부산대학교 도서관

Background: 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. In an epigenome-wide association study using population based linked records of over 18,000 people in Scotland, Robert F. Hillary and colleagues explore how differential DNA methylation correlates with incident and prevalent disease states. Author summary: Why was this study done?: Blood DNA methylation can inform us about the biological mechanisms that underlie common disease states. Epigenome-wide association studies (EWAS) investigate whether the proportion of methylation at loci termed CpG sites (cytosine-phosphate-guanine dinucleotides) associate with health outcomes of interest. There is a need for large-scale EWAS that probe for epigenetic signals across a wide range of conditions as well as a structured literature review to inform the utility of this approach in identifying disease-relevant loci. What did the researchers do and find?: DNA methylation was assayed at 752,722 CpG sites using whole-blood samples from 18,413 volunteers, which were collected at the study baseline of Generation Scotland (2006 to 2011). EWAS tested for associations between differential methylation at CpG sites and the prevalence and incidence of 14 and 19 disease states, respectively. Prevalence and incidence data were derived from self-report questionnaires and electronic health record linkage, respectively. We identified over 100 CpG associations with 4 prevalent conditions (breast cancer, chronic kidney disease, ischemic heart disease, and type 2 diabetes) and 2 incident conditions (chronic obstructive pulmonary disease and type 2 diabetes). We also found poor replicability among existing studies with lung cancer showing the highest degree of replication (17% of sites replicated in at least 2 studies). What do these findings mean?: Blood DNA methylation could act as a peripheral marker of several common disease states including breast cancer, cardiopulmonary disease, and type 2 diabetes. As population biobank resources expand, studies that examine the same condition should reach consensus on covariate strategies, phenotype definitions, and reporting guidelines. [ABSTRACT FROM AUTHOR]