Characterizing Methylomes by Next Generation Capture Sequencing Identifies Novel Disease Associated Variants. Dr. Elin Grundberg, Assistant Professor of Human Genetics, McGill University.
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I guess most of you know that complex diseases means that there are multi-factorial underlying factors with genetic and environmental playing both equally important roles.
On the genetic side, again I think most of you also know that the large efforts from genome-wide association studies in the past decade have really been successful in identifying underlying genetic factors for these complex diseases, and we've seen a large number of those traits. Each trait has a large number of common genetic variants being associated, but one key finding from these studies is that these genetic variants actually have very small effect sizes.
Another important finding from these studies is that most of these genetic variants are actually mapping to non-coding regions, which makes it more difficult to understand the mechanistic function of these variants.
One approach that my group, and many others, have been applying is to use cellular phenotypes or, more specifically, gene expression traits in eQTL as studies to understand what's the functional role of genetic variants involved in disease susceptibility. This approach of eQTLs has been very successful too. We have elucidated multiple layers of the impact for these common disease variants.
What we know now from these functional genomic studies is that using cellular phenotypes is very powerful, but it really has to be assessed in cells or tissues that are directly targeted to the disease of interest. More recently, now, we've also been able to expand these functional genomics studies to understand genetic contributions to complex diseases by also looking at epigenetic traits or epigenomic phenotypes.
Maybe one of the most common epigenetic traits that we have been able to study is DNA methylation. I guess also many of you know that DNA methylation is a chemical modification on the cytosine base in our genome. We have around 30 million of these DNA methylation sites. They're mostly occurring in a CpG.
Also, the important role of these epigenetic modifications in DNA methylation in relation to gene regulation and also its very close association to the different chromatin states that we have recently seen great efforts from the large consortiums, such as ENCODE and RoadMap, that have really shown this link between these DNA methylation patterns and the different chromatin states involved in the gene regulation machinery.
Another feature that we know from DNA methylation patterns is that it's a quantitative trait, but also that the pattern of DNA methylation is really variable across individuals and across tissue. But there's also been a challenge, given the large amount of DNA methylation sites in the CpG [contact], to understand which proportion of these sites are just random, stochastic or versus those that actually have a functional role in altering the genome regulation or the genome function.
We also know that DNA methylation is playing an important role in disease susceptibility. It is pioneered in cancer association and also that this trait, which I will talk about more from our research, is the fact that the genetic traits are impacted by both genetic and environmental factors.
