2023-11-15T14:59:39Z
dc.date.issued2023-07-06
dc.date.updated2023-11-15T13:58:33Z
dc.description.abstractBACKGROUND: DNA methylation is a dynamic epigenetic mechanism that occurs at cytosine-phosphate-guanine dinucleotide (CpG) sites. Epigenome-wide association studies (EWAS) investigate the strength of association between methylation at individual CpG sites and health outcomes. Although blood methylation may act as a peripheral marker of common disease states, previous EWAS have typically focused only on individual conditions and have had limited power to discover disease-associated loci. This study examined the association of blood DNA methylation with the prevalence of 14 disease states and the incidence of 19 disease states in a single population of over 18,000 Scottish individuals. METHODS AND FINDINGS: DNA methylation was assayed at 752,722 CpG sites in whole-blood samples from 18,413 volunteers in the family-structured, population-based cohort study Generation Scotland (age range 18 to 99 years). EWAS tested for cross-sectional associations between baseline CpG methylation and 14 prevalent disease states, and for longitudinal associations between baseline CpG methylation and 19 incident disease states. Prevalent cases were self-reported on health questionnaires at the baseline. Incident cases were identified using linkage to Scottish primary (Read 2) and secondary (ICD-10) care records, and the censoring date was set to October 2020. The mean time-to-diagnosis ranged from 5.0 years (for chronic pain) to 11.7 years (for Coronavirus Disease 2019 (COVID-19) hospitalisation). The 19 disease states considered in this study were selected if they were present on the World Health Organisation's 10 leading causes of death and disease burden or included in baseline self-report questionnaires. EWAS models were adjusted for age at methylation typing, sex, estimated white blood cell composition, population structure, and 5 common lifestyle risk factors. A structured literature review was also conducted to identify existing EWAS for all 19 disease states tested. The MEDLINE, Embase, Web of Science, and preprint servers were searched to retrieve relevant articles indexed as of March 27, 2023. Fifty-four of approximately 2,000 indexed articles met our inclusion criteria: assayed blood-based DNA methylation, had >20 individuals in each comparison group, and examined one of the 19 conditions considered. First, we assessed whether the associations identified in our study were reported in previous studies. We identified 69 associations between CpGs and the prevalence of 4 conditions, of which 58 were newly described. The conditions were breast cancer, chronic kidney disease, ischemic heart disease, and type 2 diabetes mellitus. We also uncovered 64 CpGs that associated with the incidence of 2 disease states (COPD and type 2 diabetes), of which 56 were not reported in the surveyed literature. Second, we assessed replication across existing studies, which was defined as the reporting of at least 1 common site in >2 studies that examined the same condition. Only 6/19 disease states had evidence of such replication. The limitations of this study include the nonconsideration of medication data and a potential lack of generalizability to individuals that are not of Scottish and European ancestry. CONCLUSIONS: We discovered over 100 associations between blood methylation sites and common disease states, independently of major confounding risk factors, and a need for greater standardisation among EWAS on human disease.en_GB
dc.description.sponsorshipWellcome Trusten_GB
dc.description.sponsorshipWellcome Trusten_GB
dc.description.sponsorshipWellcome Trusten_GB
dc.description.sponsorshipWellcome Trusten_GB
dc.description.sponsorshipWellcome Trusten_GB
dc.description.sponsorshipBritish Heart Foundationen_GB
dc.description.sponsorshipAlzheimer’s Societyen_GB
dc.description.sponsorshipMedical Research Councilen_GB
dc.format.extente1004247-
dc.format.mediumElectronic-eCollection
dc.identifier.citationVol. 20, No. 7, article e1004247en_GB
dc.identifier.doihttps://doi.org/10.1371/journal.pmed.1004247
dc.identifier.grantnumber104036/Z/14/Zen_GB
dc.identifier.grantnumber216767/Z/19/Zen_GB
dc.identifier.grantnumber220857/Z/20/Zen_GB
dc.identifier.grantnumber108890/Z/15/Zen_GB
dc.identifier.grantnumber218493/Z/19/Zen_GB
dc.identifier.grantnumberFS/IPBSRF/22en_GB
dc.identifier.grantnumberAS-PG-19b010en_GB
dc.identifier.grantnumberU. MC_UU_00007/10en_GB
dc.identifier.urihttp://hdl.handle.net/10871/134547
dc.identifierORCID: 0000-0002-1060-4479 (Walker, Rosie M)
dc.identifierScopusID: 23029293000 (Walker, Rosie M)
dc.language.isoenen_GB
dc.publisherPublic Library of Science (PLoS)en_GB
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pubmed/37410739en_GB
dc.relation.urlhttp://ewascatalog.org/?query=10.1101/2023.01.10.23284387en_GB
dc.rights© 2023 Hillary et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_GB
dc.subjectDiabetes Mellitus, Type 2en_GB
dc.subjectDNA Methylationen_GB
dc.subjectMethylationen_GB
dc.subjectChronic obstructive pulmonary diseaseen_GB
dc.subjectepidemiologyen_GB
dc.subjectblooden_GB
dc.subjecttreatment guidelinesen_GB
dc.subjectgenome analysisen_GB
dc.titleBlood-based epigenome-wide analyses of 19 common disease states: A longitudinal, population-based linked cohort study of 18,413 Scottish individuals.en_GB
dc.typeArticleen_GB
dc.date.available2023-11-15T14:59:39Z
dc.identifier.issn1549-1277
exeter.article-numberARTN e1004247
exeter.place-of-publicationUnited States
dc.descriptionThis is the final version. Available from Public Library of Science via the DOI in this record. en_GB
dc.descriptionData Availability Statement: EWAS summary statistics are available on the EWAS Catalog (http:// ewascatalog.org/?query=10.1101/2023.01.10. 23284387). According to the terms of consent for Generation Scotland participants, access to data must be reviewed by the Generation Scotland Access Committee. Applications should be made to access@generationscotland.orgen_GB
dc.identifier.eissn1549-1676
dc.identifier.journalPLoS Medicineen_GB
dc.relation.ispartofPLoS Med, 20(7)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_GB
dcterms.dateAccepted2023-05-25
dc.rights.licenseCC BY
rioxxterms.versionVoRen_GB
rioxxterms.licenseref.startdate2023-07-06
rioxxterms.typeJournal Article/Reviewen_GB
refterms.dateFCD2023-11-15T14:54:17Z
refterms.versionFCDVoR
refterms.dateFOA2023-11-15T14:59:48Z
refterms.panelAen_GB
refterms.dateFirstOnline2023-07-06


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© 2023 Hillary et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Except where otherwise noted, this item's licence is described as © 2023 Hillary et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.