Specific DNA modifications are linked to certain conditions, including breast cancer

A longitudinal, population-based linked cohort study of 18,413 Scottish individuals.


A dynamic epigenetic mechanism called DNA methylation occurs at cytosine-phosphate-guanine dinucleotide (CpG) sites. Epigenome-wide association studies (EWAS) examine how methylation at specific CpG sites is associated with various health outcomes, although blood methylation may be a peripheral indication of widespread disease conditions. Previous EWAS often primarily focused on specific disorders and could not find loci related to diseases.

A recent study investigated the relationship between blood DNA methylation and the incidence of 19 disease states and the prevalence of 14 disease states.

We can learn about the molecular processes behind prevalent diseases from the methylation of blood DNA. Epigenome-wide association studies (EWAS) examine the relationship between various health outcomes and methylation percentage at CpG sites (cytosine-phosphate-guanine dinucleotides) locations. To determine the usefulness of this strategy in discovering disease-relevant loci, large-scale EWAS that probe for epigenetic signals across a wide range of circumstances are required.

Scientists examined the DNA methylation at 752,722 CpG sites in whole blood samples from 18,413 individuals in the family-based, population-based cohort study Generation Scotland. EWAS examined cross-sectional and longitudinal relationships between baseline CpG methylation and 19 event illness states, including 14 common disease states. Data on prevalence and incidence were obtained from electronic health record linkage and self-report questionnaires, respectively.

Age at methylation typing, sex, predicted white blood cell composition, population structure, and 5 popular lifestyle risk factors were all considered while creating EWAS models. A rigorous literature review was also carried out to identify current EWAS for each of the 19 disease states examined.

Scientists found 69 correlations between the prevalence of 4 illnesses and CpGs, 58 of which were brand-new conditions. The diseases involved were type 2 diabetes mellitus, ischemic heart disease, chronic renal disease, and breast cancer. Additionally, scientists found 64 CpGs, of which 56 were not mentioned in the literature they surveyed, linked to the prevalence of two disease states.

Later, they evaluated replication across past investigations, defined as at least one common site reported across studies looking at the same condition.

There is a need for better uniformity among EWAS on human disease after scientists observed over 100 connections between blood methylation sites and prevalent disease states, regardless of significant confounding risk variables.

Scientists noted, “By comparing these data with our findings, we uncover 58 novel associations with the prevalence of 3 self-reported disease states at the study baseline (breast cancer, ischemic heart disease, and type 2 diabetes). We also identify 56 novel associations between CpGs and the time-to-onset of 2 disease states (COPD and type 2 diabetes). These associations were independent of common lifestyle risk factors. However, we also observe many additional associations whereby CpGs index or track associations between lifestyle factors and common disease states, further highlighting the appropriateness of DNAm as a biomarker of lifestyle behaviors.”

“The novel associations observed in this study could strengthen the evidence for candidate molecular pathways underlying peripheral disease states.”

Journal Reference:

  1. Hillary RF, McCartney DL, Smith HM, Bernabeu E, Gadd DA, Chybowska AD, et al. (2023). Blood-based epigenome-wide analyses of 19 common disease states: A longitudinal, population-based linked cohort study of 18,413 Scottish individuals. PLoS Med 20(7): e1004247. DOI: 10.1371/journal.pmed.1004247
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