The atlas, which has been established by an international consortium led by the University of Bristol and including researchers from King’s, will enable scientists to learn more about the mechanisms underpinning gene regulation.
Epigenetic variation exists but it is unclear what causes this variation. It is also unclear how genetic differences that occur between individuals’ impact on our epigenomes. The atlas of genetic effects on DNA methylation (DNAm), by the Genetics of DNA Methylation Consortium (GoDMC) of 50 universities and institutes and more than 150 scientists, including the University of Bristol, University of Exeter Medical School, King’s College London and Leiden University Medical Center, is published in Nature Genetics.
The analysis focused on the natural differences between individuals in their DNAm levels across the genome. DNAm plays a central role in gene regulation. It helps to define how cells respond to environmental signals and, ultimately, contributes to health or susceptibility to disease. However, the amount and the effects of differences in DNAm from one person to another is poorly understood.
A powerful avenue into researching the biological consequences of changes in DNAm levels is to systematically compare DNA sequence variants to DNAm levels. GoDMC has completed the largest genetic study of DNAm to date by scanning for correlations between ten million genetic variants and 420,000 DNAm sites across the genome resulting in a database of >270,000 independent associations. This means that almost half of all DNAm sites in the genome are to some extent influenced by genetic factors.
The international consortium analysed 32,851 participants collected from 38 studies across the world. By providing a world-wide platform for collaboration and combining genetic and epidemiological expertise, the scientists of GoDMC has established a large resource of genetic effects on DNAm and how this atlas can be used to understand the genetic basis of DNAm variation. The atlas has already been used for a wide range of other research projects.
The newly developed database has been used to search for instances of DNAm sites causally relating to 100 clinical characteristics and diseases. Vice versa, the study estimated the causal influences of these clinical characteristics and diseases on DNAm levels across the genome. These comparisons highlight that DNAm is unlikely to have a big role in causing disease but open the door to a range of further research. For example, this work suggests that understanding of DNAm variation between individuals and its influence on health and disease could be improved by studying other regulatory regions of the genome or other cell types.
In this study we provide a most comprehensive analysis of how human genetic variation affects the regulation of gene activity. By analysing genomic data from more than 30,000 people, we uncover thousands of new regulatory genomic regions and explore how these relate to human health and disease. Our findings shed light on multiple biological processes and help to prioritise therapeutic targets for intervention. The resource is now available to researchers worldwide.– Dr Jordana Bell, from the Department of Twin Research and Genetic Epidemiology