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Epigenetic Study Finds Novel Associations Between DNA Methylation, Common Diseases

NEW YORK — Researchers have found novel associations between DNA methylation patterns and multiple common diseases in a new blood-based epigenome-wide association study (EWAS).

In a paper published in PLOS Medicine on Thursday, a team led by researchers at the University of Edinburgh reported more than 100 associations between DNA methylation sites and more than a dozen common diseases, such as breast cancer, cardiopulmonary disease, and type 2 diabetes.

While earlier EWASs have focused on individual conditions and relied on a limited number of samples, which affected their power to discover disease-associated loci, this study looked at more than a dozen disease states in a large cohort of thousands of Scottish individuals, the authors noted.

For their study, the researchers analyzed DNA methylation patterns at 752,722 CpG sites in blood samples collected from 18,413 Scottish people from the Generation Scotland: Scottish Family Health Study, a cohort of people 18 to 99 years old. Meanwhile, they used self-report questionnaires and electronic health records to ascertain participants' health at baseline and during the course of the study.

After adjusting their EWAS model for factors like age, sex, white blood cell composition, population structure, and lifestyle risk factors, the authors noted several associations between DNA methylation patterns and the prevalence of 14 conditions and the incidence of 19 disease states.

In particular, they identified 69 associations — of which 58 were novel — between DNA methylation levels and the prevalence of four conditions: breast cancer, chronic kidney disease, ischemic heart disease, and type 2 diabetes mellitus. These associations were independent of common lifestyle risk factors, the researchers noted.

These novel associations could strengthen evidence for candidate molecular pathways underlying certain disease states, the authors said, citing the example of self-reported history of breast cancer being associated with hypomethylation at cg06072257, which is located near the UBIAD1 gene. UBIAD1 encodes an enzyme that converts vitamin K1 to menaquinone, the most abundant form of vitamin K2 in human tissue. In breast cancer, low UBIAD1 expression is linked to decreased survival, and low UBIAD1 expression is also associated with bladder cancer risk.

The researchers compared the associations they found between DNA methylation and disease with previous EWAS literature to find poor replicability, particularly as compared to genome-wide association studies, where replication rates are estimated to be between 50 percent and 90 percent. This is likely due to, they said, the genetic factors studied in GWAS remaining fixed across the life-course, unlike DNA methylation levels, which are also influenced by environmental factors. In their EWAS, associations related to lung cancer, for instance, had the highest replicability, possibly due to the strong effects of smoking on DNA methylation, the authors said.

The researchers further cautioned that their analysis was conducted on individuals of European ancestry and, therefore, the findings may not be generalizable to individuals of other ancestries. They also said that this study did not consider medications participants may have been taking, which may have confounded the associations between methylation and disease.